Treatment of intracerebral arteriovenous malformations with isobutyl 2- cyanoacrylate: initial clinical experience

From November 1976 to September 1979, 46 patients with intracranial arteriovenous malformations or fistulas participated in a clinical study using isobutyl 2-cyanoacrylate (IBCA), with tantalum, for palliative or preoperative occlusion of the blood supply to the abnormalities. Although failure to obtain satisfactory position of a functioning microcatheter precluded deposition of IBCA 10 times, a total of 51 of a possible 62 feeding vessels were occluded with the tantalum-impregnated glue. The technique, results, and complications are discussed in light of the clinical follow-up, which varied from 12 to 48 months.     

Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes

Investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human conotruncal defects is a prudent research approach. In this study we explore gene-only and gene-environment effects of 32 single nucleotide polymorphisms (SNPs) on conotruncal defect risks. The genes bearing these SNPs participate in one of five pathogenetic processes, homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with odds ratios of 2 or more, and two with odds ratios of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an odds ratio of 2.5 (95% confidence interval; 0.9-7.0), F7 promoter (-323) 10-bp del/ins with an odds ratio of 2.3 (0.8-6.8), ITGB3 leu33pro (platelet glycoprotein IIIa) with an odds ratio of 2.2 (0.9-5.7), and NPPA T2238C (atrial natriuretic precursor peptide) with an odds ratio of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G (-376A)) and ADD1 gly460trp (alpha adducin) with odds ratios of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation.     

Application of classic utilities to published pediatric cost-utility studies

ObjectiveEconomic analyses, such as cost-utility analyses (CUAs), are dependent on the quality of the data used. Our objective was to test how health utility values (measurements of patient preference) assessed by recommended methods (classic utilities) would impact the conclusions in published pediatric CUAs.MethodsClassic utilities for pediatric health states were obtained by recommended utility assessment methods, time trade-off, and standard gamble in 4016 parent interviews. To test the impact of these utilities on published studies, we obtained a sample of published pediatric CUAs by searching Medline, EMBASE, EconLit, Health Technology Assessment Database, Cochrane Database on Systematic Reviews, Database of Abstracts of Reviews of Effects, and the Cost Effective Analysis (CEA) Registry at Tufts Medical Center, using search terms for cost-utility analysis. Articles were included when results were presented as cost per quality adjusted life-years (QALYs), the interventions were for children <18 years of age and included at least one of the following health states: attention deficit hyperactivity disorder, asthma, gastroenteritis, hearing loss, mental retardation, otitis media, seizure disorder, or vision loss. Studies that did not include these or equivalent health states were excluded. For each CUA, we determined utilities (values for patient preference), the utility assessment method used, and presence of one-way sensitivity analyses (SAs) on utilities. When one-way SAs were conducted, we determined if using our classic utilities would change the result of the CUA. When an SA was not presented, we determined if using our classic utilities would tend to support or not support the published conclusions.ResultsWe evaluated 39 articles. Eighteen articles presented results of one-way SAs on utilities. Seven articles presented SAs over a range that included our classic utilities. In 4 of the 7, using classic utilities would change the conclusion of the study. For the 32 articles where no one-way SA were presented (n = 21), or where the classic utilities fell outside the range tested (n =11), a change to classic utility would tend against the study conclusion in 12 articles (31%).ConclusionsMore than a third of published CUA studies could change if pediatric utilities obtained by recommended, classic methods were used. One-way SAs on utilities are often not presented, making comparison between studies challenging.     

Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects

We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.     

Psychometric properties of the decisional balance for patient choice in substance abuse treatment

In the context of patient-centered care and the increasing number of evidence-based substance abuse treatments, outpatient substance abuse treatment programs are poised to provide patients with a menu of options. Not all patients will be ready for such an open choice field in substance abuse treatment and they will undoubtedly differ on how they weigh the risks and benefits of having autonomy to choose their own treatment. Given the lack of an existing valid measure to assess this decision making process, this study sought to establish a measure to assess the relative weight that patients give to the pros and cons of choosing their own substance abuse treatment. Construct validity of the Decisional Balance for Patient Choice in Substance Abuse Treatment was assessed in a sample of 231 outpatients using confirmatory factor analysis. As another validity aspect, the use of decisional balance across a continuum of choice options also was investigated. The model fit was acceptable (CFI = 0.904). Internal consistency of the measure was established. The final 22-item measure revealed sound psychometric properties, but further testing is warranted.     

A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida

Folate binding protein 1 (Folr1) knockout mice with low maternal folate concentrations have been shown to be excellent animal models for human folate-responsive neural tube defects (NTDs). Previous studies using the Folr1 knockout mice revealed that maternal folate supplementation up-regulates the expression of the PCMT1 gene in Folr1 nullizygous neural tube tissue during neural tube closure. PCMT1 encodes the protein repair enzyme l-isoaspartate (d-aspartate) O-methyltransferase (PIMT) that converts abnormal d-aspartyl and l-isoaspartyl residues to the normal l-aspartyl form. PIMT is known to protect certain neural cells from Bax-induced apoptosis. Pcmt1-deficient mice present with abnormal AdoMet/AdoHcy homeostasis. We hypothesized that a known functional polymorphism (Ile120Val) in the human PCMT1 gene is associated with an increased risk of folate-responsive human NTDs. A case-control study was conducted to investigate a possible association between this polymorphism and risk of spina bifida. Compared to the Ile/Ile and Ile/Val genotypes, the homozygous Val/Val genotype showed decreased risk for spina bifida (adjusted odds ratio=0.6, 95% confidence interval: 0.4-0.9). Our results showed that the Ile120Val polymorphism of PCMT1 gene is a genetic modifier for the risk of spina bifida. Val/Val genotype was associated with a reduction in risk for spina bifida.     

Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4

Background and Purpose

Previous work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells.

Experimental Approach

NF-κB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-κB activation, a pathway activated by TLR4 stimulation.

Key Results

LPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-κB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective μ opioid receptor antagonist, β-FNA. Indeed, both naloxone and β-FNA also inhibited NF-κB activation in reporter cells. Further examination of fentanyl and β-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion.

Conclusions and Implications

These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation.     

Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube

Neural tube defects (NTDs) are birth defects that can be disabling or lethal and are second in their prevalence after cardiac defects among major human congenital malformations. Spina bifida is a NTD where the spinal cord is dysplastic, and the overlying spinal column is absent. At present, the molecular mechanisms underlying the spinal bifida development are largely unknown. In this study, we present a Fkbp8 mouse mutant that has an isolated and completely penetrant spina bifida, which is folate- and inositol-resistant. Fkbp8 mutants are not embryo lethal, but they display striking features of human spina bifida, including a dysplastic spinal cord, open neural canal and disability. The loss of Fkbp8 leads to increased apoptosis in the posterior neural tube, demonstrating that in vivo FKBP8 inhibits cell death. Gene expression analysis of Fkbp8 mutants revealed a perturbation of expression of neural tube patterning genes, suggesting that endogenous FKBP8 activity establishes dorso-ventral patterning of the neural tube. These studies demonstrate that Fkbp8 is not important for embryo survival, but is essential for spinal neural tube patterning, and to block apoptosis, in the developing neural tube. The mutant Fkbp8 allele is a new experimental model which will be useful in dissecting the pathogenesis of spinal NTDs, and enhance our understanding of the etiology of human NTDs.