[Response to treatment with interferon beta in patients with multiple sclerosis. Validation of the Rio Score]. / Respuesta al tratamiento con interferon beta en pacientes con esclerosis multiple. Validacion del Rio Score.

INTRODUCTION: Different criteria have been proposed for the response to treatment with interferon beta, and the Rio Score is one of the most widely used. The aim of this study was to validate the usefulness of the Rio Score in an independent cohort. PATIENTS AND METHODS: A multi-centre, prospective, longitudinal study was conducted on patients with relapsing-remitting multiple sclerosis treated with interferon beta. The patients were classified according to the presence of attacks, active lesions (new in T2 or gadolinium enhancing lesions) in magnetic resonance imaging, a confirmed increase in disability or combinations of these variables (attacks, increase on the Expanded Disability Status Scale and active lesions) after one year's treatment. Regression analysis was used in order to identify the response-predicting variables after a three-year follow-up. RESULTS: The sample consisted of 249 patients with relapsing-remitting multiple sclerosis. The logistic model confirmed that the presence of two (odds ratio = 6.6; CI 95% = 2.7-16.1; p < 0.0001) or three (odds ratio = 8.5; CI 95% = 1.6-46; p < 0.01) positive variables during the first year of treatment were indicative of a significant risk of activity (attacks or progression) in the next two years. CONCLUSIONS: The usefulness of the Rio Score is confirmed, in an independent cohort, as a means of identifying patients with a higher risk of developing clinical activity or progression of disability during treatment with interferon beta.

TITLE: Respuesta al tratamiento con interferon beta en pacientes con esclerosis multiple. Validacion del Rio Score.Introduccion. Se han propuesto diferentes criterios de respuesta al tratamiento con interferon beta, y el Rio Score es uno de los mas utilizados. El objetivo de este estudio fue validar la utilidad del Rio Score en una cohorte independiente. Pacientes y metodos. Estudio multicentrico, prospectivo y longitudinal de pacientes con esclerosis multiple remitente recurrente tratados con interferon beta. Los pacientes fueron clasificados basandose en la presencia de brotes, lesiones activas (nuevas en T2 o lesiones que captaban gadolinio) en la resonancia magnetica, incremento confirmado de la discapacidad o combinaciones de estas variables (brotes, incremento en la Expanded Disability Status Scale y lesiones activas) tras un año de tratamiento. Se utilizo un analisis de regresion con el fin de identificar las variables de prediccion de respuesta despues de un seguimiento de tres años. Resultados. Se incluyo a 249 pacientes con esclerosis multiple remitente recurrente. El modelo logistico confirmo que la presencia de dos (odds ratio = 6,6; IC 95% = 2,7-16,1; p < 0,0001) o tres (odds ratio = 8,5; IC 95% = 1,6-46; p < 0,01) variables positivas durante el primer año de tratamiento conferia un riesgo significativo de actividad (brotes o progresion) en los siguientes dos años. Conclusiones. Se confirma, en una cohorte independiente, la utilidad del Rio Score para identificar a pacientes con un mayor riesgo de desarrollar actividad clinica o progresion de la discapacidad durante el tratamiento con interferon beta.

Chronic interstitial pulmonary fibrosis following Mycoplasma pneumoniae pneumonia.

An unusual case of chronic interstitial fibrosis that developed as a sequela of Mycoplasma pneumoniae pneumonia is described. Predominant manifestations included progressive exertional dyspnea, shortness of breath, persisting lung infiltrates, low lung volumes, and low pulmonary diffusing capacity. Open lung biopsy one year after the acute stage of mycoplasma pneumonia revealed focal interstitial fibrosis with early pleural thickening, hypertrophic alveolar lining cells, and peribronchiolar lymphoid cell infiltrates. Improvement in clinical manifestations, radiologic findings, and pulmonary function results occurred with steroid therapy.

Placental histopathology in syphilis.

Placental evaluation is important in congenital syphilis (CS) since clinical and serologic findings necessary to fulfill the diagnostic criteria of syphilis may be absent at birth, making early accurate diagnosis difficult. We examined 25 placentas from mothers with syphilis as confirmed by positive RPR rapid plasma reagin and fluorescent treponemal antibody absorption tests to determine which histopathologic features should raise the suspicion of CS. The 25 examined placentas were from 162 syphilitic mothers who delivered at our institution in 1990. Of the 27 infants delivered (including two pairs of twins), four were stillborn and three died at 1 day of age. Eleven of 23 liveborn infants fulfilled the Centers for Disease Control criteria of probable CS. Seven of the 25 placentas showed a well-defined constellation of histopathologic changes that included proliferative vascular changes, chronic villitis, relative villous immaturity, and, in six placentas, acute villitis. All seven of these placentas showed the presence of spirochetes by special stains. Six also had plasma cells in the basal decidua. Recognition of these placental changes, although nondiagnostic, should lead the pathologist to seek additional clinical history and ancillary tests. Placental histopathologic examination is an additional parameter to be considered in the diagnosis of CS.

Studies of in vitro synergy between several beta-lactam and aminoglycoside antibiotics against endocarditis strains of Pseudomonas aeruginosa.

Ten strains of Pseudomonas aeruginosa isolated from patients with endocarditis (1969-1975) and eight similar strains (1980) were assayed for minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) to several aminoglycosides (gentamicin, tobramycin, amikacin) and beta-lactam antibiotics (ticarcillin, piperacillin, azlocillin, moxalactam and MKO 787). In vitro synergy (1969-1975 series) between beta-lactam and aminoglycoside antibiotics was shown uniformly with azlocillin (100 per cent) followed by moxalactam (80 per cent), piperacillin and ticarcillin (66 per cent) and MKO 787 (13.3 per cent). Results were similar in 1980. Synergy of azlocillin was demonstrated with five strains previously not showing synergy between carbenicillin and an aminoglycoside. In 1980 four of eight patients infected with pseudomonads that were not synergistically affected in vitro were refractory to treatment with the piperacillin-aminoglycoside combination. In vitro synergy of the infecting strain is necessary for successful medical treatment of patients with P. aeruginosa infective endocarditis.

The effects of pre-existing coxsackievirus B4 myocardial disease on the expression of coxsackievirus B3 myocarditis.

OBJECTIVE: To assess the expression of coxsackievirus B3 (CB3) myocarditis in mice with pre-existing CB4 myocardial disease. DESIGN: Double blind comparative study of CB3 myocarditis in CD1 mice with or without prior CB4 induced cardiac damage. INTERVENTIONS: Antecedent myocardial injury was produced by CB4 infection intraperitoneally at age two days. Two to three weeks later, when CB4 myocarditis was established, infected and control animals were inoculated intraperitoneally with CB3. They were then sacrificed over a 45-day period. Virus and neutralizing antibody titres were measured on days 3 and 13 after CB3 infection, respectively. The incidence of myocarditis and the intensity of histopathological changes (assessed according to a semiquantitative grading scale from 0 to 4) over a 45-day period were compared. MAIN RESULTS: Among animals with prior CB4 disease, CB3 titres were lower (2.3 +/- 1.7 versus 3.6 +/- 0.8, tissue culture infective dose 50, P = 0.05) and neutralizing antibody response was slightly higher. The incidence of myocarditis was diminished (59.1 versus 89.3%, P = 0.01) and the indices of pathological changes were lower but the differences were not significant (0.68 +/- .54 versus 1.10 +/- 0.20, 1.38 +/- 0.43 versus 1.50 +/- 0.25, 0.56 +/- 0.56 versus 1.26 +/- 0.75, 0.38 +/- 0.58 versus 1.30 +/- 0.78, 0.12 +/- 0.28 versus 0.47 +/- 0.2 on days 3, 9, 13, 30 and 45 post infection, respectively, P > 0.1). CONCLUSION: These results demonstrate that prior exposure to CB4 offers some protection from subsequent CB3 infection. Moreover, they show that antecedent CB4 myocardial damage does not predispose to a worsened expression of CB3 myocarditis.

Focal ventricular thinning caused by indomethacin in the late phase of coxsackievirus B4 murine myocarditis.

Indomethacin has been shown to increase virus titers and to worsen cardiac injury in the acute phase of coxsackievirus B4 murine myocarditis. The authors evaluated the effects of indomethacin on the histopathologic changes in a later phase of this disease after virus clearance. Two-day old CD1 mice were infected with coxsackievirus B4. Ten days later, surviving animals were randomized to receive indomethacin or saline intraperitoneally for 10 days. They were then euthanatized, and their hearts were examined for the presence of inflammation, necrosis, scarring, and focal thinning. Mortality was slightly higher among treated animals (7/15 versus 2/12, p = 0.3). The index of inflammation (0.6 +/- 0.5 versus 0.7 +/- 0.5) necrosis and scarring (0.4 +/- 0.5 versus 0.3 +/- 0.5) among treated and control animals, respectively, was not significantly different, but the size of involved myocardium (149742 +/- 201982 versus 35300 +/- 45413 microns2) was remarkably larger (p less than 0.05), and focal ventricular thinning (5/12 versus 0/10, p = 0.03) was encountered among indomethacin recipients exclusively. These findings indicate that indomethacin treatment in the late phase of coxsackievirus B4 myocarditis enhances myocardial damage and increases the incidence of focal ventricular thinning.

Prevalence and incidence of multiple sclerosis in Las Palmas, Canary Islands, Spain.

OBJECTIVES: To determine the prevalence and incidence of multiple sclerosis (MS) in the city of Las Palmas (Canary Islands, Spain), geographically belonging to north-western Africa, but with European ancestry. METHODS: This population-based survey was conducted for a period of 5 years (1998-2002) in a Sanitary District of Las Palmas city (28 degrees 20' N), with a population of 82,623 inhabitants. Multiple sources were periodically investigated for case ascertainment. Patients with definite and probable MS were included. RESULTS: Sixty-four patients with MS were identified on prevalence day, December 31, 2002. According to Poser's criteria the crude prevalence rate was 77.5 per 100,000 (95% CI: 59.7-98.9). This rate decreased to 73.8 (95% CI: 56.5-94.8) according to McDonald's criteria. Age-adjusted rates for the world and European standard populations were 61.6 (95% CI: 47.1-78.9) and 70.6 (95% CI: 55-89), respectively. Prevalence was higher for women aged 25-44 years. In 17 patients onset of MS occurred within the study period. Average annual incidence was 4.1 per 100,000 (95% CI: 2.4-6.6). CONCLUSIONS: The prevalence and incidence rates in Las Palmas city are close to those reported from Continental Spain and other countries of southern Europe with similar social and ethnic background. These results highlight the role of racial-ethnic factors in the genesis of MS.

Current problems in the treatment of infective endocarditis due to Pseudomonas aeruginosa.

Mortality from pseudomonas infective endocarditis remains high despite optimal use of available antibacterial agents. Infection of the tricuspid valve is subacute, but involvement of the mitral or aortic valve precipitates more serious disease. Most valvular infections are due to a single pseudomonad immunotype, but 20% of cases are mixed infections. Antimicrobial susceptibility tests and tests of synergy by beta-lactam and aminoglycoside antibiotics in combination were performed on 30 isolates of Pseudomonas aeruginosa. Azlocillin was the most effective beta-lactam in combination with an aminoglycoside; MKO 787 was least effective. Among the aminoglycosides tested, netilmicin was the most effective. Medical treatment combined with valvulectomy (without valve replacement) is now standard treatment for refractory right-sided endocarditis at this medical center. A high dose of aminoglycoside in combination with a beta-lactam has proved efficacious. For left-sided infection, immediate valve replacement accompanied by a six-week course of the high dose-combined drug regimen is recommended. Newer beta-lactam antibiotics, such as piperacillin, may be limited in usefulness due to beta-lactamase inactivation.

Interferon and neutralizing antibody in sera of exercised mice with coxsackievirus B-3 myocarditis.

Weanling ICR albino Swiss mice were inoculated ip with 1.9 x 10(4) PFU of coxsackievirus B-3 (Nancy) and subsequently forced to swim vigorously daily in a preheated pool (33 degrees). Viremias and virus in hearts of exercised mice were respectively 75 x 1000 x greater than in infected, but not exercised mice. At 24 hr after inoculation, pooled serum from mice that had been swum had no circulating interferon, while infected but not swum mice had interferon activity at a dilution of 1:10. At 72 hr after infection, circulating interferon disappeared from infected (not swum) mice, but continued to be present in high titers through the sixth day in sucklings forced to swim. Interferon was first detected in the hearts of both groups at 48 hr. Quantities in both infected groups were generally similar. Neutralizing antibodies were found in these baby mice on the 13th day of infection and were 16 x greater in nurslings that were not exercised. Measures of corticosterone taken at 4 PM daily were similar in infected, infected-swum, and uninfected mice.

An enterovirus-induced murine model of an acute dilated-type cardiomyopathy.

After coxsackievirus B3 (CB3) infection of mice, migration of transfused sensitized and nonsensitized 51Cr-labelled T lymphocytes was followed. At autopsies on days 5.5, 6, 7, and 9 after infection, T-cell-dependent in situ calcification was assessed by cardiac xeroradiographs. In CB3-infected animals from group 2 that were not forced to swim (Gr. 2, Inf +, Ex -), significant rerouting of sensitized 51Cr-labelled T cells to the heart occurred beginning on the 9th day after infection. This was accompanied by myocardial calcification. When mice with CB3 myocarditis were forced to swim (Gr. 3, Inf +), 4 times the density of sensitized 51Cr-labelled T cells was redirected to the heart. At xeroradiography, severe myocardial calcification was shown to accompany cardiac dilatation.

The effect of subsequent myocardial damage on the expression of coxsackievirus B4 myocarditis and the development of ventricular aneurysms.

Coxsackievirus B (CB) 4 causes transmural myocarditis in suckling mice with ensuing development of focal ventricular thinning or aneurysms. We studied whether subsequent infection with another cardiotropic virus influences the expression of CB4 disease. CB4 infection was established in 2-day-old CD1 mice by intraperitoneal (IP) inoculation. Three weeks later, surviving animals were randomized to receive CB3 or saline IP. They were then killed over a 45-day period. CB4 neutralizing antibody (NA) titres were comparable in both groups (31 +/- 23 vs 37 +/- 19). CB3 NA were detected in CB3 infected animals only (72 +/- 86 versus 0). The incidence of myocarditis was comparable (67.4% vs 55.2%). The indices of histopathological changes (assessed according to a semiquantitative grading scale from 0-4) were greater among CB3 recipients on day 9 post CB3 challenge (1.38 +/- 0.43 vs 0.46 +/- 0.4, P < 0.001) and to a lesser extent, on day 13 (0.56 +/- 0.56 vs 0.19 +/- 0.38, P > 0.1). On days 30, and 45, these indices became similar in both groups. Focal thinning was noted on days 45 in 6/11 animals with CB4 infection alone and in 0/11 mice with subsequent CB3 infection (P = 0.006). These findings show that CB3 myocarditis can be expressed in mice with prior CB4 disease, that sequential infections do not lead to cumulative cardiac injury, and that subsequent CB3 infection suppresses the formation of CB4 induced ventricular aneurysms.

Effects of various handling and storage conditions on stability of Treponema pallidum DNA in cerebrospinal fluid.

Treponema pallidum DNA from even small numbers of organisms was detectable in cerebrospinal fluid (CSF) stored at room temperature or at 4 degrees C for several hours and in CSF subjected to three freeze-thaw cycles. These results suggest that negative PCR results for T. pallidum from patients diagnosed with T. pallidum invasion of the central nervous system are probably not due to the loss of target DNA prior to testing.

Coxsackievirus B3 myocarditis in C3H/HeJ mice: description of an inbred model and the effect of exercise on virulence.

The effect of forced exercise on the development of coxsackievirus B3 myocarditis in inbred C3H/HeJ mice was studied. Four groups of mice (30 per group) were formed: infected-exercised (Group I); infected-unexercised (Group II); uninfected-exercised (Group III); and uninfected-unexercised (Group IV). Infected mice were inoculated intraperitoneally with 1.0 x 10(2.1) TCID50 coxsackievirus B3. Exercised animals were swum daily for 60 minutes on days 1-9. Myocardial viral titers were acutely elevated on day 3 of infection and were augmented significantly by exercise on days 6 and 9. Exercise increased the overall mortality from 0-10% to 20-40%; significantly increased heart: body weight ratios on days 6, 9 and 13; and increased the extent of myocardial fiber necrosis. We have reproduced the acceleration of CB3 myocarditis by exercise in the inbred C3H model.

Vancomycin during pregnancy: does it cause hearing loss or nephrotoxicity in the infant?

Vancomycin was administered intravenously to 10 pregnant women for the treatment of methicillin-resistant Staphylococcus aureus infections. Auditory brainstem response testing and renal function studies were performed on the 10 babies in the experimental group and 10 babies in each of two control groups to determine the safety of vancomycin use during pregnancy. Auditory brainstem responses were not normal at birth in six infants from the three different groups studied (N = 30) but were normal at 3 months in five. The sixth infant had conductive hearing loss unrelated to vancomycin use that spontaneously disappeared at 12 months of age. Renal function was normal in all infants. Vancomycin was detected in cord blood in two patients and in breast milk in one. Adequate serum levels were achieved with routine doses in eight mothers tested; no adverse reactions occurred. It appears that vancomycin use during the second and third trimesters of pregnancy does not produce sensorineural hearing loss or nephrotoxicity in the infant.