Immune reactions associated with silicone-based ventriculo-peritoneal shunt malfunctions in children

The implantation of ventriculo-peritoneal (VP) shunting systems is the most commonly performed neurological procedure in children with hydrocephalus. Although the overall complication risk is low, the cumulative risk of shunt failure is high and unfortunately results in a high prevalence of revision surgeries. In this study, we explored the concept that some pediatric patients may develop an immune response to either the proteins attached to the silicone implant surface or to the biomaterial itself, and that this reaction may contribute to VP shunt failure in some individuals. The data displays that the sterile shunt malfunction group had a higher rate of protein deposition and increased levels of autoantibodies to the extracted surface proteins as compared to individuals with functioning shunting systems. The precise nature of the shunt-bound proteins that serve as antigens in this experiment have not yet been determined. The data also indicated that some individuals develop antibodies to polymeric substances that cross-react with partially polymerized acrylamide. The detection of significant amounts of shunt-bound protein, antibody responses to these proteins and to polymeric substances suggest that an immunological response to these proteins may play a role in the mechanism behind sterile shunt malfunctions.     

Aqueous polymerization of methacrylamide initiated by the redox system K2S2O8/ascorbic acid

The polymerization of methacrylamide initiated by the redox system K₂S₂O₈/ascorbic acid has been studied at 35 ± 0,2°C under the influence of atmospheric oxygen. The molecular oxygen autocatalyses the polymerization rate. The rate of polymerization is independent of the activator (ascorbic acid) concentration within the range 2,83 · 10^?3 to 11,3 · 10^?3 mol · l^?1, this does not hold below or above the given concentration range. The rate varies linearly at low monomer concentration (up to 17,76 · 10^?2 mol · l^?1). The catalyst exponent decreases from nearly unity (0,94) to 0,57 with increasing concentration of the catalyst probably due to participation of primary radicals in the termination of growing chain. The initial rate is not changed by the addition of a strong acid (H₂SO₄) within the range 15 · 10^?5 to 30 · 10^?5 mol · l^?1. With the activator (ascorbic acid) alone, an optimum is observed within the pH range 2,9–3,5. The initial rate and the limiting conversion increases with increasing polymerization temperature. The overall energy of activation as calculated from the ARRHENIUS plot has been found to be 16,0 kcal.mol^?1 within the temperature range 30–45°C. Organic solvents (water miscible only) and small amounts of neutral salts, (KCl, Na₂SO₄) depress the initial rate and the maximum conversion. The addition of small amounts of catalysts like Cu^2⊕, Mn^2⊕, Ag^oplus; increases the initial rate but no appreciable increase in the limiting conversion is observed.     

Study on the anatomical dimensions of the human sigmoid colon

Although the sigmoid colon is commonly afflicted with disease, studies on its anatomical dimensions are scarce. It is suspected that dimensions of the sigmoid colon change with age. This study documents data on the anatomical measurements of the sigmoid colon in 70 Indian subjects (51 live and 19 cadavers). Seven parameters of sigmoid colon anatomy measured included length and width of the sigmoid colon and mesocolon at specific points. Three mesocolic indices (width to length ratios) were calculated. Comparisons of measurements in the live and cadaver subjects and in the two sexes were made. The relationship of change in parameters with age was assessed. Appropriate statistical methods were used and the differences were considered significant at P < or = 0.05. The study showed wide ranging variations in the values of various measured parameters of the sigmoid colon. Seven patterns of the shape of the sigmoid loop were identified. In the commonest pattern the sigmoid mesocolon was vertically longer than wide (dolichomesocolic), the sigmoid loop having its maximum convexity located just a little proximal to the apex. Patterns where the width of the mesocolon was greater than the vertical length (brachymesocolic) were also observed. The gender analysis showed that the sigmoid mesocolon of the female was brachymesocolic (wider than long), whereas that of the male was dolichomesocolic (longer than wide). This might explain the higher incidence of sigmoid volvulus in the male. This study also showed that the measurements of the sigmoid colon and its mesocolon do not change significantly within the age range of 16-60 years in the two sexes. Also noteworthy is the observation that in the cadaver the sigmoid colon shows considerable shrinkage, particularly of its mesocolon; consequently the data from cadaver subjects, though valuable for anthropometric use, have limitations when used for clinical applications.     

Mitochondrial diseases: an overview of genetics, pathogenesis, clinical features and an approach to diagnosis and treatment

Defects in structures or functions of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis and other metabolic pathways have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogenecity of mitochondrial diseases. This article focuses on the recent advances in the field of mitochondrial disorders with respect to the consequences for an advanced clinical and genetic diagnostics. In addition, an overview on recently identified genetic defects and their pathogenic molecular mechanisms are given.     

Genes for immunodominant protein antigens are highly homologous in Mycobacterium tuberculosis, Mycobacterium africanum, and the vaccine strain Mycobacterium bovis BCG.

The relatedness of immunodominant protein antigens in Mycobacterium tuberculosis, M. africanum, and M. bovis BCG was investigated by comparing the genes that encode major protein antigens in M. tuberculosis with their counterparts in the other two mycobacteria. Genes encoding homologs of M. tuberculosis major protein antigens were isolated from M. africanum and M. bovis BCG by constructing lambda gt11 recombinant DNA expression libraries and screening them with murine monoclonal antibodies and DNA probes. The antibodies were directed against four major protein antigens of M. tuberculosis with molecular masses of 71, 65, 19, and 14 kilodaltons. The isolated M. africanum and M. bovis BCG DNA clones were mapped with restriction endonucleases, and the maps of the mycobacterial genes were confirmed by Southern analysis of mycobacterial genomic DNA. The restriction maps of DNA containing the four genes in M. tuberculosis, M. africanum, and M. bovis BCG are identical, indicating that the immunodominant proteins that they encode are highly homologous in the three mycobacteria. Thus, the immunity against tuberculosis engendered by M. bovis BCG vaccination could be provided, at least in part, by the immune response to these homologous antigens.     

Cellular immune responses of patients with juvenile chronic arthritis to retinal antigens and their synthetic peptides

The objective of this study was to determine the proliferative responses of peripheral blood lymphocytes of ocular antigens like retinal S-antigen, peptides M and G of S-antigen, yeast histone H3 peptide 106–121 homologous to peptide M and peptide R16 of interphotoreceptor retinoid binding protein (IRBP) in children with juvenile chronic arthritis (JCA). We have studied the in vitro proliferative response of peripheral blood lymphocytes from 41 patients with JCA (10 with and 31 without uveitis) and 23 healthy controls against the above antigens. The responders were retested after 1 or 6 months. Fifty (5/10) and 9.7% (3/31) of JCA patients with and without uveitis, respectively, responded (stimulation index >3) to S-antigen or one of its peptide listed above or yeast histone H3 peptide or R16 of IRBP. None of the healthy controls responded to any of these antigens. The difference in the frequency of responders (SI>3) between JCA associated with uveitis and healthy controls was statistically significant (p=0.001). Similarly, the difference between JCA with and without uveitis was also significant (p=0.013). Our findings suggest that these antigens may have a role in the pathogenesis of uveitis in a subset of patients with JCA.     

MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients

In order to investigate major histocompatibility complex (MHC) class I chain-related gene A (MICA), tumor necrosis factor (TNFa), -308TNFA, and human leukocyte antigen (HLA-DR/DQ) polymorphisms in mixed connective tissue disease (MCTD), we analyzed 24 patients and 229 healthy controls from Sweden. MICA and TNFa typing was performed by polymerase chain reaction (PCR) and genotyping. HLA-DR and -DQ were genotyped using PCR-sequence specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotide probe (PCR-SSOP), respectively. For analysis of -308TNFA polymorphisms we performed PCR with restriction endonuclease enzymes. We found that the MICA5.1-5.1 genotype was positively associated with MCTD. Shared epitope genes (DRB1*01 and DRB1*04) were also significantly positively associated with MCTD. Polymorphism of -308TNFA was not differently distributed in MCTD patients compared with controls. Furthermore, we demonstrated that frequencies of three estimated haplotypes were increased in MCTD patients compared with controls. Interestingly, the haplotype with MICA allele 4 together with DRB1*04 and TNF1 alleles gives the most specific pattern for MCTD patients compared with controls. Our study demonstrates a clear contribution of HLA loci in susceptibility to MCTD in the Swedish population. Susceptibility to MCTD may be linked to the MICA4/HLA-DRB1*04/TNF1 haplotype and MICA 5.1-5.1 genotype. Mixed connective tissue disease was also associated with shared epitope genes, which in RA has been associated with a more severe disease. Whether these genotypes affect the clinical phenotype of MCTD needs to be determined.     

Elevated glucocorticoid receptor levels in lymphocytes of children with the fetal hydantoin syndrome (FHS)

Our recent studies of the teratogenic mechanisms of phenytoin (DPH) and glucocorticoids in mice have indicated that DPH utilizes the anti-inflammatory pathway of glucocorticoids in producing congenital defects, such as cleft palate. This pathway is influenced by H-2 and H-3 histocompatibility-linked genes in the mouse, such that congenic strains have H-2 or H-3 alleles that confer susceptibility to DPH-induced congenital defects, and susceptible H-2 congenic strains have high glucocorticoid receptor levels. However, other H-2 or H-3 alleles confer resistance to these defects in their otherwise genetically identical congenic partner strains, and "resistant" H-2 alleles are associated with low levels of these receptors. To determine whether this animal work is applicable to the human, we have sought to investigate whether the level of glucocorticoid receptors in circulating lymphocytes of children with the fetal hydantoin syndrome (FHS) is as it is in the animals. We found that children with FHS had glucocorticoid receptor levels significantly elevated above those of unaffected children with similar DPH exposure in control families. The receptor level of affected children was also significantly elevated above that of fathers of children with the FHS and of fathers and mothers of control children. These findings are consistent with those documented in the animal models and suggest that an elevated level of glucocorticoid receptors in lymphocytes may be a marker for susceptibility to the FHS syndrome.