Rga (Rodgers) and the HLA Region: Linkage and Associations

In 19 families with 97 children the segregation of Rg^a (Rodgers) was found to be compatible with Mendelian inheritance and five backcross and 14 intercross families were found among HLA and Bf typed families. Close linkage (lods + 17.82) without recombination was found between Rg and the HLA region, with a direct count of 96 nonrecombinant meioses for Rg-HLA-B. Kg- was strongly associated with HLA-B8 (29 of 30 haplotypes) and probably associated with Bw40, but did occur on other HLA-B haplotypes. By inference.Rg^- is negatively associated with Ch^- (Chido). The Rg^-Ch^- haplotype has not been observed. Rg³ and Ch^a may or may not be coded for by different sites of the same cistron closely linked to HLA-B:C and cannot as yet be excluded from being parts of B or C.     

New catheter for endovascular interventional procedures

A new catheter suitable for selective angiography, embolization, and controlled infusion of chemotherapeutic agents is described. The catheter is made from a composite construction of polyethylene; it is graded in shaft thickness and outer diameter from a 2.7-F tip to a 3-F (1.0-mm) proximal section. Use of the catheter with a 0.018-inch or smaller steerable guide wire facilitates placement of the catheter in distal tortuous vessels. The catheter enabled successful completion of 20 of the 22 intracranial and extracranial intervention procedures (11 patients) in which it was used.     

Bladder injury in blunt pelvic trauma

Clinical and radiologic findings in 97 patients with bladder injury secondary to blunt pelvic trauma were reviewed. Fifty-five patients had extraperitoneal bladder rupture; 35, intraperitoneal rupture; two, interstitial bladder injury; and five, combined intraperitoneal and extraperitoneal bladder rupture. Of the 61 of 97 patients with film studies available for review, two patients with surgically proved intraperitoneal rupture had false-negative cystograms. In two other cases of intraperitoneal rupture, the diagnosis was established with cystography but was not demonstrated with urography. All cases of extraperitoneal rupture were demonstrated cystographically; in 15 cases in this group, the injury was complex, with extravasation of contrast material beyond the confines of the perivesical space. In two additional patients, incomplete bladder injury termed "interstitial bladder rupture" was identified. A classification of bladder injury based on cystographic patterns of extravasation is proposed.     

A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43)

We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.      

A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2

Type I and type II keratins form the heteropolymeric intermediate filament cytoskeleton, which is the main stress-bearing structure within epithelial cells. Pachyonychia congenita (PC) is a group of autosomal dominant disorders whose most prominent phenotype is hypertrophic nail dystrophy accompanied by other features of ectodermal dysplasia. It has been shown previously that mutations in either K16 or K6a, which form a keratin expression pair, produce the PC-1 variant (MIM 184510). Mutations in K17 alone, an unpaired accessory keratin, result in the PC-2 phenotype (MIM 184500). Here, we describe a family with PC-2 in which the K17 locus on 17q was excluded and linkage to the type II keratin locus on 12q was obtained (Z max 3.31 at straight theta = 0). Mutation analysis of candidate keratins revealed the first reported missense mutation in K6b, implying that this keratin is the previously unknown expression partner of K17, analogous to the K6a/K16 pair. Co-expression of these genes was confirmed by in situ hybridization and immunohistochemical staining. These results reveal the hitherto unknown role of the K6b isoform in epithelial biology, as well as genetic heterogeneity in PC-2.      

Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects

It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD.     

Comparative genome maps of the pangolin, hedgehog, sloth, anteater and human revealed by cross-species chromosome painting: further insight into the ancestral karyotype and genome evolution of eutherian mammals

To better understand the evolution of genome organization of eutherian mammals, comparative maps based on chromosome painting have been constructed between human and representative species of three eutherian orders: Xenarthra, Pholidota, and Eulipotyphla, as well as between representative species of the Carnivora and Pholidota. These maps demonstrate the conservation of such syntenic segment associations as HSA3/21, 4/8, 7/16, 12/22, 14/15 and 16/19 in Eulipotyphla, Pholidota and Xenarthra and thus further consolidate the notion that they form part of the ancestral karyotype of the eutherian mammals. Our study has revealed many potential ancestral syntenic associations of human chromosomal segments that serve to link the families as well as orders within the major superordinial eutherian clades defined by molecular markers. The HSA2/8 and 7/10 associations could be the cytogenetic signatures that unite the Xenarthrans, while the HSA1/19p could be a putative signature that links the Afrotheria and Xenarthra. But caution is required in the interpretation of apparently shared syntenic associations as detailed analyses also show examples of apparent convergent evolution that differ in breakpoints and extent of the involved segments.     

Balance of cell proliferation and apoptosis in breast carcinogenesis

We determined the mitotic and apoptotic index through the spectrum of preinvasive ductal breast lesions to invasive carcinoma in search of disturbances in the proliferation/cell death balance in breast carcinogenesis. Seventytwo pure preinvasive ductal breast lesions (without invasive carcinoma) and 103 invasive breast carcinomas were used. The numbers of mitotic and apoptotic cells were microscopically counted in hematoxylin and eosin stained sections (MI and Al, respectively), and the ratio of the values of MI and AI was calculated for each individual case (M/A index).A distinction was made between well differentiated and poorly differentiated breast lesions, based on histological type and nuclear grade, to arrive at two plausible progression models for breast carcinogenesis. For the well differentiated breast lesions, the MI was rather equal for hyperplasias and well differentiated DCIS, but increased 6fold from DCIS to well differentiated invasive carcinoma. The AI remained in the same range, resulting in a 4fold increase of the M/A index. For the poorly differentiated breast lesions, a significant increase in MI and AI was found from hyperplasia to poorly differentiated DCIS. From DCIS to poorly differentiated invasive carcinoma, the MI increased significantly and the AI decreased 2fold (n.s.), resulting in a 2.5fold significant increase of the M/A index.In conclusion, the net increase of the number of cells in the transition from well differentiated preinvasive to well differentiated invasive carcinoma is accompanied by an increase of cell proliferation rather than decrease in apoptosis, suggesting that in these lesions, proliferation related mechanisms are most important in carcinogenesis and progression. In contrast, in poorly differentiated breast lesions, decreased apoptosis seems to be also important in carcinogenesis and progression. At present, we are gathering patients with invasive breast cancer who had a previous biopsy with a preinvasive lesion to obtain further more direct evidence for this hypothesis.