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.

Venous thromboembolism and the utility of the Padua Prediction Score in patients with sepsis admitted to internal medicine departments.

BACKGROUND: Sepsis is prevalent in internal medicine (IM) departments. Elderly patients with sepsis and chronic medical conditions are at an increased risk for venous thromboemolism (VTE). The objective of this study was to assess the rate of VTE and the accuracy of the Padua Prediction Score (PPS) to predict VTE in patient with sepsis admitted to IM departments. METHODS: We prospectively collected data on septic patients admitted to IM departments in a community-based medical center. Additionally, we retrospectively collected VTE risk factors and events throughout a 1-year post hospitalization period. We computed the PPS for every patient, and analyzed the data accordingly. RESULTS: In total, 1080 patients were included in the study. The mean age was 74.68 ± 16.1 years. The average PPS was 4.86 ± 2.26, and 71.2% of the patients had a positive PPS. Only 17.8% of the patients received anticoagulant prophylaxis during their hospital stay. Seven patients had VTE on admission, 14 (1.29%) acquired in-hospital VTE, and 7 (0.65%) had VTE post discharge throughout 1 year. In all, 21.9% patients died during hospitalization, and the overall survival rate was 64%. PPS was not correlated with anticoagulant administration (P = 0.36), in-hospital VTE (P = 0.23) or 1-year VTE (P = 0.40), but was significantly associated with in-hospital death and survival (P < 0.0001). CONCLUSION: The rate of VTE in medical patients with sepsis in IM departments is low, and PPS lacks granularity in detecting patients at risk of acquiring it. In this population, a positive PPS is highly associated with death, and may reflect a more general co-morbidity and disease severity index.

Sepsis in nonagenarians admitted to internal medicine departments: a comparative study of outcomes.

BACKGROUND: Elderly patients are at a higher risk of acquiring sepsis, and are largely being treated in Internal Medicine (IM) departments. AIM: To characterize the differences between nonagenarians and other age groups in patients admitted to IM departments with sepsis, and to assess predictors for survival in patients older than 90 years of age. DESIGN AND METHODS: A prospective registry of all-comers with sepsis admitted to IM departments in a community-based Medical Center was build. Patients' demographics, medical history, clinical presentation and outcomes were recorded and analyzed according to age groups. RESULTS: One thousand and eighty patients were followed for a mean of 83.63 ± 65.90 days. Nonagenarians constituted 10.93% (118/1080) of our cohort. Of these, 70.48% had a cognitive impairment and 82.60% had reduced functional state. Of these, 5.61 and 10.50% fulfilled the criteria of septic shock and severe sepsis, respectively. Sepsis category was significantly influenced by age groups (P < 0.001). Complications secondary to sepsis at admission and throughout hospitalization, and mortality rates, were higher in the nonagenarian population (61.86 vs. 51.14%, P = 0.032 and 37.29 vs. 20.06%, P < 0.001, respectively), and overall survival was significantly lower in the nonagenarian population (40.68 vs. 66.84%, P < 0.001). CONCLUSION: Patients treated in IM departments for sepsis are old, and a significant percentage is older than 90 years of age with reduced function and mental status at baseline. These frail patients are afflicted by a worse outcome, which is most likely associated with poor functional status at baseline and severe deconditioning during the acute illness. Prognostic tools are needed to address today's trends in patient-mix and disease severity, specifically for very-old patients admitted with sepsis cared for in IM departments.

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.

Kikuchi fujimoto disease in Israel--more than a pain in the neck.

OBJECTIVE: Kikuchi Fujimoto disease (KFD) is a rare, benign disorder, usually characterized by cervical lymphadenopathy. Most available data on KFD has come from the Far East. We examined the characteristics of KFD in Israel. METHODS: A retrospective analysis of the records of all patients diagnosed as KFD in seven medical centers in Israel and all the cases previously reported as having occurred in Israel in the literature. RESULTS: Nineteen patients were included, 13 new cases and six from the literature. Mean age of patients was 23 (range 9-50) years. Female/male ratio was 1.1:1. Cervical lymphadenopathy, the hallmark of KFD in the Far East (97%), was less frequent in Israel (44%). However, Israeli patients presented more often with generalized (26%) or retroperitoneal (21%) lymphadenopathy (P < 0.01). Systemic signs such as fever (73%), night sweats (21%), weight loss (21%), hepatomegaly or splenomegaly (25%), and elevated sedimentation rate (52%) were more common in Israeli patients compared to most reports from other parts of the world, excluding Germany (P < 0.05). Leukopenia was evident in most Israeli patients (72%) in contrast to other countries (P < 0.01). Clinical presentation of KFD in Germany was comparable to Israel in most aspects. CONCLUSION: The clinical presentation of KFD in Israel often resembles a systemic disease with fever, leukopenia and generalized or retroperitoneal lymphadenopathy in more than half of the cases, contrary to the presentation in the Far East, which typically includes cervical lymphadenitis, and less frequently, systemic manifestations.

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.

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.

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.

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.

Exercise stress testing, myocardial perfusion imaging and stress echocardiography for detecting restenosis after successful percutaneous transluminal coronary angioplasty: a review of performance.

When chest symptoms recur in a patient who underwent percutaneous transluminal coronary angioplasty (PTCA), it is necessary to rule out restenosis (R). Three main noninvasive tests suggest the presence of R: exercise stress test (XT), myocardial perfusion imaging (MPI) and stress echocardiography (s-echo). The objectives of this review were: (1) to estimate the pretest probability of R as a function of time after PTCA in symptomatic patients and (2) to obtain an approximation of the diagnostic parameters of the XT, MPI and s-echo for detecting R. A MEDLINE search (English-language, years: 1980-2001) was conducted to identify studies examining post-PTCA functional testing for diagnosing R. Data from the studies were pooled. Comparing studies was often difficult due to varying methodology in the studies. Pretest probability of R in symptomatic patients increases in a nonlinear fashion from 20% or less at 1 month, to nearly 90% at 1-year postangioplasty. The approximated accuracy of the XT, MPI, and s-echo for detecting R was 62, 82 and 84%, respectively. During the first month after PTCA, none of the noninvasive modalities is able to accurately detect R. Late (7-9 months) after PTCA, the pretest probability of R is high and therefore the noninvasive measure may be spared. Our analysis suggests that MPI and s-echo should be preferred over the XT for diagnosing R.

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.

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.

Effects of exposure to low concentrations of carbon monoxide on exercise performance and myocardial perfusion in young healthy men.

OBJECTIVE: To assess the effects of exposure to low concentrations of carbon monoxide (CO), as commonly measured in atmospheric urban air pollution and certain occupational environments, on exercise performance and myocardial perfusion in young healthy men, and the possible need for tighter restrictions on ambient concentrations of CO. METHODS: 15 young, healthy non-smoking men, 18-35 years old, were exposed blindly and randomly to air or to a mixture of CO and air, followed by an exercise treadmill test with thallium heart scintigraphy. Blood was drawn for determination of carboxyhaemoglobin before and at the end of the exposure, and for lactic and pyruvic acid at the beginning and the end of the exercise test. The main outcome measures include the duration of the exercise test, the maximal effort expressed in metabolic equivalent units (METs), the mean plasma lactic to pyruvic acid ratio at the end of the ergometry, ECG changes in the exercise test, and perfusion deficits in thallium heart scintigraphy. RESULTS: At the end of exposure to CO, the mean (SD) blood carboxyhaemoglobin concentration rose from 0.59% (0.08%) to 5.12% (0.65%) (p < 0.0001). At the end of the exercise period, the mean (SD) plasma lactate/pyruvate ratio, which reflects the level of anaerobic metabolism (69.9 (5.9) after air and 75.9 (7.0) after CO), was not significantly different between the two experimental groups. Exercise induced electrocardiographic changes were noted in only one subject after exposure to CO. No arrhythmias were detected in any of the subjects. Significant differences were found in the mean duration of the exercise test (p = 0.0012) and the METs (p = 0.0001). The mean adjusted difference of exercise duration between exposure to air and CO was 1.52 minutes 95% confidence interval (95% CI) 0.73 to 2.32 minutes. The mean adjusted difference of METs between exposure to air and CO was 2.04 95% CI 1.33 to 2.76. The models for duration of exercise and METs showed no significant sequence and period effects. Thallium myocardial perfusion imaging disclosed normal perfusion in all regions of the heart, with no significant differences in perfusion between the two exercise tests (after air or CO). CONCLUSION: Acute exposure to a low concentration of CO which produces blood carboxyhaemoglobin concentrations of 4%-6% significantly decreases exercise performance in young healthy men. No ischaemic electrocardiographic changes or disturbances in myocardial perfusion were found by graded exercise with thallium scintigraphy. Our findings suggest that pollution of atmospheric air by CO at concentrations which are commonly found in urban and industrial environments may exert an adverse effect on skeletal muscles, manifesting as decreased exercise performance.

Abdominal surgery reduces the ability of rat spleen cells to synthesize and secrete active tumour necrosis factor-alpha (TNF-alpha) by a multilevel regulation.

We have previously shown that abdominal surgery (explorative laparotomy) reduces the ability of lipopolysaccharide (LPS)-triggered spleen macrophages to secrete TNF-alpha. In this study we characterize possible mechanisms which could be responsible for the reduction in splenic production of TNF-alpha. Post-operative and control (unoperated) rat splenocytes or enriched splenic macrophages were cultured with LPS. Steady-state levels of TNF-alpha mRNA were determined by Northern and slot blot analyses, and validated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The amount of TNF-alpha protein was measured by Western blot analysis, and its biological activity was determined by the fibroblast L-929 cytotoxicity assay. Surgery induced a 12-fold inhibition in TNF-alpha activity (P < 0.02), caused up to two-fold reduction in the accumulation of TNF-alpha mRNA (P < 0.01), and suppressed TNF-alpha protein maturation into its 17-kD form in cellular extracts. Post-surgical spleen supernatants revealed mainly a band of a lower molecular weight (14 kD). Our data suggest a multilevel regulation of post-operative inhibition of TNF-alpha response to LPS, at the accumulation of mRNA, translational and secretory levels. We also suggest that the reduced bioactivity could be partially caused by a proteolytic cleavage of TNF-alpha. Since TNF-alpha is an important participant in immune responses, its reduced production and activity may be a central mechanism of post-operative immunosuppression.

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.

Effects of severe hemorrhage on plasma ANP and glomerular ANP receptors.

Atrial natriuretic peptide (ANP) plays an important role in blood volume and electrolyte homeostasis in normovolemia and in hypervolemic states. The currently available information on the effects of hypovolemia on plasma ANP is contradictory. Moreover, possible regulation of ANP receptors during severe hemorrhagic hypovolemia has not been investigated. This study evaluated the effects of severe hemorrhage on plasma ANP and on the regulation of glomerular ANP receptor subtypes in anesthetized rats. Constant rate bleeding of 50% of total blood volume within 2 h induced a reproducible shock state characterized by marked decreases in blood pressure, heart rate, and hematocrit and an increase in plasma renin activity and aldosterone. Hemorrhaged rats exhibited a gradual significant increase in plasma ANP from 39.3 +/- 2.9 to 114.7 +/- 20.0 pmol/l 1 h after the bleeding (P < 0.001 from the initial value and P < 0.02 from the final value of sham-shock rats). Hemorrhage induced a significant decrease in total glomerular ANP binding sites (172 +/- 25 vs. 363 +/- 39 fmol/mg protein in hemorrhaged and sham-shock rats, respectively, P < 0.05). This decrease was mainly due to a significant decrease in ANPC receptors (132 +/- 22 vs. 312 +/- 40 fmol/mg protein in hemorrhaged and sham-shock rats, respectively, P < 0.05). Hemorrhage did not change glomerular ANPA receptor density. No significant differences in the affinity of the glomerular receptor subtypes for ANP were detected. Our data indicate that plasma ANP increases after prolonged severe hemorrhage. It is suggested that downregulation of renal ANPC receptors leads to reduced clearance of ANP and contributes to elevation of its plasma level after severe hemorrhage.