Functional antagonism of different angiotensin II type I receptor blockers in human arteries

Objectives. To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type 1 receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries. Methods. Human internal mammary arteries were obtained as excess graft material during coronary bypass surgery. Vessels were prepared as rings and mounted in an organ bath in which vasoconstriction and -dilation can be measured. Concentration-response curves of angiotensin II-mediated vasoconstriction were measured in absence or presence of different concentrations of one of the ARBs. Results. Losartan showed a rightward shift of the angiotensin II-mediated vasoconstriction, whereas addition of its metabolite EXP 3174 caused a decrease of the maximal effect of angiotensin II. Incubation with valsartan and candesartan also resulted in a decrease of the maximal effect. The inhibiting effects on the angiotensin II-mediated vasoconstriction by the highest concentration of EXP 3174, valsartan and candesartan did not differ significantly. Conclusion. In human internal mammary arteries, losartan acts as a surmountable antagonist. On the other hand, EXP 3174, valsartan and candesartan demonstrate an insurmountable type of antagonism. Furthermore, the inhibiting effects of EXP 3174, valsartan and candesartan in our study are equal in the highest concentrations.     

A genome-wide search for linkage-disequilibrium with type 1 diabetes in a recent genetically isolated population from the Netherlands

Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24.     

Identification of novel mutations in classical galactosemia

Classical galactosemia is an autosomal recessive disorder of galactose metabolism due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Treatment through restriction of dietary galactose intake is lifesaving, but, in spite of this diet, most patients develop abnormalities. In this paper we report the mutational spectrum of classical galactosemia in a cohort of 123 Dutch patients, all with biochemically proven classical galactosemia. In the human GALT gene, which is located on chromosome 9p13, we identified 24 different mutations, including nine mutations that have not been reported previously. The novel mutations include five missense mutations (c.152G>A/p.R51Q, c.404C>T/p.S135W, c.687G>T/p.K229N, c.756G>T/p.Q252H, and c.1140A>C/p.X380C), a frame shift mutation (c.410dupT), a splice site mutation (c.821-2A>G), a possible branch point mutation (c.508-29delT), and a large deletion encompassing at least exons 1-11. Six of these novel mutations were found in patients of Dutch descent: p.R51Q, p.S135W, p.K229N, p.Q252H, p.X380C, and c.410dupT.     

Widespread transfer of resistance genes between bacterial species in an intensive care unit: implications for hospital epidemiology

A transferable plasmid encoding SHV-12 extended-spectrum beta-lactamase, TEM-116, and aminoglycoside resistance was responsible for two sequential clonal outbreaks of Enterobacter cloacae and Acinetobacter baumannii bacteria. A similar plasmid was present among isolates of four different bacterial species. Recognition of plasmid transfer is crucial for control of outbreaks of multidrug-resistant nosocomial pathogens.     

Thyroid cancer incidence near nuclear sites in Belgium: An ecological study at small geographical level

In Belgium, variations in thyroid cancer incidence were observed around the major nuclear sites. The present ecological study investigates whether there is an excess incidence of thyroid cancer among people living in the vicinity of the four nuclear sites at the smallest Belgian geographical level. Rate ratios were obtained from a Bayesian hierarchical model for areas of varying sizes around the nuclear sites. Focused hypothesis tests and generalized additive models were performed to test the hypothesis of a gradient in thyroid cancer incidence with increasing levels of surrogate exposures. No evidence was found for more incident cases of thyroid cancer near the two nuclear power plants. Regarding the two industrial and research nuclear sites, no evidence for a higher incidence in the vicinity of Mol-Dessel was observed, whereas a slightly nonsignificant higher incidence was found in the close vicinity of Fleurus. In addition, significant gradients for thyroid cancer incidence were observed with the different types of surrogate exposure considered in the 20 km area around the site of Fleurus (decreasing distance, increasing wind direction frequency and increasing exposure to estimated hypothetical radioactive discharges of iodine-131). In the investigation at the smallest Belgian geographical level, variations in thyroid cancer incidence were found around the Belgian nuclear sites. Significant exposure–response relationships were also observed for the site of Fleurus. Further investigations into these findings could be useful to allow inferring causal relationships on the origin of variations in incidence and to provide information at the individual level.     

Clear cell chondrosarcoma in Von Hippel-Lindau disease

Familial Cancer - A diagnosis of clear cell chondrosarcoma of the ulna was made in a patient with Von Hippel-Lindau disease (VHL). After surgery, genetic analysis of the tumor tissue showed loss of...     

Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q

PURPOSE: Three forms of idiopathic partial epilepsy with autosomal dominant inheritance have been described: (a) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); (b) autosomal dominant lateral temporal epilepsy (ADLTE) or partial epilepsy with auditory features (ADPEAF); and (c) familial partial epilepsy with variable foci (FPEVF). Here we describe linkage analysis in a Dutch four-generation family with epilepsy fulfilling criteria of both ADNFLE and FPEVF. METHODS: Clinical characteristics and results of EEG, computed tomography (CT), and magnetic resonance imaging (MRI) were evaluated in a family with autosomal dominantly inherited partial epilepsy with apparent incomplete penetrance. Linkage analysis was performed with markers of the ADNFLE (1p21, 15q24, 20q13.3) and FPEVF (2q, 22q11-q12) loci. RESULTS: Epilepsy was diagnosed in 10 relatives. Age at onset ranged from 3 months to 24 years. Seizures were mostly tonic, tonic-clonic, or hyperkinetic, with a wide variety in symptoms and severity. Most interictal EEGs showed no abnormalities, but some showed frontal, central, and/or temporal spikes and spike-wave complexes. From two patients, an ictal EEG was available, showing frontotemporal abnormalities in one and frontal and central abnormalities in the other. Linkage analysis with the known loci for ADNFLE and FPEVF revealed linkage to chromosome 22q in this family. CONCLUSIONS: The clinical characteristics of this family fulfilled criteria of both ADNFLE and FPEVF. The frequent occurrence of seizures during daytime and the observation of interictal EEG abnormalities originating from different cortical areas were more in agreement with FPEVF. The observed linkage to chromosome 22q supported the diagnosis of FPEVF and confirmed that this locus is responsible for this syndrome.     

Effects of multidose combination chemotherapy on the humoral immune system

Patients receiving multidose combination chemotherapy are at risk for severe, life-threatening infections, caused by among others encapsulated bacteria like Streptococcus pneumoniae. The splenic marginal zone is essential in the initiation of immune responses to S. pneumoniae. We analyzed effects of multidose combination chemotherapy on B-cell subpopulations. Immune response capacity was evaluated by using Pneumovax (PPS) or Tetavax (TT) as antigenic challenge. Three days after finishing therapy, all B-cell subpopulations in bone marrow and spleen were severely reduced, including the mature marginal zone B-cell population. When analyzing the anti-PPS immune response capacity at 3 days after finishing therapy, we found that the IgM antibody levels did not differ significantly from control immunized rats. The IgG antibody levels were significantly lower compared to control immunized rats but still significantly higher compared to unimmunized rats. The depletion of marginal zone B cells by multidose combination chemotherapy most likely contributes to the prolonged period that patients are at risk for developing severe infections after chemotherapy, despite the capacity to generate sufficient antibody levels. It is conceivable that the local (temporary) loss of immunological memory, together with the supposed inability to generate a humoral response in a short time frame, plays an important role in this vulnerability.     

Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions

Familial hemiplegic migraine (FHM) is a rare, severe, autosomal dominant subtype of migraine with aura. Up to 75% of FHM families have a mutation in the P/Q-type calcium channel Ca(v)2.1 subunit CACNA1A gene on chromosome 19p13. Some CACNA1A mutations also may cause epilepsy. Here, we describe novel missense mutations in the ATP1A2 Na(+),K(+)-ATPase pump gene on chromosome 1q23 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q mutation was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate. In this family, all available affected family members with FHM, benign familial infantile convulsions, or both, carry the ATP1A2 mutation. Like FHM linked to 19p13, FHM linked to 1q23 also involves dysfunction of ion transportation and epilepsy is part of its phenotypic spectrum.