Psoriatic arthritis treatment and the risk of herpes zoster.

OBJECTIVES: To study the association between traditional disease-modifying antirheumatic drugs (c-DMARD) or anti-TNF-α agents and herpes zoster (HZ) in patients with psoriatic arthritis (PsA). METHODS: A retrospective cohort study was conducted in patients with PsA between 2002 and 2013. Patients were grouped as follows: no DMARDs (Group A); c-DMARDs (Group B); anti-TNF-α agents (Group C); anti-TNF-α agents in combination with c-DMARDs (Group D). Crude incidence rates (IR) were calculated as number of HZ episodes per 1000 patient-years. A Cox regression model was used to adjust for HZ risk factors (age, gender, steroid use, Charlson Comorbidity Index score, and previous treatment) in order to estimate their contribution to the risk of the first HZ event. RESULTS: The study included 3128 patients, mean age 50.26±14.54 years; 46.2% male. During a period of 20 096 person-years 182 HZ events were observed. The crude IR (95% CI) of HZ in the study population was 9.06 per 1000 patient-years, and in Groups A-D 7.36 (5.41 to 9.79), 9.21 (7.5 to 11.21), 8.64 (4.84 to 14.26), 17.86 (10.91 to 27.58), respectively. In a multivariate analysis, age (HR 1.01, 95% CI 1.00 to 1.02), treatment with steroids (HR 1.08, 95% CI 1.04 to 1.13), and a combination of anti-TNF-α agents and c-DMARDs (HR 2.37, 95% CI 1.32 to 4.22) were significantly associated with HZ events. CONCLUSIONS: In our database, the risk of HZ was significantly increased with age, treatment with steroids, and combination of anti-TNF-α agents and c-DMARDs, but not with c-DMARDs or anti-TNF-α therapy alone. Time to HZ event was shorter in patients treated with anti -TNF-α agents.

Trends in outpatient antibiotic use in Israel during the years 2000-2010: setting targets for an intervention.

PURPOSE: The abundant use of antibiotics (Abs) in the community plays a major role in inducing Ab resistance, but the literature concerning patterns in outpatient Ab use is limited. This study aims to lay the foundations for future policy and interventional programs to address the rise in Ab resistance by looking at long-term trends in Ab usage in Israel. METHODS: Defined daily doses per 1,000 inhabitants per day (DID) of total Ab use, consumption in different age groups, and of different Ab preparations were calculated for the years 2000, 2005, and 2010 in the eight districts of Israel. Data were collected from the pharmacy registries of "Clalit Health Services", the largest Health Maintenance Organization (HMO) in Israel, covering 4 million patients, representing 53 % of the population. Trends in use over time were analyzed. RESULTS: The overall Ab usage in Israel has remained constant in the last decade. Three significant trends were identified in this study: an increase in the consumption of expensive, broad-spectrum Abs, paralleled by a reduction in narrow-spectrum Abs; an increase in Ab consumption among the elderly, counteracted by reduced usage among children; large regional variations in the overall and specific use of Ab agents. CONCLUSIONS: Our main findings of increased broad-spectrum Ab consumption, primarily among the adult population in Israel, and a wide variability in Ab use between the regions in Israel, can focus our future studies on searching for the factors behind these trends to aid in constructing interventional methods for decreasing outpatient Ab overuse.

Immunological arousal during acute Q fever infection.

Physicians often encounter patients who present with a vague clinical syndrome. A wide serological workup is often ordered, which may include tests for Coxiella burnetii in endemic areas. Often, the results of these tests pose new dilemma, with overlapping positive laboratory assays. The objective of this investigation was to characterise the serological overlap between acute Q fever and other infectious and immunological diseases. We retrospectively scanned the files of patients with a positive or equivocal immunoglobulin (Ig) M for C. burnetii phase II over a period of 8 years in a general hospital. Clinical and laboratory data, including antibodies to infectious agents and antibodies related to immunological states, were recorded. Anti-nuclear antibody (ANA), smooth muscle antibody (SMA) and rheumatoid factor were positive in 38%, 33.3% and 22.2% of the cases, respectively. In patients with acute Q fever, elevated IgM levels for Epstein-Barr Virus (EBV), cytomegalovirus (CMV), Mycoplasma pneumoniae, parvovirus, Bordetella pertussis, Rickettsia conorii and R. typhi were noted in 13.8%, 8.3%, 12.12%, 22.2%, 25%, 13% and 21.7% of cases, respectively. Acute Q fever induces a non-specific immunological arousal in a significant number of patients. This may interfere with diagnosis and delay treatment. Caution, clinical judgment and serological follow-up is warranted in such conditions.

ECG variability contour--a reference for evaluating the significance of amplitude ECG changes in two states.

The sensitivity of the standard 12-lead ECG for detecting myocardial ischemia is low perhaps because in the printed ECG only three to five complexes are examined, only absolute amplitude (voltage) criteria are used, and amplitude changes are sought only in the ST segment and T wave regions. A computerized method is proposed for evaluating the significance of ECG amplitude changes detected in one state compared with another (e.g. rest and stress). Amplitude changes were considered significant if they were consistently greater than the 'ECG variability contour' (EVC), which is a graphic measure introduced in this study, calculated from the reference ECG signal. Rest and stress simulation ECG (SECG) were constructed. Mean rest SECG complex was subtracted from rest and stress SECG complexes to result in rest and stress residue matrices, respectively. The percentage of the normalized cumulative sum (NCS) of the residues during stress (and rest) lying outside the EVC served as a measure for evaluating ECG changes associated with stress (and rest). With this method, amplitude changes of magnitude similar to that of the noise, which were difficult to detect visually, were easily detected and accurately allocated to the component of the ECG complex where they occurred. The proposed method may be useful in cases where amplitude changes are too subtle and thus overlooked or not detected by the standard examination of three to five complexes or underestimated due to unmet clinical (voltage) criteria, or occur in ECG components that are not regularly examined.

Effect of elevated intra-abdominal pressure and hyperoxia on portal vein blood flow, hepatocyte proliferation and apoptosis in a rat model.

BACKGROUND/PURPOSE: Indications for a laparoscopic approach for the management of biliary atresia in children are not clearly defined. We have recently shown that persistent intra-abdominal pressure (IAP) significantly decreased portal vein (PV) flow. Ventilation with a high concentration of oxygen after abdomen deflation raises concerns of increased oxidative stress but has also been shown to exert beneficial effects on splanchnic ischemia/reperfusion. The purpose of the present study was to evaluate the effects of IAP and hyperoxia on liver histology, hepatocyte proliferation and apoptosis in a rat model of abdominal compartment syndrome (ACS). METHODS: Male Sprague-Dawley rats were anesthetized with intraperitoneal ketamine and xylasine. After a midline laparotomy, the PV was isolated. Ultrasonic blood flow probes were placed on the vessel for continuous measurement of regional blood flow. Mean arterial blood pressure (MABP) was continuously measured. Two large-caliber percutaneous peripheral intravenous catheters were introduced into the peritoneal cavity for inflation of air and measurement of IAP. Rats were divided into three experimental groups: 1) Sham rats were subjected to IAP of 0 mmHg; 2) ACS rats were subjected to IAP of 6 mmHg for 2 hours and were ventilated with air; and 3) ACS-O (2) rats were subjected to IAP of 6 mmHg for 2 hours and were ventilated with 100 % O (2) during the operation and ventilation was continued for 6 hours after operation. Liver structural changes, hepatocyte proliferation (using BrdU assay) and apoptosis (using Tunel assay) were determined 24 hours following operation. RESULTS: IAP at 6 mmHg caused a twofold decrease in PV flow compared to sham animals. Hyperoxia resulted in a less significant decrease in PV flow compared to air-ventilated animals. Despite a significant decrease in PV blood flow, 24 hours after abdominal deflation only a few animals demonstrated histological signs of liver damage. The small histological changes were accompanied by increased hepatocyte apoptosis and enhanced hepatocyte proliferation in 25 % of animals, suggesting a liver repair response. CONCLUSIONS: Despite a significant decrease in PV blood flow, persistent IAP for 2 hours results in few changes in liver histology, and stimulates hepatocyte proliferation and apoptosis in only a few animals, supporting the presence of a recovering mechanism. Treatment with hyperoxia did not significantly change hepatocyte proliferation and apoptosis.

Severe orthostatic hypotension following weight reduction surgery.

Surgical interventions for morbid obesity are common practice in many countries, especially when other treatment options have failed or when rapid weight loss is desired. The association between weight and blood pressure is well established, especially the paradigm of obesity-related hypertension. We describe a 45-year-old obese woman with a medical history of hypertension and type 2 diabetes mellitus who lost 57 kg within a few months after a weight reduction surgery. She suffered from severe orthostatic hypotension, which probably resulted from sympathetic nervous system dysfunction. Our patient's clinical status improved with pharmacological interventions, but her symptoms resolved completely after she gained weight following a surgical reversal of the gastric partitioning owing to a local complication. Autonomic nervous system activity does change with the changes in body weight, but after evaluation of this patient, we believe that rapid weight loss may impair sympathetic function and blood pressure control. Although losing weight is a known treatment option for hypertension, exaggerated reversal of obesity-related hypertension might result in orthostatic hypotension.

Central vein catheterization. Failure and complication rates by three percutaneous approaches.

We prospectively studied the results of 714 attempts at central venous catheterization during an eight-month period in our intensive care department. We compared the rates of failure of catheterization and early complications among three percutaneous approaches: subclavian, anterior jugular, and posterior jugular veins. The procedures were performed by experienced staff or resident physicians and inexperienced interns and residents under teaching supervision. Overall rates of failure and complication were similar for each percutaneous approach within each group of physicians. Overall failure rate was 10.1% for the experienced group and 19.4% for the inexperienced. The complication was 5.4% for experienced and 11% for inexperienced. Among inexperienced physicians, the success rate was 86.7% and the complication rate 7.6% in unconscious patients, whereas in conscious patients these rates were 70.5% and 13.8%, respectively. The inexperienced physicians caused fewer complications in mechanically ventilated than in spontaneously breathing patients. We suggest that inexperienced physicians should first attempt central vein catheterizations in unconscious and mechanically ventilated patients.

Cardioprotective actions of human superoxide dismutase in two reperfusion models of myocardial ischaemia in the rat.

1. In rats under ether anaesthesia, the left coronary artery was ligated and reperfused after 10 min of ischaemia. Forty-eight hours later the myocardium was analyzed for creatine kinase (CK) activity. 2. Human superoxide dismutase (h-SOD) given 1 min after occlusion and again 6 h later significantly improved survival and retarded the loss of myocardial CK. 3. In rat isolated hearts perfused at 15% of normal flow for 30 min followed by re-establishment of normal flow for 20 min, perfusion pressure increased by 72% and myocardial CK decreased by 44%. No significant changes occurred in wet-to-dry heart weight ratio. 4. Administration of h-SOD at 2.5 or 5.0 mg, significantly attenuated the elevated post-ischaemic perfusion pressure and the loss of myocardial CK activity in rat perfused hearts. 5. h-SOD appears to be an effective anti-ischaemic agent in the intact animal as well as the isolated perfused heart of the rat subjected to low flow followed by reperfusion at normal flow. The mechanism of this cardioprotective effect is not totally dependent upon the formed elements of the blood, but may be partially due to a direct cytoprotective effect.

The effect of nitric oxide synthase inhibition on hypertonic saline treatment of controlled hemorrhagic shock.

The effect of the nitric oxide (NO) donor, L-arginine, and the NO synthase inhibitor, L-NAME on hypertonic saline (HTS) infusion in controlled hemorrhagic shock was studied in anesthetized rats. Hemorrhagic shock was induced by arterial bleeding of 35% of the total blood volume in 90 min. After 110 min, the animals were divided into two groups: in Group A, 5 mL/kg NaCl 7.5% (HTS) was infused. In Group B HTS was not infused. After 135 min the animals in both groups were divided into 4 subgroups: Group 1 (n = 8) was untreated, Group 2 (n = 8) was treated after 135 min with 100 mg/kg L-arginine, in Group 3 (n = 8) 100 mg D-arginine was infused, and in Group 4 (n = 8) 50 mg/kg L-NAME was infused. Arterial bleeding in Group A1 resulted in a fall in mean arterial pressure (MAP) to 43.5 +/- 5 mmHg (p < .001)) in 90 min. A similar fall in MAP was observed in all groups. HTS infusion in Group A1 was followed by an increase in MAP to 82.3 +/- 6 (p < .01)) after 125 min followed by a gradual decrease to 61.5 +/- 8 mmHg (p < .01)) after 4 h. Infusion of L-NAME in Group A4 resulted in an increase in MAP to 87.4 +/- 5 mmHg (p < .01)) that then rapidly dropped to 61.7 +/- 11 (p < .01)) after 4 h. Infusion of L-NAME in Group B4 resulted in an increase in MAP to 96.7 +/- 9 mmHg (p < .001)) which was maintained after 4 h at 92.2 mmHg, and was significantly higher than MAP in Group A4 (p < .01). We concluded that HTS infusion leads to a significant increase in MAP in controlled hemorrhagic shock. NO synthase inhibition by L-NAME in hemorrhagic shock leads to a protracted, significant increase in MAP. Infusion of HTS prevented the significant and sustained rise in MAP induced by L-NAME.

Influence of hypertonic saline on bacterial translocation in controlled hemorrhagic shock.

Translocation of enteric bacteria has been described in rats following hemorrhagic shock (HS). The aim of the present study was to evaluate the effect of hypertonic saline (HTS) on bacterial translocation (BT) in the setting of controlled HS in rats. The study included 2 arms. Arm I was a qualitative assessment of translocation. Sixty-eight anesthetized animals were studied. The rats were divided into 5 groups. Group I (n = 10) was sham shock controls. In groups II-V, HS was induced by arterial bleeding to mean arterial pressure (MAP) of 35-45 mmHg, which was maintained for 30 min. The animals were then allocated into 4 groups: group II (n = 19) untreated HS; group III (n = 13) normal saline (NS) treated; group IV (n = 13) HTS-treated; and group V (n = 13) HTS and blood treated. Mesenteric lymph nodes, liver, spleen, portal, and systemic blood were sent for culture after 24 h. Translocation occurred if enteric bacteria were cultured from at least one site. Arm II was a quantitative assessment of translocation. Two groups were studied: untreated HS (n = 7) and HTS treated (n = 6). In the qualitative arm, the 24-h mortality in untreated rats (group II) was 31.5% compared to 5.1% in treated animals (groups II-V) (P = 0.01). No BT was detected in control animals (group I). BT after HS was not different between groups II, III, and IV (92.3%, 91.6%, and 100%, respectively). Group V showed fewer translocations than groups II-IV, a difference that was especially significant compared with group IV (P = 0.039). However, BT to distant sites (systemic blood and spleen) was significantly lower in group V than in groups II-IV (P < 0.05). In the quantitative arm, the mortality rate was 16.7% in the untreated group. Although no qualitative significant difference in the translocation rate was found between the two groups (67% in untreated animals vs. 50% in HTS treated), there was significant quantitative difference: in HTS-treated group a significantly lesser bacteria translocated than in untreated animals (0.4 x 10(5) cfu/g vs. 4.2 x 10(5) cfu/g, respectively [P = 0.001]). We concluded that whereas assessed qualitatively, in this model of severe HS in rats, the hemorrhagic insult itself resulted in BT in most animals and treatment with NS, HTS, and blood resulted in reduced early mortality but did not alter significantly the translocation rate. Only the combination of HTS and blood resulted in reduced BT to distant sites. However, quantitative assessment showed that HTS significantly reduced the number of translocating bacteria.

Divergent effects of ischemia/reperfusion and nitric oxide donor on TNFalpha mRNA accumulation in rat organs.

We previously showed that serum TNFalpha bioactivity in rats is proportional to the extent of graded tissue injury caused by laparotomy, intestinal ischemia, and reperfusion and that the spleen is an important source of TNFalpha secretion in this condition. TNFalpha production varies, depending on the type and duration of tissue injury. It is also affected by other mediators, such as nitric oxide (NO). TNFalpha is known to increase NO production, but the effect of NO on the production of TNFalpha has not yet been fully elucidated. In this study we determined the levels of TNFalpha mRNA in rat organs after graded injury caused by anesthesia, laparotomy, intestinal ischemia, and reperfusion and evaluated the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on it. Samples from different organs were removed, and TNFalpha gene expression was evaluated by semiquantitative RT-PCR. TNFalpha mRNA was not detected in the intestine (the ischemic organ) and in the kidney, brain, heart, or liver after all 4 experimental protocols. In the mesenteric lymph node (draining the ischemic organ) a basal level of expression of TNFalpha mRNA was detected in the control (anesthesia alone) group, which was increased significantly after ischemia. In the spleen (a remote immune organ not directly involved in the ischemia), a significant gradual increase in TNFalpha mRNA, which correlated to the severity of the experimental protocol, was observed. In the lung (a central participant in post-injury multiple organ failure), all interventions increased TNFalpha mRNA. Infusion of SNAP exerted a differential effect on TNFalpha mRNA: diminished its accumulation in the lymph node, enhanced it in the lung, and had no effect in the spleen. The divergent organ pattern of TNFalpha transcription emphasizes the importance of its localized expression, which is critical to the understanding of its autocrine and paracrine actions in ischemia and reperfusion.

L-arginine-NO pathway and CNS oxygen toxicity.

The involvement of the L-arginine-nitric oxide (NO) pathway in the pathogenesis of hyperoxia-induced seizures was studied by using agents controlling NO levels. We selected two inhibitors of nitric oxide synthase, the systemic inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) and the novel cerebral-specific inhibitor 7-nitroindazole, and two generators of NO, the NO donor S-nitroso-N-acetylpenicillamine and the physiological precursor L-arginine. Rats with chronic cortical electrodes were injected intraperitoneally with different doses of one of the agents or their vehicles before exposure to 0.5 MPa O2 and O2 with 5% CO2 at an absolute pressure of 0.5 MPa. The duration of the latent period until the onset of electrical discharges in the electroencephalogram was used as an index of central nervous system O2 toxicity. The two nitric oxide synthase inhibitors L-NAME and 7-nitroindazole significantly prolonged the latent period to the onset of seizures on exposure to both hyperbaric O2 and to the hypercapnic-hyperoxic mixture. Pretreatment with the NO donor S-nitroso-N-acetylpenicillamine significantly shortened the latent period, whereas L-arginine, the physiological precursor of NO, significantly prolonged the latent period to onset of seizures. Our results suggest that the L-arginine-NO pathway is involved in the pathophysiology of hyperoxia-induced seizures via various regulating mechanisms.

Effect of hyperbaric oxygen on tissue distribution of mononuclear cell subsets in the rat.

In a previous study we found a significant temporary decrease in the ratio of CD4/CD8 (helper, inducer/suppressor, cytotoxic) T lymphocytes in the peripheral blood of healthy human volunteers after exposure to a single commonly used profile of hyperbaric oxygen (HBO). The transient nature of the changes suggested redistribution of T-cell subsets. The purpose of the present study was to verify such a redistribution and to locate possible target organs in an animal model. A single exposure of rats to HBO (0.28 MPa) induced a highly significant rapid decrease in the CD4/CD8 ratio in peripheral blood count (P < 0.0001), confirming our previous findings in humans. HBO also induced a significant increase in the CD4/CD8 ratio in the lungs and lymph nodes (P < 0.001) and a significant decrease in the ratio in the spleen (P < 0.01). Furthermore, exposure to HBO induced a significant increase in T cells bearing surface interleukin-2 receptors in the blood, spleen, lungs, and lymph glands (P < 0.001) and a significant decrease in T cells expressing alpha beta-receptors in the lungs (P < 0.001) and lymph glands (P < 0.05). Our findings suggest rapid T-cell activation after a brief exposure to HBO, with shifts of CD4 and CD8 subsets and variations in T-cell receptor type. These rapid changes in the parameters of cell-mediated immunity may represent the activation of protective mechanisms against the toxic effect of oxygen or the early stages of pulmonary oxygen toxicity.

Use of a novel peptide leukotriene receptor antagonist, Ly-163443, in splanchnic artery occlusion shock.

We studied the effects of LY-163443, a novel selective receptor antagonist of LTD4 and LTE4, in splanchic artery occlusion (SAO) shock. LY-163443 antagonized the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats. Anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 minutes developed a severe shock state usually resulting in a fatal outcome within two hours after release of the occlusion. SAO shock rats pre-treated with LY-163443 before the occlusion of the splanchnic arteries maintained post-release MABP at significantly higher values compared to rats receiving either the vehicle or LY-163443 as a post-treatment 15 min after occlusion (final MABP 96 +/- 8 vs 51 +/- 1, p less than 0.01 and 53 +/- 3, p less than 0.01, respectively). Pre-treatment with LY-163443 attenuated the release of the lysosomal hydrolase, cathepsin D (p less than 0.01 from vehicle and p less than 0.05 from post-treatment groups), and the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in the pre-treatment group than in the vehicle group (27 +/- 3 vs 51 +/- 6 U/ml, p less than 0.01). SAO shock rats pretreated with LY-163443 also exhibited significantly higher survival rates (p less than 0.01 from vehicle and post-treatment groups), and prolonged survival times (p less than 0.01 from vehicle and post-treatment groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Salutary consequences of blockade of platelet activating factor in hemorrhagic shock.

We studied the effects of a potent, specific platelet activating factor (PAF) antagonist, CV-6209, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CV-6209 (1 mg/kg) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg) of CV-6209 (final MABP 88 +/- 4 vs. 57 +/- 4, vs. 61 +/- 7 mm Hg, respectively). CV-6209 (1 mg/kg) also significantly attenuated the increase in plasma cathepsin D activity following hemorrhage compared with hemorrhaged rats receiving only its vehicle (i.e. 0.9% NaCl). CV-6209 (1 mg/kg) also significantly decreased the plasma accumulation of free amino-nitrogen compounds and the plasma activity of a myocardial depressant factor (MDF) compared to hemorrhaged rats receiving 0.9% NaCl. Rats receiving CV-6209 (1 mg/kg) exhibited a significantly increased survival rate and survival time post-reinfusion compared to rats receiving only the vehicle. These data indicate that PAF is an important mediator of hemorrhagic shock in the rat and that PAF receptor antagonists may be useful in hemorrhagic shock states.

Protective effects of a specific platelet activating factor (PAF) antagonist, WEB 2086, in traumatic shock.

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using WEB 2086, a specific antagonist of PAF. WEB 2086 (0.5 mg/kg) significantly reversed the decrease in mean arterial blood pressure (MABP) induced by PAF (0.3 micrograms/kg) in anesthetized rats. Anesthetized rats were subjected to Noble-Collip drum trauma. Traumatized rats treated with WEB 2086 (0.5 mg/kg bolus followed by infusion at 0.5 mg/kg/hr) maintained a higher MABP than those receiving only the vehicle (0.9% NaCl). Improvement in MABP paralleled a significant increase in overall survival time (p less than 0.01) in rats receiving WEB 2086 (0.5 mg/kg). WEB 2086 also significantly attenuated the plasma accumulation of the lysosomal hydrolase, cathepsin D and of free amino-nitrogen compounds, compared to shocked rats receiving only the vehicle. Furthermore, the production of the cardiotoxic peptide, myocardial depressant factor (MDF) was also blunted by WEB 2086. These results suggest that PAF may be an important mediator in the pathogenesis of traumatic shock in rats. Furthermore, PAF receptor antagonists may be useful as therapeutic agents when given early in the course of ischemic and shock states.

Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock.

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane stabilizing agent with beneficial effects in ischemia and shock. We studied defibrotide, a new agent which enhances PGI2 release from vascular tissue, to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with defibrotide maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving the vehicle (final MABP, 100 +/- 3 vs. 69 +/- 7 mm Hg, p less than 0.01). Defibrotide attenuated the release of the lysosomal hydrolase cathepsin D (p less than 0.02), and the plasma accumulation of free amino-nitrogen groups (p less than 0.02). The plasma activity of a myocardial depressant factor (MDF) was significantly lower in defibrotide treated shocked rats than in the vehicle group (29 +/- 4 vs. 61 +/- 8 U/ml, p less than 0.01). Moreover, plasma i6-keto-PGF1 alpha concentrations increased 3-fold above haemorrhaged rats receiving only the vehicle. This, as well as the improved MABP, was abolished by indomethacin. Additionally, defibrotide exerts an anti-proteolytic action in pancreatic homogenates, and a lysosomal stabilizing effect in large granule fractions of rat liver homogenates. Moreover, defibrotide enhanced the recovery from norepinephrine induced vasoconstriction in rat aortic rings having an intact endothelium (p less than 0.01 from vehicle), and augmented the release of i6-keto-PGF1 alpha, the stable metabolite of PGI2, from isolated rat aortae. Our results indicate that enhancement of endogenous vascular PGI2 release coupled with direct, or PGI2 mediated antiproteolytic and membrane stabilizing actions may be important physiological mechanisms counteracting the deleterious effects of hemorrhagic shock.

Non-invasive computerised detection of acute coronary occlusion.

The goal of this study was to evaluate the role of a computerised, non-invasive ECG method for detecting acute coronary occlusion (ACO). Ninety-five standard ECG leads were recorded, before and during ACO, from 18 patients undergoing balloon angioplasty. ECG amplitude and derivative parameters were calculated for the ORS, ST and T components of the ECG signal, before and during ACO. Results were obtained for each lead. Sensitivity of the standard visual ECG analysis for detecting ACO was 48%, whereas the percentage of conventional ECG changes during baseline was 14%. For the best ECG parameter, the amplitude parameter of the ORS component, sensitivity was 82%, and the percentage of parameter changes during baseline was 20%. The sensitivity for detecting ACO with five of the six ECG parameters studied was greater than that of the standard visual analysis. Ischaemic changes were detected in 4.3 +/- 1.6 leads per patient using the amplitude parameter of the ORS component, whereas, with the standard visual analysis, 2.5 +/- 2.1 leads demonstrated such changes (p<0.001). Results were then summarized per patient. The standard visual ECG analysis detected ACO in 15 of 18 patients (83%), if at least one lead showed ischaemic changes. The computerised analysis detected ACO in all 18 patients using the same criterion. The sensitivity of the computerised method for detecting ACO in the clinical setting of angioplasty was greater than that of the standard visual analysis. It is suggested that the computerised method may be useful for detecting myocardial ischaemia in other clinical settings of acute myocardial ischaemia.

Beneficial actions of RO 15-1788, a benzodiazepine receptor antagonist, in hemorrhagic shock.

We studied RO 15-1788, a new benzodiazepine receptor antagonist, [ethyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo (1, 5a) (1, 4) benzodiazepine-3-carboxylate] to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with RO 15-1788 maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving only the vehicle (final MABP 114 +/- 4 vs 82 +/- 4 mmHg, p less than 0.001). Moreover, RO 15-1788 decreased the release of the lysosomal hydrolase, cathepsin D (p less than 0.02) into the circulation and blunted the plasma accumulation of free amino-nitrogen groups (p less than 0.01). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in RO 15-1788 treated rats subjected to hemorrhagic shock than in those given the vehicle (18 +/- 2 vs 42 +/- 4 U/ml, p less than 0.01). Additionally, in vitro analysis indicated that RO 15-1788 antagonizes PAF induced coronary vasoconstriction and cardiac depression observed in perfused rat hearts, as well as inhibiting PAF induced platelet aggregation in cat platelet rich plasma. Our results suggest that antagonism of PAF actions can contribute significantly to the beneficial effects of RO 15-1788 in hemorrhagic shock.

The added value of spiral computed tomographic angiography after lung scintigraphy for the diagnosis of pulmonary embolism.

OBJECTIVES: The objectives of this study were to evaluate the added clinical value of spiral computed tomographic angiography (CTA) after ventilation-perfusion lung scintigraphy (V/Q) for the management of patients with suspected pulmonary embolism (PE). METHODS: Of 987 patients who had V/Q during 2001, 64 patients (6%) had CTA performed for further evaluation. V/Q and CTA findings were retrospectively analyzed by 2 clinicians who were blinded to the patients' outcome. Patient management was determined based on clinical and V/Q data and was reassessed after the addition of CTA data. RESULTS: CTA was performed in 2 patients with normal V/Q, 16 patients with low probability, 28 patients with intermediate, 4 patients with high probability, and 14 patients with nonconclusive V/Q. Three patients (19%) with low probability, 9 (32%) with intermediate probability, 4 (29%) with nonconclusive, and 4 (100%) with high probability V/Q had PE diagnosed by CTA. CTA findings changed the management in 2 patients (13%) with low probability, 15 (54%) with intermediate probability, and 4 (29%) with nonconclusive V/Q. CONCLUSION: In our institution, V/Q remains the main imaging modality for evaluation of patients with clinically suspected PE. CTA was performed after V/Q in 6% of patients. Patients with intermediate probability and those with nonconclusive V/Q, and to a much lesser extent, patients with low probability V/Q could benefit from the addition of CTA after V/Q. In patients with normal V/Q and those with high-probability V/Q, the addition of CTA does not seem to influence patient management.