Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes

Valproic acid (VPA), an inhibitor of histone deacetylases, inhibits the growth of leukemia cells and induces their differentiation in vitro. In the present study, VPA in combination with two differentiating agents, 13-cis retinoic acid and 1,25-dihydroxyvitamin D3, was given to 19 previously untreated patients with MDS or CMML. Eight patients had to discontinue treatment before week 16 due to toxicity. According to international working group criteria, three patients (16%) responded to treatment. No correlation between VPA serum level, histone acetylation or clinical response was observed.     

Diet does not explain the high prevalence of dyslipidaemia in paediatric renal transplant recipients

Dyslipidaemia exists frequently after renal transplantation (RTx) and promotes atherosclerosis. In this study, we examined the association between daily intake of nutrients and serum lipids after paediatric RTx. We studied 45 children with acceptably functioning kidney grafts and adequately completed food records at a median age of 10.6 years (range 4.3–17.2 years), a median 5.2 years (range 1.0–11.0) after RTx, and 178 healthy controls at a median age of 9.0 years (range 3.2–18.7 years). Serum total cholesterol (TC), triglyceride, and apolipoprotein B concentrations were higher in the RTx patients than in the controls (P < 0.001), despite similar dietary intakes of saturated and polyunsaturated fats, and cholesterol. Both the RTx patients and controls ingested a low amount of polyunsaturated fats [mean (SD) percent of total calories (E%) 4.8 (1.3) and 4.6 (1.5), respectively] and an excessive amount of saturated fats [mean (SD) E% 14.4 (2.4) and 14.1 (2.8), respectively]. In multiple regression analyses, dietary fibre was negatively associated with serum TC concentration. The standard deviation score for body mass index was negatively associated with serum concentration of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein diameter, and positively with serum triglyceride concentration. In addition, dietary total fat intake was positively associated with serum HDL-C. In conclusion, the higher prevalence of dyslipidaemia in our paediatric RTx patients than in the controls was not explained by the diet. However, the type of fat consumed implicates the counselling for a healthier dietary lifestyle, with an increase in the ingestion of polyunsaturated fats and a decrease in that of saturated fats.     

NORDTOX 1994: Interphase between Human Toxicology and Ecotoxicology: Skørping,Denmark — May 20-23, 1994

Abstract Endothelial damage, synovial oedema, fibrin deposition, polymorphonuclear cell (PMN) invasion, and mild lining cell hyperplasia characterize acute inflammatory arthritis. Later on, perivascular tissue is infiltrated by mononuclear cells. The early events are mediated by interactions between PMNs and endothelial cells. Both parts in the adhesion event are activated with multiple stimuli resulting in complex interactions of varying intensity and duration. Adhesion molecules present on the surface of PMNs (L-selectin) or induced by inflammatory stimuli (β₂-integrins) mediate PMN adhesion to activated endothelium, which has counter receptors (E-selectin for L-selectin and ICAM-1 and ICAM-2 for β₂-integrins). At the initial phase L-selectin initiates the rolling of PMNs on endothelial cells. Further stimuli result in a more prolonged adhesion between PMNs and endothelium. At the side of endothelium, induction of P-selectin and PAF by histamine, thrombin and LTC, contribute to the acute rolling of PMNs on endothelial surface. Tumor necrosis factor (TNF), interleukin-1 (IL-1) and lipopolysaccharide activate endothelial cells to synthesize interleukin-8 (IL-8), a potent chemotactic and proadhesive mediator for PMNs, and further adhesion molecule (E-selectin), a mediator of long-term adhesion between PMN and endothelium. After adhesion and migration to the focus of inflammation, PMNs induce inflammation by aggregating, releasing hydrolyzing enzymes, generating lipid peroxidation products such as prostaglandins and LTB₄, and oxygen derived free radicals. In studies on the pathogenesis of seronegative spondyloarthropathies, we have shown persistently aberrant PMN function evidenced by enhanced chemotaxis and high production of toxic oxygen derived free radicals by PMN. In the development of chronic inflammation, these aberrations may play a role. Lipopolysaccharide, shown to persist in such patients, could act as a priming factor. The triggering factor(s) and factors contributing to the chronic inflammation in rheumatoid arthritis are not known. In chronic diseases, synovial inflammation is characterized by monocyte/macrophage products such as IL-1, TNF, interleukin-6 (IL-6), IL-8, colony-stimulating factors, lysosomal enzymes, PGE₂, LTB₄, and oxygen derived free radicals. However, in the acute phase or during flare-up of chronic diseases, PMNs contribute to the inflammation by ingesting rheumatoid factors and immune complexes and by producing oxygen derived free radicals. During the first 1-2 years of rheumatoid arthritis, a low response to chemotactic stimuli and low production of oxygen radicals by peripheral blood PMNs seem to be associated with benign disease and a lack of early destruction of joints measured by the presence of radiological erosions.     

Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis.

Antibodies to the stratum corneum of rat oesophagus (antikeratin antibodies) were assayed by indirect immunofluorescence in a prospective study of patients with early rheumatoid arthritis (RA). At the beginning of the study, antikeratin antibodies of IgG class were detected in serum samples from 27/71 (38%) patients compared with 1/20 (5%) control patients with reactive arthritis, and 1/38 (3%) healthy blood donors. At the end of the two year follow up, 27/67 (40%) patients with RA were positive for antikeratin antibodies. The patients with RA who were initially positive for antikeratin antibodies had a more active disease course than the patients negative for antikeratin antibodies as measured by clinical, laboratory, and radiological variables. The prevalence of positivity for antikeratin antibodies fluctuated during the follow up, the variation paralleling the disease activity. The occurrence of HLA-DR4 was similar in patients with RA who were positive and negative for antikeratin antibodies. Antikeratin antibodies were also found in seronegative patients with RA, confirming that antikeratin antibodies do not have rheumatoid factor activity. These results show that antikeratin antibodies are detectable at the time of the initial diagnosis of RA and that the positivity for antikeratin antibodies may have prognostic significance in early RA.     

Secondary Cerebral Astrocytoma 3 Years After Diagnosis of Primary Osteogenic Sarcoma: A Case Report

A secondary astrocytoma appearing 3 years after diagnosis of osteosarcoma is reported in a boy 11 years old. The boy had been treated with cytostatics according to the T-10 protocol. Treatment had been discontinued 2 years before diagnosis of the astrocytoma.     

A formative evaluation to develop a school health nursing early intervention model for adolescent substance use

OBJECTIVE: To improve an early intervention (EI) triggered by the Adolescents' Substance Use Measurement (ADSUME) as a method to prevent substance abuse among adolescents. We assessed how ADSUME and EI work in practice and how EI could be improved. DESIGN AND SAMPLE: School health nurses (n=10) tested ADSUME and EI on 14- to 18-year-old adolescents (n=228). Six months later, these nurses and their professional partners were invited to assess EI in focus group interviews. METHODS: Four focus group interviews involving a total of 24 nurses and partners were implemented. Interview data were analyzed with qualitative content analysis. RESULTS: ADSUME concretized assessment, activated profound dialogue, and proved to be an important part of EI. It was important to assess the adolescent's resources in addition to the ADSUME score. EI worked well in confidential dialogues after the adolescent and the PHN reached a consensus on the level of concern about the adolescent's substance use. The recommended EI enabled individual brief intervention in all four stages of substance use, from abstinence or experimental use to hazardous use. CONCLUSIONS: EI was improved practically, and the contents of the intervention were reformulated. It is important to integrate EI with the preventive efforts of the school.     

Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is a common adulthood mature B-cell neoplasm. Infections are the most important cause of mortality in this condition, and Streptococcus pneumoniae has been considered the most important single pathogen. We investigated the immunogenicity of 7-valent pneumococcal conjugate vaccine in patients with CLL. The study material comprised 52 patients with CLL and 25 age- and sex-matched controls. The subjects were vaccinated with Prevenar pneumococcal conjugate vaccine. Serum samples were taken for antibody determinations before and four weeks after vaccination. Antibody response rates to vaccine antigens were lower in patients with CLL compared to controls. However, if the vaccine had been administered at an early stage of the disease, i.e. before commencement of chemotherapy and the development of hypogammaglobulinaemia, a significant vaccination response to at least six antigens was obtained in almost 40% of the CLL patients. Our results indicate that early administration of conjugate vaccine may be beneficial in CLL.     

Oscillatory motor cortex-muscle coupling during painful laser and nonpainful tactile stimulation

Noxious stimulation activates-in addition to the brain structures related to sensory, emotional, and cognitive components of pain-also the brain's motor system. Effect of noxious input on the primary motor (MI) cortex remains, however, poorly understood. To characterize this effect in more detail, we quantified the ongoing oscillatory communication between the MI cortex and hand muscles during selectively noxious laser stimulation. The subjects maintained an isometric contraction of finger muscles while receiving the laser stimuli to the dorsum of the hand. Tactile stimuli with well-known effects on the MI cortex reactivity served as control stimuli. Cortex-muscle coherence was computed between magnetoencephalographic (MEG) signals from the contralateral MI and electromyographic (EMG) signals from the hand muscles. Statistically significant coherence at approximately 20 Hz was found in 6 out of 7 subjects. The coherence increased phasically after both types of stimuli but significantly later after laser than tactile stimuli (mean +/- SEM peak latencies 1.05 +/- 0.12 s vs. 0.58 +/- 0.06 s; P < 0.05), and the coherence increase lasted longer after laser than tactile stimuli (0.87 +/- 0.09 s vs. 0.50 +/- 0.06 s, P < 0.05). The observed coherence increase could be related to stabilization of the motor-cortex control after sensory input. Our findings add to the clinically interesting evidence about the cortical pain-motor system interaction.     

Complement activation and HLA-B27.

The efficiency of complement activation was studied in sera from HLA-B27 positive and negative subjects (27 with previous yersinia arthritis and 35 controls). Activation of complement with zymosan induced higher mean levels of the anaphylatoxin C3a in HLA-B27 positive sera (mean (SD) 7.40 (1.66) mg/l) than in HLA-B27 negative sera (6.41 (1.79) mg/l). Similarly, higher levels of C3d,g, another C3 breakdown fragment, were obtained in HLA-B27 positive sera after Escherichia coli 0111:B4 lipopolysaccharide treatment (17.6 (3.7)% v 15.0 (3.8)%). The differences occurred irrespective of previous arthritis, complement C4 or Bf phenotype, or variation in background complement levels. The findings suggest that an increased responsiveness to complement activators may contribute to the pathogenesis of HLA-B27 associated inflammatory diseases.