Comparative molecular field analysis (CoMFA) of a series of selective adenosine receptor A2A antagonists

Selective and potent antagonists for the A_2A adenosine receptors have been described recently. The most potent compounds have a triazolo‐pyrimidine structure, whereas 8‐styryl‐xanthines usually possess lower affinity at the A_2A receptor. We have examined the quantitative structure activity relationships of 34 triazolo‐pyrimidines using the Comparative Molecular Field Analysis (CoMFA). The model developed accounts in a satisfactory manner for the structure‐activity relationships within this series of A_2A receptor antagonists (q² = 0.840, r² = 0.970) and, consequently, it can be used as a guide in the design of novel analogs with optimized antagonistic activity. The overall predictivity of this model was tested on the published data of a set of external molecules giving acceptable results. The validity of the CoMFA approach as an effective tool for studying the 3D‐QSAR of series of biologically active compounds is confirmed, even if additional efforts clearly are needed for trying to extend the models to structurally more varied series of derivatives. Drug Dev. Res. 46:126–133, 1999. © 1999 Wiley‐Liss, Inc.     

Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects(NTD)

A number of studies have demonstrated that the common polymorphism 677C→T in the gene encoding 5, 10-methylenetetrahydrofolate reductase (MTHFR) leads to a thermolabile variant with decreased enzyme activity and to mildly elevated plasma homocysteine. 677TT homozygosity was shown to be more frequent in NTD probands compared with controls in some studies. Recently, another polymorphism, 1298A→C, in the MTHFR gene was described and combined heterozygosity 677CT/1298AC was suggested to be an additional risk factor for NTD. The present study examines the genotype and haplotype distribution of the two polymorphisms in the German population and evaluates the impact on NTD individuals and their relatives. To determine the haplotype of all individuals tested, we developed an easy-to-perform ARMS-RFLP test. Our data show that the two polymorphisms are in linkage disequilibrium in the general population and in NTD individuals. There was no statistically significant difference in allele and genotype frequency between probands (patients, fetuses) and controls (P > 0.10) and between observed and expected values for mother–child pairs (P > 0.80). Taking into account gender, an increased rate of 677CT heterozygotes was found in affected and unaffected males compared to affected and unaffected females. A family-based association study using a multiallelic transmission disequilibrium test (TDT) also shows that transmission rates do not deviate significantly from equilibrium (P > 0.50). Thus, our data provide no evidence for an association between NTD phenotype and MTHFR 677C/T-1298A/C genotypes and haplotypes. Am. J. Med. Genet. 87:23–29, 1999. © 1999 Wiley-Liss, Inc.     

Complicaciones relacionadas con el cateterismo cardíaco pediátrico y cardiopatías congénitas

Introduction:

Congenital heart diseases are the most common congenital abnormalities in newborns with a prevalence of 1%. Therapeutic and diagnostic cardiac catheterization has revolutionized the treatment of these diseases; however, it can be associated with complications.

Objective:

To describe the incidence and type of complications associated with pediatric cardiac catheterization in a reference center for congenital heart defects.

Methodology:

Retrospective observational study, with analytical intention based on records of cardiac catheterization performed on patients with congenital and acquired heart disease.

Results:

2,688 records were included for nine consecutive years. 53.9% were men, 21.3% with ages between 2 and 5 years and 20.3% between 6 months and 2 years. 63.5% of the procedures were elective. The prevalence of complications in the first 24 hours after catheterization was 6.7% (4.2% minor and 2.4% major). Early death occurred in 0.8% of the procedures. Factors associated with complications were age at catheterization <28 days (OR 2.18, 95% CI ^[1.28-3.70]), precatheter oxygen saturation <79% (OR 2.15, 95% CI ^[1.02-4.53]), use of pre-catheter inotropics (OR 3.00, 95% CI ^[1.68-5.33]). The variables included in the model explain 38% of the variance of post-cardiac catheterization complications in patients younger than 18 years.

Discussion:

Cardiac catheterization is associated with major and minor complications including death. The associated factors were less than 28 days, lower oxygen saturation and use of pre-catheter inotropics.Key words: Complications, Cardiac catheterization, Child, Mortality, Incidence     

Role of clinicopathological variables in predicting recurrence and survival outcomes after surgery for non-metastatic renal cell carcinoma: Systematic review and meta-analysis

Renal cell carcinoma (RCC) represents 2% of all diagnosed malignancies worldwide, with disease recurrence affecting 20% to 40% of patients. Existing prognostic recurrence models based on clinicopathological features continue to be a subject of controversy. In this meta-analysis, we summarized research findings that explored the correlation between clinicopathological characteristics and post-surgery survival outcomes in non-metastatic RCC patients. Our analysis incorporates 99 publications spanning 140 568 patients. The study's main findings indicate that the following clinicopathological characteristics were associated with unfavorable survival outcomes: T stage, tumor grade, tumor size, lymph node involvement, tumor necrosis, sarcomatoid features, positive surgical margins (PSM), lymphovascular invasion (LVI), early recurrence, constitutional symptoms, poor performance status (PS), low hemoglobin level, high body-mass index (BMI), diabetes mellitus (DM) and hypertension. All of which emerged as predictors for poor recurrence-free survival (RFS) and cancer-specific survival. Clear cell (CC) subtype, urinary collecting system invasion (UCSI), capsular penetration, perinephric fat invasion, renal vein invasion (RVI) and increased C-reactive protein (CRP) were all associated with poor RFS. In contrast, age, sex, tumor laterality, nephrectomy type and approach had no impact on survival outcomes. As part of an additional analysis, we attempted to assess the association between these characteristics and late recurrences (relapses occurring more than 5 years after surgery). Nevertheless, we did not find any prediction capabilities for late disease recurrences among any of the features examined. Our findings highlight the prognostic significance of various clinicopathological characteristics potentially aiding in the identification of high-risk RCC patients and enhancing the development of more precise prediction models.     

Absence of serological evidence for foamy virus infection in patients with amyotrophic lateral sclerosis

Foamy virus (FV) infection has been implicated in the pathogenesis of sporadic motor neuron disease (MND) by means of serological assays. To confirm these results we tested serum and cerebrospinal fluid (CSF) samples from 23 cases of clinically verified non-familial MND and 11 cases of suspected non-familial MND for the presence of FV infection as determined by Western blot (WB) and indirect immunofluorescence assay (IFA). Using the same tests we also screened sera from 87 healthy chimpanzees for the presence of FV antibodies. None of the human samples in question tested positive. However, the testing revealed that 84 of 87 chimpanzees (96.6%) were seropositive for FV, indicating that combined WB and IFA are suitable methods for the serodiagnosis of FV infection. Given these results an association of FV infection and sporadic MND is highly improbable. Furthermore a suggested therapeutic trial with anti-retroviral drugs appears unjustified. © 1996 Wiley-Liss, Inc.     

Altered function of the glutamate–aspartate transporter GLAST,a potential therapeutic target in glioblastoma

In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate–aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST-expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST-depleted glioma. Despite their GLAST expression, GBM stem-like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+-ATPase. Overexpression of Na+/K+-ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH-101. In glioma-bearing mice, a single intratumoral injection of UCPH-101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target.