Renal injury in patients with rheumatoid arthritis treated with gold.

While severe nephrotoxicity is uncommon during gold therapy of rheumatoid arthritis (RA), the prevalence of mild nephrotoxicity has not been investigated. To study this, levels of leucine aminopeptidase (LAP) and N-acetyl-beta-glucosaminidase (NAG) (nmole/hr/mg urinary creatinine), and beta 2-microglobulin (beta 2M) (microgram/mg urinary creatinine) were measured in urine samples from 33 patients with RA receiving gold and 28 patients with various musculoskeletal diseases not receiving gold. Each patient had a normal urinalysis and blood urea nitrogen or serum creatinine. LAP was above 30 in 55% of RA patients and 7% of controls (p < 0.01). NAG was above 100 in 70% of RA patients and 14% of controls (p < 0.01). In 8 RA patients, NAG was over 200; LAP was over 100 in 4, but in none of the controls. Beta 2M was above 0.32 in 7 of 23 female RA patients and in none of 12 female controls (p = 0.012) and none of the male patients. Patients who excreted high levels of beta 2M also excreted high levels of NAG and LAP. These data show that gold in therapeutic doses affects renal tubular cells, cauing the release of NAG and LAP from lysosomes and brush borders of the cells. This may represent the mildest stage of nephrotoxicity. Elevated beta 2M in the urine of some patients indicate a degree of nephrotoxicity sufficient to cause renal tubular dysfunction.

Pulmonary and extrapulmonary effects of increased colloid osmotic pressure during endotoxemia in rats.

OBJECTIVES: We tested the hypothesis that an increase in the blood colloid osmotic pressure (COP) that is maintained during early-stage endotoxemia may decrease fluid flux across capillaries and may reduce pulmonary and multiple-organ edema. DESIGN: Prospective study. SETTINGS: Research laboratory in a hospital. SUBJECTS: Male albino Sprague-Dawley rats. INTERVENTIONS: Rats were anesthetized with pentobarbital, underwent tracheotomies, were cannulated in the femoral vein and artery, and were randomly assigned to the following four groups comprising 11 rats each: group I, controls (saline solution treatment); group II, albumin treatment (three doses of 1 g/kg 25% human albumin every 2 h); group III, endotoxin treatment with a single IV dose of 4 mg/kg endotoxin; and group IV, endotoxin and albumin-treatment (4 mg/kg endotoxin plus albumin treatment). Experiments lasted for 6 h while fluid intake was equally maintained in all groups. MEASUREMENTS AND RESULTS: COP and other variables were measured every 2 h. To determine the water content of an organ, after the rat was killed, the lung, heart, kidney, intestine, and liver were removed. Albumin treatment alone (group II) generated significant increases in COP (maximum, 58% from the baseline measurement) but did not change the water content of the organ, compared with saline solution-treated controls. Endotoxin-treated rats (group III) developed significant reductions in COP, with significant increases in pulmonary, renal, and heart water content compared with controls. Albumin treatment in endotoxemic rats (group IV) significantly increased the COP without improving the endotoxemia-induced organ edema. Pulmonary edema, however, was increased further, compared with endotoxemia alone. CONCLUSIONS: COP elevation by albumin administration during the early stage of endotoxemia does not ameliorate pulmonary or multiple-organ edema and may aggravate pulmonary edema.

The Carpentier-Edwards pericardial aortic valve. Ten-year results.

To evaluate the function of the Carpentier-Edwards pericardial valve in the aortic position, we analyzed the results of 310 aortic valve replacements performed between 1982 and 1985. Mean age was 64.2 +/- 10.8 years (range 22 to 95 years); 190 patients (61.3%) were male patients. There were 18 hospital deaths (5.8%), and none were valve related. Follow-up of the 292 survivors was 100% complete at a mean of 7.8 +/- 2.9 years; 2290 patient-years of follow-up were available for analysis. There were 133 late deaths (45.5%). Actuarial survivals at 5 and 10 years were 82.5% and 45.9%, respectively. The 10-year actuarial freedom from events was 88.7% +/- 2.1% for thromboembolism, 90.9% +/- 1.8% for hemorrhage, 94.3% +/- 1.6% for endocarditis, and 91.2% +/- 2.6% for structural deterioration. The 153 hospital survivors 65 years of age or older had an extremely low incidence of structural valve deterioration, with only four explants and 95.5% actuarial freedom from explantation at 10 years, and a linearized rate of 0.3 +/- 0.2 per patient-year compared with 88.6% and 0.7 +/- 0.2 for patients younger than 65 years of age. Twelve valves were explanted for structural deterioration. Of these, 11 (93%) had leaflet calcification causing stenosis and one had a wear-related leaflet tear. The Carpentier-Edwards pericardial valve has a low incidence of valve-related complications. The freedom from structural valve deterioration is low at 10 years, particularly in patients 65 years of age and older.

Serological differentiation between acute (late control) and endocarditis Q fever.

AIMS: To differentiate the serological profiles of chronic (endocarditis) Q fever from the late follow up of acute cases. METHODS: Twenty patients (10 diagnosed with acute and 10 with endocarditis Q fever) were studied. Those diagnosed with acute infection were followed up from 2.5 to 88 months (mean 35.8 months). Serological variables included indirect immunofluorescence against phase I and II of Coxiella burnetii (IgM, IgG, and IgA), complement fixation and rheumatoid factor (RF). RESULTS: All patients with titres of IgA against phase I, after IgG removal, equal to or above 320 and a complement fixation value equal to or above 128 had endocarditis. No patient with acute Q fever had such a serological profile. CONCLUSIONS: The combination of IgA against phase I and complement fixation values may be sufficient to differentiate the serological profile of chronic (endocarditis) Q fever from the late follow up of acute cases.

Effect of hypothermia on ventilation in anesthetized, spontaneously breathing rats: theoretical implications for mechanical ventilation.

OBJECTIVE: To test if hypothermia, induced by a sustained pentobarbital anesthesia, in rats can reduce ventilatory demands without compromising pulmonary gas-exchange efficiency. DESIGN: Prospective study. SETTING: Research laboratory in a hospital. SUBJECTS: One group of 11 female Sprague Dawley rats. INTERVENTIONS: The rats were anesthetized with 45 mg/kg pentobarbital, tracheostomized and intubated; their femoral veins and arteries were cannulated. After surgery, anesthesia and fluid balance were maintained (10 mg/kg per h pentobarbital, and 5 ml/kg per h saline, i.v.). Rectal temperature, mean arterial blood pressure (MAP), and heart rate (HR) were continuously monitored. The respiratory variables and gas-exchange profiles were determined at 38 degrees C (normothermia), and during stepwise hypothermia at 37, 35, 33, 31 and 29 degrees C. The arterial pressure of carbon dioxide (PaCO2), pH and arterial pressure of oxygen (PaO2) during hypothermia were corrected at body temperature. MEASUREMENTS AND RESULTS: Graded systemic hypothermia, with maintained anesthesia, produced a strong correlation between reduction in the respiratory frequency and rectal temperature (r2 = 0.55; p < 0.0001; n = 66). The minute volume was significantly reduced, starting at 35 degrees C, without significant changes in the tidal volume (repeated measures of analyses of variance followed by Dunnett multiple comparisons test). No significant changes occurred in the PaCO2, pH, PaO2, hemoglobin oxygen saturation, the calculated arterial oxygen content and estimated alveolar-arterial oxygen difference during mild hypothermia (37-33 degrees C). The PaO2, however, was significantly reduced below 31 degrees C. The MAP remained stable at different levels of hypothermia, whereas HR was significantly reduced below 33 degrees C. CONCLUSIONS: Mild hypothermia in rats, induced by a sustained pentobarbital anesthesia, reduces ventilation without compromising arterial oxygenation or acid-base balance, as measured at body temperature. Theoretically, our observations in spontaneously breathing rats imply that a combination of mild hypothermia with anesthesia could be safely utilized to maintain adequate ventilation, using relatively low minute ventilation. We speculate that such a maneuver, if applied during mechanical ventilation, may prevent secondary pulmonary damage by allowing the use of lower ventilator volume-pressure settings.

Homografts in the treatment of prosthetic valve endocarditis.

Homografts may provide unique technical advantages in the setting of aortic root destruction from prosthetic valve endocarditis. Viable cryopreserved homografts are relatively resistant to infection, do not require anticoagulation, and exhibit satisfactory long-term durability. In a group of 33 patients undergoing homograft replacement for active prosthetic valve endocarditis, left aortoventricular discontinuity was present in 11 patients, periannular abscesses were found in 21 patients, 15 patients had vegetations covering most of the prosthesis, and severe valve dehiscence was present in 10 patients. The homograft proved versatile in allowing various techniques for aortic root reconstruction. All patients survived operation. Two late hospital deaths accounted for a hospital mortality rate of 6%. Of 31 hospital survivors, 26 (83%) remained free of major events at a mean of 20.1 months. Overall late survival including all deaths was 73.1% +/- 11.98%. All but one patient is FC 1. In addition to the technical advantages offered by the homograft, the relatively low morbidity and mortality incidence associated with its use in prosthetic valve endocarditis makes it an appealing alternative in this setting.

Experimental critical care in ventilated rats: effect of hypercapnia on arterial oxygen-carrying capacity.

PURPOSE: We have previously demonstrated an increased arterial O2-carrying capacity in normal ventilated dogs subjected to both acute and prolonged exogenous hypercapnia. In the present study, we tested if arterial hypercapnia, during controlled ventilation, can increase O2-carrying capacity also in rats. MATERIALS AND METHODS: Twenty young male Sprague Dawley rats were anesthetized (60 mg/kg pentobarbital), tracheostomized, intubated, and one femoral vein and artery were cannulated. Anesthesia and paralysis were maintained using 15 mg/kg/h pentobarbital intravenously, and 2 mg/kg/h vecuronium bromide. The fluid balance (5 mL/kg/h saline), normothermia, and minute volume were maintained. The mean arterial blood pressure and heart rate were continuously monitored. Experiments included the following: (1) a control group, ventilated with normoxic air for 150 minutes (n = 5); (2) mild hypercapnia, a group of eight rats ventilated with normoxic air for 30 minutes and then ventilated with a mixture of normoxic air at 60 mm Hg CO2 (8 kPa) for 1 hour; and (3) severe hypercapnia, a group of seven rats were treated exactly as in group II, except a 90 mm Hg (12 kPa) CO2 during hypercapnia. Gas-exchange profile, arterial hemoglobin (Hb) concentration, arterial Hb-oxygen saturation (Hb-O2), and arterial O2 content were periodically determined during normocapnia and 1 hour of hypercapnia. RESULTS: Exposures to mild and severe hypercapnia, in rats with maintained ventilation, significantly reduced the arterial O2 content by 20% and 33%, respectively, without significant changes in the arterial Hb concentration (-2%). Severe hypercapnia generated a significant reduction of -14% in the PaO2, but not in PaO2/ FiO2 ratio. CONCLUSION: Rats subjected to controlled ventilation and permissive hypercapnia, unlike dogs and perhaps humans, show no augmentation of Hb concentration. Hypercapnia in rats also provokes much stronger Bohr effect than in dogs. Hypercapnia-induced Bohr effect in rats is accompanied with extreme desaturations of Hb-O2, and substantial reduction in the O2-carrying capacity. We speculate that the strong hypercapnia-induced Bohr effect in rats may prevent hypoxia at the tissue level. However, to maintain a stable oxygen-carrying capacity in rats used for pulmonary critical care studies with hypercapnia, we suggest to use hyperoxia, with or without a mild hypothermia.

Very high resistance to amoxicillin in Streptococcus pneumoniae: an epidemiological fact or a technical issue?

To explore reproducibility of high amoxicillin minimum inhibitory concentrations (MIC(AMX) ), isolates received during 2002 and 2003 in the National Reference Laboratory of Streptococcus pneumoniae with an amoxicillin MIC of 16 microg/ml (43 strains) and 8 g/ml (12 strains) when singly determined on a routine basis in this center by agar dilution, were retested 10 times by agar dilution and microdilution following NCCLS guidelines, not only using double dilutions but also dilution steps of 2 microg/ml (i.e, 2, 4, 6, 8, 10, 12, 14 and 16 microg/ml). A significant (p<0.05) shift to a higher MIC(AMX )was obtained with microdilution vs. agar dilution. Routine MIC(AMX )of 16 microg/ml were confirmed in 0 strains by agar dilution and in 6 by microdilution, when retested. These 6 strains presented a modal MIC(AMX )value of 10 microg/ml (5 cases) and of 14 micro g/ml (1 case) when using 2 microg/ml microdilution steps. There is low reproducibility of the highest MIC(AMX )values.

Autoantibody profiles in the sera of patients with Q fever: characterization of antigens by immunofluorescence, immunoblot and sequence analysis.

Recent reports have shown that some of the immunological aspects of Q fever, a rickettsiosis caused by Coxiella burnetii, could be related to self-antigen responses. The aim of this study was to determine the specificity of the autoantibody response of patients with acute and chronic Coxiella infections. Smooth muscle and cardiac muscle-specific autoantibodies were observed in significant percentages in acutely or chronically affected Q fever patients when compared to healthy volunteers. Moreover, the incidence of cardiac muscle-specific autoantibody was significantly higher among chronically ill patients compared to acutely ill patients. Moreover, a band of 50 kD of a HeLa extract was detected in most of the sera of individuals with chronic infections and previous sequence analysis suggests that this antigen presents a high degree of homology with the human actin elongation factor 1 alpha. Further research would be necessary to confirm if antibodies to human cytoskeletal proteins could be of clinical importance in chronically infected Q fever patients.

Role of immunoglobulin G subclasses in Q fever.

The progression of Q fever to either acute or chronic disease has been attributed both to biological characteristics of the bacteria and to the host immune response. In order to determine whether a specific immunoglobulin G (IgG) subclass distribution could play a diagnostic or prognostic role in Q fever, IgG subclass levels were measured in patients with acute or chronic disease. It was observed that (i) IgG1 and IgG3 levels were elevated in patients with chronic Q fever compared to patients with acute disease or normal controls; (ii) variations over time reflected inverse complementary relationships of subclass levels, such as between IgG1 and IgG3 compared with IgG2 and IgG4, or an inverse relationship between IgG1 and IgG2; (iii) variations in IgG2 and IgG3 total subclass levels during follow-up of patients with chronic Q fever showed a decrease in IgG2 with a concomitant increase in IgG3 two years from disease onset. These findings indicate that measurements of IgG subclasses may be a simple, additional tool useful in the diagnosis of Q fever. This data raises the question of an unusual immunoregulatory mechanism in Q fever that is implicated in the presentation of the clinical disease.

Distribution of immunoglobulin G (IgG) and A (IgA) subclasses following Q fever vaccination with soluble phase I Coxiella burnetii extract.

High levels of IgG1, IgG3 and IgA2 antibodies have been observed in patients with Q fever following Coxiella burnetii infection. This IgG subclass distribution is more typical of viral and autoimmune diseases than of bacterial infections. It seemed, therefore, of interest to carry out a prospective study of the distribution of immunoglobulin subclasses after vaccination with phase I C. burnetii tricloroacetic soluble extracts to detect possible differences with respect to natural infection. The antibody response found in vaccinees was mainly restricted to the IgG1, IgG2 and IgA1 subclasses. These findings confirm differences in isotype distribution when compared to those of patients with acute or chronic Coxiella infections and opens an area of interest with respect to the role of IgA subclasses.

The use of alteplase in a newborn receiving extracorporeal membrane oxygenation.

OBJECTIVE: To present a case of the use of alteplase for the successful resolution of an upper extremity occlusion in a newborn receiving extracorporeal membrane oxygenation (ECMO). CASE SUMMARY: A two-day-old full-term Hispanic girl receiving ECMO support developed a left upper extremity occlusion distal to the brachial artery. Alteplase therapy was initiated with a bolus dose of 0.48 mg/kg followed by a continuous infusion of 0.27 mg/kg/h for three hours. A repeat Doppler ultrasound revealed little improvement, resulting in continuation of alteplase therapy at an infusion rate of 0.27 mg/kg/h for an additional three hours. At the completion of the infusion, perfusion was greatly improved with palpable radial pulse present. While remaining on ECMO support, a brain ultrasound approximately 13 hours after alteplase therapy revealed a grade I right caudate head hemorrhage with normal ventricles. ECMO support was discontinued during the next 24 hours, with a repeat brain ultrasound three days later indicating no acute hemorrhage, normal ventricles, and almost complete resolution of the intraventricular hemorrhage. The neonate was discharged 19 days after discontinuing ECMO support. DISCUSSION: Patients receiving ECMO support are at risk of hematologic complications, including thrombi formation. Moreover, limited information is available regarding the most appropriate thrombolytic therapy for patients receiving ECMO support. Alteplase is an attractive thrombolytic agent given its antigenicity, clot specificity, and pharmacokinetic profile. However, both ECMO support and thrombolytic therapy are risk factors for the development of intraventricular hemorrhage, which our patient developed. Therefore, close monitoring of patients receiving ECMO support and alteplase therapy is essential given the potential for hematologic adverse effects. CONCLUSIONS: Alteplase is an effective thrombolytic agent in neonates receiving ECMO support. Additional experience with alteplase is necessary to determine the optimal dose and duration of therapy in this patient population.

Experimental critical care in rats: gender differences in anesthesia, ventilation, and gas exchange.

OBJECTIVE: To compare normative ventilatory and gas-exchange data and anesthetic requirements in male and female rats subjected to critical care conditions. DESIGN: Prospective study. SETTING: Critical care research laboratory in a hospital. SUBJECTS: Twenty-two age-matched young male and female rats (Sprague-Dawley, Long Evans strain). INTERVENTIONS: Anesthesia was induced with 65 and 45 mg/kg pentobarbital in male and female rats, respectively. The rats were then tracheostomized and cannulated in one femoral vein and artery. Anesthesia was maintained using 8-15 mg/kg/hr pentobarbital (iv) and controlled by continuous hemodynamic monitoring. MEASUREMENTS AND MAIN RESULTS: Normoxic baselines for breathing frequency, tidal volume, minute volume, inspiratory-to-expiratory ratio, inspiratory drive (tidal volume/inspiratory time), respiratory system compliance, peak airway pressure, and gas-exchange profiles were established. Ventilatory and gas-exchange responses to oxygen and CO2 were then determined by exposure to 10 mins of hyperoxia (100% oxygen), two levels of mild and severe hypercapnic hyperoxia (inspired Pco2 of 30 and 60 torr; 4 and 8 kPa), and two levels of mild and severe normocapnic hypoxia (inspired PO2 of 81 and 48 torr; 10.7 and 6.3 kPa). The average anesthetic requirement (during a 5- to 6-hr experiment) was 30% less in the female rats than in the male rats (p < .05). Female rats showed significantly lower breathing frequency, minute volume (mL/min/kg), and inspiratory drive (mL/kg/sec) during hyperoxia, mild and severe hypercapnia, and mild hypoxia. Pulmonary peak airway pressure was significantly lower in the female rats, consistent with a significantly higher weight-indexed compliance during all exposures. The female rats also had significantly higher inspiratory-to-expiratory ratio and higher PaCO2 with lower pH during normoxia, hyperoxia, and mild hypercapnia. These gender differences had no effect on PaO2, which was similar in all exposures. CONCLUSIONS: There are significant gender differences in ventilation, gas exchange, and anesthetic requirements in rats subjected to critical care conditions. The gas-exchange values observed in these spontaneously breathing rats may represent the optimal levels attainable during pentobarbital anesthesia with normal lungs. They may serve as standards for ventilator settings in the rat models used for critical care studies.

Removal of infected pacemaker leads with deep hypothermic circulatory arrest and open surgical exploration of the superior vena cava and innominate veins.

Despite the use of transvenous methods for extraction of infected leads, failed attempts may result in retained lead fragments. Retained lead fragments may be a focus of continued infection leading to sepsis. We present two patients in which conversion from cardiopulmonary bypass to hypothermic circulatory arrest allowed direct visualization, using venotomies in the superior vena cava and innominate vein to achieve complete removal of retained pacemaker lead fragments. Use of venotomies in the extracardiac venous system is a technical addition to prior descriptions of lead extraction using deep hypothermia and circulatory arrest.

Distribution of IgA subclass response to Coxiella burnetii in patients with acute and chronic Q fever.

The progression of Coxiella burnetii infection to acute or chronic Q fever has been attributed to biological characteristics of the bacterium and to the host immune response. We measured whether serum levels of total and specific subclasses IgA1 and IgA2 could be correlated with the course of disease in acute and chronic Q fever infections, and with the occurrence of endocarditis. In patients with chronic infection, total IgA2 levels were significantly increased. Q-fever-specific IgA1 antibodies were detectable in both acute and chronic infections, but only patients with endocarditis had IgA2 antibodies to C. burnetii phase II antigens. These findings indicate that the measurement of IgA subclasses may be a useful aid in the serological diagnosis of Q fever. Our results reinforce the idea that immunologically mediated host factors are important in the pathogenesis of Q fever and in the disease outcome of this infection.

Antimicrobial susceptibility and pneumococcal serotypes.

The increase in antibiotic resistance and the possible changes in serotype prevalence as a consequence of a new conjugated vaccine have contributed to renewed interest in the study of pneumococcal serotypes and their antibiotic resistances. Spain still has one of the highest penicillin resistance rates, but in the past 4-5 years a slight decrease has been observed. The level of resistance has not increased either, 12.7% of the 11 165 isolates studied showed high-level penicillin resistance but 94% of these had an MIC of only 2 mg/L. Serotypes 6, 9, 14, 19 and 23 included 83% of the penicillin-resistant pneumococci; the remaining 17% belonged to 18 different serotypes. We analysed these minor penicillin-resistant serotypes in view of their potential increase following a possible child vaccination programme. Four of these serotypes (11, 15, 21 and 35) were the most prevalent, and among them serotype 15 was particularly frequent with >50% of its strains resistant. The effective control of these minor penicillin-resistant serotypes should be based on continuous surveillance of pneumococcal epidemiology.