Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria

Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1null) mice, which were as susceptible as wild-type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-gamma was found between infected wild-type and Tnfr1null or Tnfr2null mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1null mice-both of which developed CM-whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2null mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1null or Tnfr2null mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 up-regulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.     

Infection and antibiotic therapy in 4000 burned patients treated in Milan, Italy, between 1976 and 1988

The pathogenic flora, isolated from burn wounds of patients admitted to a burn care unit during the years between 1976 and 1988 were typed and the in vitro susceptibility to antibacterial agents was recorded. Between 1976 and 1988 the general therapeutic approach was changed three times, in congruence with the prevalent nosocomial bacterial resistance. The most frequent isolates were: Pseud. aeruginosa, Staphylococcus aureus, Enterococcus spp., Proteus mirabilis, Escherichia coli, Enterobacter cloacae, Klebsiella spp. and other Enterobacteriaceae, such as Acinetobacter, Citrobacter. The most striking finding was the increase in antibiotic-resistant Enterococcus isolates. Staph. aureus, Klebsiella and E. cloacae showed susceptibility to cephalosporins, imipenem, pefloxacin, vancomycin; Enterococcus susceptibility to pefloxacin and vancomycin, and Pseud. aeruginosa sensitivity to piperacillin, amikacin, tobramycin was generally good. E. coli showed a satisfactory susceptibility on average, and P. mirabilis showed a good sensitivity to piperacillin, cephalosporins, amikacin, tobramycin, aztreonam and imipenem. Thus, the general bacterial flora and susceptibility have remained mostly unchanged over the years, with the conspicuous exception of Enterococcus spp. and E. cloacae, which demonstrated a marked increase in incidence, with a concomitant dramatic decrease in the sensitivity of Enterococcus spp. to antibiotics.     

Influence of aging on the pharmacokinetics and pharmacodynamics of doxacurium

OBJECTIVE: Different sets of diagnostic criteria have been proposed for Sj?gren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community. METHODS: The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study included 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II. RESULTS: The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined. CONCLUSION: Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.     

Transient neonatal nonketotic hyperglycinemia: a 13-year follow-up

We report on a patient with transient nonketotic hyperglycinemia (NKH). Onset, clinical features, biochemical and electroencephalographic findings were consistent with neonatal nonketotic hyperglycinemia. The normalization of clinical, biochemical and electroencephalographic features on day 9 without specific therapy suggested a transient form. At the last follow-up the girl was 13 years old, had a normal mental development, no EEG abnormalities or neurological deficits.     

Occurrence of papillary carcinoma in a hyperfunctioning thyroid nodule: report of a case and diagnostic considerations

HIV-infected patients commonly experience haematological disturbances including anemia, neutropenia or thrombocytopenia. Bone marrow failure may be caused by HIV itself, or by secondary involvement by opportunistic pathogens and malignancy. The need for multiple concomitant suppressive treatments may increase the risk of cytopenias. Strategy to reduce both anemia and neutropenia as well as to improve the haematological tolerance to myelotoxic agents have been developed by using haematological growth factors. So far, erythropoietin and granulocyte(macrophage) colony-stimulating factors have been successfully used in clinical trials including HIV-patients with either zidovudine-associated anemia or severe HIV or drug-induced neutropenia. However, according to the cost of these palliative approaches, there is a need for more reliable data showing that these growth factors could really have a major impact on the patient's compliance to therapy, reduction of hospitalization and infection rate and improvement of the overall survival.     

Asymptomatic dystrophinopathy

A 4-year-old girl was referred for evaluation for a mild but persistent serum aspartate aminotransferase (AST) elevation detected incidentally during routine blood screening for a skin infection. Serum creatine kinase activity was found to be increased. Immunohistochemical study for dystrophin in her muscle biopsy showed results consistent with a carrier state for muscular dystrophy. Molecular work-up showed the proposita to be a carrier of a deletion mutation of exon 48 of the dystrophin gene. Four male relatives also had the deletion mutation, yet showed no clinical symptoms of muscular dystrophy (age range 8-58 yrs). Linkage analysis of the dystrophin gene in the family showed a spontaneous change of an STR45 allele, which could be due to either an intragenic double recombination event, or CA repeat length mutation leading to identical size alleles. To our knowledge, this is the first documentation of an asymptomatic dystrophinopathy in multiple males of advanced age. Based on molecular findings, this family would be given a diagnosis of Becker muscular dystrophy. This diagnosis implies the development of clinical symptoms, even though this family is clearly asymptomatic. This report underscores the caution which must be exercized when giving presymptomatic diagnoses based on molecular studies.