Assessing carrageenan-induced locomotor activity impairment in rats: comparison with evoked endpoint of acute inflammatory pain.

BACKGROUND: Most animal models currently used to evaluate antinociceptive efficacy of analgesics rely on the assessment of evoked pain behaviours as primary endpoints. METHODS: Here, we have developed and characterized the carrageenan-induced locomotor activity impairment (CLAIM) model to objectively assess non-evoked inflammatory pain behaviour in rats. In this model, 100 µL of 1% carrageenan was subcutaneously injected into the plantar aspect of the right hind paw and exploratory behaviour in the novel testing chamber was recorded using an automated locomotor activity system. RESULTS: Carrageenan-injected animals exhibited an exploratory behavioural deficit 2-7 h following injection compared to saline-injected animals. The severity of impairment was carrageenan dose related, and sensitive to the light intensity in the testing room. The effects of standard analgesics on CLAIM were examined 2 or 3 h following carrageenan injection. Diclofenac and ibuprofen, in a dose range exerting no effect on locomotor activity in naïve rats, exhibited dose-related reversal of CLAIM (ED(50) = 1.5 and 5.0 mg/kg, respectively), with comparable efficacy on carrageenan-induced thermal hyperalgesia (ED(50) = 2.0 and 6.0 mg/kg, respectively). Gabapentin and duloxetine produced no reversal of CLAIM, or attenuation of thermal hyperalgesia. Efficacy discrepancy was noted for morphine on thermal hyperalgesia and CLAIM. Additionally, amphetamine dose dependently reversed CLAIM, and similarly increased locomotor activity in normal animals. DISCUSSION AND CONCLUSION: The results presented here demonstrate that CLAIM provides an objective assessment of non-evoked pain behaviours for acute inflammatory pain. The pharmacological profile of standard analgesics supports that CLAIM model can be used to identify agents to treat acute inflammatory pain in the clinic.

Characteristics of norovirus gastroenteritis outbreaks in a psychiatric centre.

Noroviruses are an important aetiological agent of acute gastroenteritis. They are responsible for large outbreaks of disease in the community, hospitals and long-term-care facilities. The clinical manifestations of norovirus outbreaks in psychiatric units are rarely described. The disease burden and impact highlight the importance of timely notification and investigation of these outbreaks. We analysed the characteristics of four norovirus outbreaks which occurred during a 3-year period in an in-patient psychiatric care unit. A total of 184 patients were affected which included 172 hospitalized patients, seven healthcare workers (HCWs) and five psychiatric nursing-home residents. The mean incidence rate of norovirus gastroenteritis (NVG) in hospitalized patients during these outbreaks was 12·7%. These outbreaks were characterized by higher incidence in middle-aged male patients, predominant sickness of diarrhoea, short duration of illness, peaks in late winter and early spring, and higher susceptibility in acute psychiatric patients. HCWs had longer duration of illness than psychiatric patients. More than 10% of affected patients experienced ≥ 2 infections. Infection control measures were instituted and a comprehensive, responsive standard operating procedure for NVG and outbreak management was developed. After implementation of these measures, no further outbreaks of NVG occurred during the study period.

Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain.

BACKGROUND AND PURPOSE: Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain. EXPERIMENTAL APPROACH: WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB(1) and CB(2) receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB(1) and CB(2) receptor antagonists. KEY RESULTS: WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB(1) versus CB(2) receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB(1) receptor antagonist, but not with a CB(2) receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB(1) and CB(2) antagonists blocked systemic WIN-induced analgesic activity. CONCLUSIONS AND IMPLICATIONS: Both CB(1) and CB(2) receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB(1) but not CB(2) receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB(1) receptors in the brain.

In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models.

BACKGROUND AND PURPOSE: Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are mu-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist. EXPERIMENTAL APPROACH: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and mu-opioid receptor antagonists. KEY RESULTS: A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or mu-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. CONCLUSIONS AND IMPLICATIONS: These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain.

Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI.

BACKGROUND AND PURPOSE: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. EXPERIMENTAL APPROACH: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. KEY RESULTS: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. CONCLUSION AND IMPLICATIONS: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.

Role of CXCR3 and CCR5 in allograft rejection.

UNLABELLED: Chemokines are known to participate in allograft rejection by mediating leukocyte trafficking. Despite redundancy in chemokine family, several chemokine-chemokine receptor interactions have proven critical in alloimmune responses. We sought to determine the effect of combined blockade of CXCR3 and CCR5, two critical chemokine receptors, in acute rejection. METHODS: Heterotopic heart transplantation was performed using BALB/c to B6/129 mice deficient in CCR5. Following transplantation these mice were treated with goat anti-CXCR3 serum every other day. In the control group, BALB/c hearts were transplanted in wild type B6/129 recipients and treated with goat serum alone. No immunosuppression was given to either group. Recipient mice were then assessed daily for allograft function by abdominal palpation, and graft survival was confirmed by laparotomy. RESULTS: The donor hearts in the control group were rejected at 6 +/- 1 days posttransplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival versus control; all allografts survived to 24 days. In addition, there was a decrease in graft infiltrating CD4 and CD8 lymphocytes in the experimental group at 24 days. CONCLUSION: Combined CXCR3 and CCR5 blockade is effective in prolonging allograft survival in a fully MHC mismatched murine model. Combined chemokine blockade holds promise in control of acute rejection in organ transplantation.

Cytoprotective gene HO-1 and chronic rejection in heart transplantation.

Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. We hypothesized that induction of HO-1 by D4-F, an apoA-I mimetic peptide with potent antiinflammatory/antioxidant properties, attenuated CAV. We utilized a previously characterized murine model of CAV. B6.C-H2(bml2) hearts were heterotopically transplanted into C57BL/6 mice. In the control group, recipient mice were treated with 20 microg of saline daily. In experimental group I, mice were treated daily with 20 microg of D4-F. In experimental group II, mice were treated daily with 20 microg of D4-F daily, plus CuPP, which does not have any effect on HO-1 activity. In experimental group III, recipient mice were treated with 20 mug of D4-F daily, plus SnPP, which is a competitive inhibitor of HO-1. Donor hearts were harvested on day 24 after transplantation. The donor hearts in the control group developed severe intimal lesions. In experimental group I, treatment with D4-F was associated with upregulation of HO-1 and a marked reduction in intimal lesions, which was consistent in experimental group II. In experimental group III, inhibition of HO-1 was associated with partial restoration of intimal lesions. Induction of HO-1 by an apoA-1 mimetic peptide was effective to control CAV. This class of antiinflammatory peptides, which show an ability to induce HO-1, provides a novel strategy for the treatment of CAV.

Prolonged menstrual cycles in female workers exposed to ethylene glycol ethers in the semiconductor manufacturing industry.

BACKGROUND: It has been shown that female workers exposed to ethylene glycol ethers (EGEs) in the semiconductor industry have higher risks of spontaneous abortion, subfertility, and menstrual disturbances, and prolonged waiting time to pregnancy. AIMS: To examine whether EGEs or other chemicals are associated with long menstrual cycles in female workers in the semiconductor manufacturing industry. METHODS: Cross-sectional questionnaire survey during the annual health examination at a wafer manufacturing company in Taiwan in 1997. A three tiered exposure-assessment strategy was used to analyse the risk. A short menstrual cycle was defined to be a cycle less than 24 days and a long cycle to be more than 35 days. RESULTS: There were 606 valid questionnaires from 473 workers in fabrication jobs and 133 in non-fabrication areas. Long menstrual cycles were associated with workers in fabrication areas compared to those in non-fabrication areas. Using workers in non-fabrication areas as referents, workers in photolithography and diffusion areas had higher risks for long menstrual cycles. Workers exposed to EGEs and isopropanol, and hydrofluoric acid, isopropanol, and phosphorous compounds also showed increased risks of a long menstrual cycle. CONCLUSIONS: Exposure to multiple chemicals, including EGEs in photolithography, might be associated with long menstrual cycles, and may play an important role in a prolonged time to pregnancy in the wafer manufacturing industry; however, the prevalence in the design, possible exposure misclassification, and chance should be considered.

Activation of soluble guanylate cyclase causes relaxation of corpus cavernosum tissue: synergism of nitric oxide and YC-1.

Nitric oxide (NO) activates corpus cavernosum smooth muscle soluble guanylate cyclase (sGC) and increases the synthesis of cGMP that results in smooth muscle relaxation and ultimately, penile erection. To characterize sGC and define the potential synergy between NO and the allosteric activator YC-1 in corpus cavernosum, rat sGC was activated by either sodium nitroprusside (SNP) or YC-1, and YC-1 potentiated the effects of SNP with a 200-fold activation of sGC. Both SNP and YC-1 decreased the Km and increased the Vmax. ODQ significantly inhibited sGC activated by SNP with IC50 of 0.5 nM, but did not affect the sGC activated by YC-1 as well as basal sGC activity. SNP and YC-1 synergistically increased intracellular cGMP levels in rabbit corpus cavernosum smooth muscle cell cultures. YC-1 significantly relaxed rabbit cavernosum tissue strips in organ baths with an EC50 of 8.4 microM. In the presence of L-nitroarginine methyl ester to block endogenous NO production, co-administration of SNP shifted the dose response of YC-1 to the left, showing the synergism of SNP and YC-1 in tissue strips. In view of the clinical efficacy of phosphodiesterase-5 inhibitors, activation of sGC may provide an alternative means for enhancing the activity of neurally derived NO during sexual stimulation in the corpus cavernosum, representing a novel approach for the treatment of erectile dysfunction.

Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction.

Soluble guanylate cyclase (sGC) is an important enzyme in corpus cavernosum smooth muscle cells as it is one of the regulators of the synthesis of cGMP. The efficacy of sildenafil (Viagra) in the treatment of male erectile dysfunction indicates the importance of the cGMP system in the erectile response as the increased levels of cGMP induce relaxation of the corpus cavernosum. sGC is physiologically activated by nitric oxide (NO) during sexual stimulation, and its activity can be pharmacologically enhanced by several NO-donors. Agents like YC-1 can also activate sGC after binding to a novel allosteric site in the enzyme, a site different from the NO binding site. YC-1 can relax rabbit cavernosal tissue and it facilitates penile erection in vivo. This review summarizes the enzymology, biochemistry and pharmacology of this novel allosteric site and its relevance for the regulation of penile function. This type of sGC activators represent a new class of compounds with a different pharmacological profile in comparison to the classical NO-donors and they could be beneficial for the treatment of male erectile dysfunction.

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone.

The potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male erectile dysfunction has recently been suggested based on positive clinical outcomes following intra-cavernosal administration of pinacidil. Agents that increase the levels of cGMP via elevation of nitric oxide (NO) nitroglycerin, for example, are also effective in improving erectile function preclinically and clinically. The aim of the present study was to determine the effects and mechanism of the action of nicorandil on rabbit corpus cavernosum. The in vitro regulation of smooth muscle tone was assessed in isolated cavernosal tissues pre-contracted with phenylephrine. Nicorandil, but not its major metabolite, relaxed phenylephrine-precontracted cavernosum smooth muscle with an EC(50) of 15 microM. The effects of nicorandil were only partially reversed by the K(ATP) channel blocker glyburide (10 microM) or by a soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 microM). However, a combination of ODQ and glyburide completely blocked the relaxant effects of nicorandil. The results of the present study indicate that nicorandil can relax rabbit cavernosal tissue in vitro via a mechanism that involves activation of K(ATP) channels and stimulation of soluble guanylate cyclase.

Low valsalva leak-point pressure and success of retropubic urethropexy.

The aim of this study was to determine whether an isolated low Valsalva leak-point pressure (VLPP) is predictive of intrinsic sphincter deficiency (ISD) and can be an independent risk factor for retropubic urethropexy failure in patients with a normal maximal urethral closure pressure (MUCP). Twenty-four women with urodynamically proven genuine stress incontinence with low VLPP (<60 cmH2O) and normal MUCP (>20 cmH2O) were evaluated subjectively and objectively by complex urodynamic testing before and after undergoing a modified Burch urethropexy. Success rates were then compared to historical success rates for subjects with ISD treated with retropubic urethropexy using an exact one-sample test for binomial proportions. Patients were followed postoperatively for a mean of 11.1 months, with a range of 5-16 months. Twenty-two of the 24 (91.7%) were continent on postoperative cystometry. This differs significantly from the published success rates of 50% (P < 0.001), if a low VLPP alone were predictive of ISD. Retropubic urethropexy was successful in the majority of our patients with genuine stress incontinence with a low VLPP and normal MUCP.

Impact of race on the outcome of carotid endarterectomy: a population-based analysis of 9,842 recent elective procedures.

OBJECTIVE: To examine the influence of race and other potentially confounding variables on the outcome of carotid endarterectomy (CEA). SUMMARY: Previous studies have demonstrated that CEA is performed less frequently in black patients, although little attention has been focused on the influence of race on the outcome of surgery. METHODS: The Maryland Health Services Cost Review Commission database was reviewed to identify all elective CEA procedures performed in all nonfederal acute care hospitals in the state from 1990 through 1995 to examine the influence of race and other factors on the rates of in-hospital complications, in-hospital stroke, length of stay, and total hospital charges. RESULTS: Carotid endarterectomy was performed in 9,219 (94%) white and 623 (6%) black patients during this period. The in-hospital stroke rate was 1.7%-3. 1% among black patients and 1.6% among white patients. Black patients had a longer length of stay and higher mean hospital charges than white patients. Multivariate logistic regression analysis identified black race as an independent risk factor for in-hospital stroke. Performance of CEA by a high-volume surgeon was protective for the combined occurrence of in-hospital stroke or death, and whites were more than twice as likely to undergo surgery performed by high-volume surgeons. Conversely, undergoing surgery in a low-volume hospital was associated with in-hospital stroke, and blacks were four times as likely to use low-volume hospitals. CONCLUSIONS: Black patients who underwent elective CEA in Maryland from 1990 to 1995 had an increased incidence of in-hospital stroke, a longer hospital stay, and higher hospital charges than whites. Black race was identified as an independent risk factor for in-hospital stroke, although the reasons for this influence of race on outcome are undefined. The authors' observations also suggest the possibility of limited access to optimal surgical care among blacks, and this issue warrants further study.

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.

The risk of carcinogenesis from radiographs to pediatric orthopaedic patients.

This study set out to determine whether cumulative radiograph exposure of children significantly increases their risk of radiation-induced carcinogenesis or hereditary defects. Records of children treated for idiopathic scoliosis, hip dysplasia, or leg-length discrepancy between 1980 and 1993 at the Shriners Hospital in Spokane, WA, were retrospectively reviewed. Total radiation and organ dose exposures were calculated using information from individual radiology reports. Surgically treated idiopathic scoliosis patients had the largest total radiation skin entrance and organ dose exposures. This group's risks for developing leukemia, breast cancer, or a heritable defect, respectively, were 0.8%, 2.1%, and 3.0% higher than baseline risks. The other treatment groups had increased carcinogenic risks of <1%. The use of serial radiographs during the treatment of idiopathic scoliosis, hip dysplasia, and leg-length discrepancy appears relatively safe. The increased risk of carcinogenesis or hereditary defects in these patients is minimal.

Seroprevalence of CMV antibodies in a blood donor population and premature neonates in the south-central Taiwan.

Infection of cytomegalovirus (CMV) via contaminated blood may endanger immunocompromised patients that require transfusion therapy. The aim of this study is to determine the prevalence of CMV antibodies in the blood donor population in Southern-central Taiwan. A total of 1800 consecutive sera, obtained from Tainan Blood Center of Chinese Blood Services Foundation (CBSF), were tested for CMV antibodies by two commercial enzyme immunoassays (EIAs). Of the sera tested, 150 (8.3%) were found to be CMV seronegative. The frequency of CMV seropositivity revealed no significant difference between male and female donors. The frequency of CMV seronegativity showed a stepwise decrease with the increase of donor age. In addition, the prevalence of HBsAg, antibodies to hepatitis C virus (anti-HCV), antibodies to human immunodeficiency viruses type 1 and 2 (anti-HIV 1 + 2) and antibodies to human T-cell lymphotropic viruses type I and II (anti-HTLV I/II) were compared between CMV seropositive and seronegative groups. Our results showed that there was no significant difference in seroprevalence of these markers between CMV seropositive and seronegative groups. Our findings also showed that six out of twenty (30.0%) premature neonates were CMV-seropositive. These premature specimens and those EIA discrepancy samples were confirmed by specific nucleic acid amplification using polymerase chain reaction (PCR). Our results suggest that a program which aims to supply CMV seronegative blood or blood components to the patients, should not solely depend on current antibody screening methods in an area where CMV infection is highly endemic. Amendments such as PCR testing, leukocyte reduction by filtration before transfusion may be more practical.

Complex gastrointestinal surgery: impact of provider experience on clinical and economic outcomes.

BACKGROUND: Commonly performed elective gastrointestinal surgical procedures are carried out with low morbidity and mortality in hospitals throughout the United States. Complex operative procedures on the alimentary tract are performed with a relatively low frequency and are associated with higher mortality. Volume and experience of the surgical provider team have been correlated with better clinical and economic outcomes for one complex gastrointestinal surgical procedure, pancreaticoduodenectomy. This study evaluated whether provider volume and experience were important factors influencing clinical and economic outcomes for a variety of complex gastrointestinal surgical procedures in one state. STUDY DESIGN: Complex high-risk gastrointestinal surgical procedures were defined as those with statewide in-hospital mortality of > or = 5%, frequency of greater than 200 per year in the state, and requiring special surgical skill and expertise. Six procedures met these criteria. Using publicly available discharge data, all patients discharged from Maryland hospitals from July 1989 to June 1997 with a primary procedure code for one of the six study procedures were selected. Hospitals were classified into one of six groups based on the average number of study procedures per year: 10 or less; 11 to 20; 21 to 50; 51 to 100; 101 to 200; and 201 or more procedures per year. A hospital was included if at least one procedure was performed there during the study period. No providers fell within the 51 to 100, and 101 to 200 groups, so all analyses were performed for the remaining four volume groups that were classified, respectively, as minimal (10 or fewer procedures), low (11 to 20 procedures), medium (21 to 50 procedures), and high-volume groups (201 or more procedures). Poisson regression was used to assess the relationship between in-hospital mortality and hospital volume after case-mix adjustment. Multiple linear regression models were used to assess differences in average length-of-stay and average total hospital charges among hospital volume groups. We further analyzed mortality, length-of-stay, and charges at the procedural level to understand these subgroups of complex gastrointestinal patients. We also examined the relationship between provider volume and outcomes for malignant versus benign diagnosis groups. RESULTS: Complex gastrointestinal surgical procedures were performed on 4,561 patients in Maryland from July 1989 through June 1997. The study population averaged 61.6 years of age, was 55% male, 71% Caucasian, and had predominantly Medicare as a payment source. After case-mix adjustment, patients who underwent complex gastrointestinal surgical procedures at the medium-, low-, and minimal-volume provider groups had a 2.1, 3.3, and 3.2 times greater risk of in-hospital death, respectively, than patients at the high-volume provider (p < 0.001 for all comparisons); longer lengths-of-stay, 16.1, 15.7, and 15.5 days at the low-, medium-, and minimal-volume groups, respectively, versus 14.0 days for the high-volume provider (p < 0.001 for all comparisons). Similarly, adjusted charges at the high-volume provider were, on average, 14% less than those of the low-volume group, which had the next lowest charges. Although mortality rates differed by procedure type, for each procedure, mortality increased as provider volume decreased, following the pattern found in the aggregate analysis. After case-mix adjustment, the risk of in-hospital death for patients with malignant diagnoses was significantly higher for the medium-, low-, and minimal-volume groups compared with patients at the high-volume provider, relative risk of 3.1, 4.0, and 4.2, respectively, (p < 0.001 for all comparisons). CONCLUSIONS: This study demonstrates that increased hospital experience is associated with a marked decrease in hospital mortality. The decreased mortality at the high-volume provider was also associated with shorter lengths-of-stay and lower hospital char

Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin.

Rapamycin, a macrolide antibiotic known to prevent allograft rejection, is a potent inhibitor of cell proliferation. Therefore we studied the effects of orally administered rapamycin in a pig model of balloon injury in an attempt to reduce the cellular proliferation and neointimal formation thought to play a role in restenosis. Twenty Yucatan minipigs, divided into groups of 10 animals each, were subjected to balloon inflation of the carotid arteries. One group received the methylcellulose vehicle for rapamycin, whereas the second group was treated for a total of 31 days with 2.0 mg/kg of rapamycin administered daily by oral gavage. This dose and treatment regimen produced significant (p < 0.05) reductions in neointimal area (59%) and in the maximal thickness of the neointima (59%) when comparisons were made with vehicle-treated animals. These effects were accompanied by a significant increase in the lumen area in animals that received rapamycin (33%). Medial area was decreased by 18% in these animals. Blood samples from rapamycin-treated pigs indicated peak concentrations of 1.87 +/- 0.45 and 1.70 +/- 0.24 ng/ml at 2 and 4 weeks after balloon angioplasty, respectively. Significant increases in blood pressure of 21 mm Hg and decreases in heart rate of 25 beats/min also were observed in rapamycin-treated animals relative to those that received vehicle. These results indicate that the antiproliferative effect of rapamycin can be demonstrated after oral dosing in a pig vascular injury model, suggesting a possible therapeutic utility for rapamycin or its analogs in patients undergoing balloon angioplasty.