Somatic mutation of bcl-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia

Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated V(H) genes consistent with a naive B cell, and the other with mutated V(H) genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5' noncoding region of the bcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in V(H) and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated V(H) genes, with 4 of 10 cases clearly showing mutations in bcl-6. In those CLLs defined by somatically mutated V(H) genes, 4 of 9 cases predictively showed bcl-6 mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of V(H) genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the V(H) and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.     

Endoluminal reconstruction of the arterial wall with endothelial cell/glue matrix reduces restenosis in an atherosclerotic rabbit

OBJECTIVES: The objectives of this study were 1) to improve the attachment of reimplanted endothelial cells (EC) using a fibrin glue, and 2) to assess the impact of endothelial reseeding on restenosis eight weeks after balloon angioplasty. BACKGROUND: A possible mechanism contributing to restenosis after balloon angioplasty is the loss of the EC lining. Previous attempts to reseed EC had little effect due to rapid loss of the seeded cells. METHODS: Twelve atherosclerotic rabbits were subjected to angioplasty of iliac arteries and reseeding procedure. One iliac artery was subjected to EC/glue reconstruction and a contralateral site to EC seeding without glue. The animals were sacrificed after 4 h. In another series 12 rabbits were treated in the same fashion and were restudied at eight weeks. Additionally, in 10 animals one iliac was subjected to glue treatment, and another served as control. RESULTS: Histological examination demonstrated the ability of this method to reattach the EC/glue matrix circumferentially to 68.0 +/- 6.7% of the arterial wall in comparison with 13.5 +/- 3.9% reattachment after EC seeding. Morphometry at eight weeks showed that the lumen area was significantly greater in the EC/glue group (1.23 +/- 0.35 mm2) than in the EC seeding alone (0.65 +/- 0.02 mm2) and 0.72 +/- 0.41 mm2 in the glue group. This was principally accounted for by the statistically significant differences in the intimal area (0.76 +/- 0.18 mm vs. 1.25 +/-0.26 mm2 and 1.01 +/- 0.53 mm2, respectively). CONCLUSIONS: The attachment of EC after angioplasty can be greatly improved with fibrin glue matrix. The near 70% endothelial coverage achieved by this method resulted in a significant reduction of restenosis in atherosclerotic rabbit.     

Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a population-based study of African Americans

A significant interaction among total serum cholesterol (TC), APOE genotype, and AD risk was found in a population-based study of elderly African Americans. Increasing TC was associated with increased AD risk in the group with no epsilon4 alleles, whereas TC was not associated with increased AD risk in the group with one or more epsilon4 alleles. Further study of the relationship between cholesterol and APOE genotype is needed to confirm this association, but the results suggest that cholesterol may be a potentially modifiable environmental risk factor for AD.     

Outcome of 1355 consecutive transabdominal chorionic villus samplings in 1351 patients

Mipdre-tnriamtaels tdeirag naomsntiicoc epnrotecseidsur ies th arou wghell -wehstiacbhli sfheteadl samples are retrieved for chromosomal or genetic studies· The major disadvantage of amniocentesis is that the result is usually available after 18 weeks of gestation·Early amniocentesis before 14 weeks has been shown to be associated with a significantly higher fetal loss rate and therefore should no longer be practiced·1On the other hand, first trimester transabdominal chorionic villus sampli…     

Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity

BACKGROUND: Osteopontin (OPN) is reported to have two distinct functions in kidney disease: Promotion of inflammation at sites of tissue injury, and inhibition of calcium oxalate monohydrate stone formation. However, many of the studies supporting these functions were carried out in animal models of acute renal injury or in cultured cells; thus, the role of OPN in chronic renal disease is not well defined. We examined the role of OPN in adenine phosphoribosyltransferase (Aprt) knockout mice, in which inflammation and formation of 2,8-dihydroxyadenine (DHA) kidney stones are prominent features, by generating Aprt/Opn double knockout mice. METHODS: We characterized the phenotypes of six- and 12-week-old Aprt-/- Opn-/-, Aprt-/- Opn+/+, Aprt+/+ Opn-/-, and Aprt+/+ Opn+/+ male and female mice using biochemical, histologic, immunohistochemical, and in situ hybridization techniques. RESULTS: At 6 weeks of age, there was no difference in phenotype between double knockout and Aprt knockout mice. At 12 weeks, there was increased adenine and DHA excretion, renal crystal deposition, and inflammation in double knockout versus Aprt knockout male mice. Double knockout and Aprt knockout female mice at 12 weeks had less pathology than their male counterparts, but kidneys from double knockout females showed more inflammation compared with Aprt knockout females; both genotypes had similar levels of DHA crystal deposition. CONCLUSION: We conclude that (1) OPN is a major inhibitor of DHA crystal deposition and inflammation in male mice; and (2) OPN is a major modifier of the inflammatory response but not of crystal deposition in female mice. Thus, separate mechanisms appear responsible for the tissue changes seen in DKO males versus females.     

Impact of hypertensive disorders of pregnancy at term on infant birth weight

This study was performed to investigate the impact of hypertensive disorders of pregnancy at term on neonatal birth weight. All singleton live births delivered between 37 and 42 weeks of gestation complicated by hypertensive disorders over a 7-year period (n = 362) was compared to 34 783 uncomplicated singleton deliveries in the same period. The individualized gestation-related optimal weight (GROW) was calculated for each individual case adjusted for the effects of maternal booking weight, height, parity, gestation at delivery, and fetal sex. Small-for-gestational-age (SGA) was defined as a birth weight less than the 10th percentile of the GROW. The incidence of SGA babies was significantly higher in subjects with preeclampsia and eclampsia than in control subjects (24.6 versus 11.3%; odds ratio = 2.55; 95% CI: 1.84, 3.55). Preeclampsia significantly reduced fetal birth weight by 130 g or 4.3%. Those with eclampsia on average had a neonatal birth weight 349 g or 11.0% below that of the GROW. In contrast, there was no significant difference in the incidence of SGA babies or degree of deviation from GROW between those with or without gestational hypertension.     

External cephalic version induced fetal cerebral and umbilical blood flow changes are related to the amount of pressure exerted

OBJECTIVE: To correlate the applied pressure during external cephalic version with the changes in fetal middle cerebral arterial and umbilical arterial flow before and after the procedure. DESIGN: A prospective observational study over a two-year period. SETTING: External cephalic version was performed in a university hospital. POPULATION: Sixty-nine women with singleton breech-presenting pregnancy at or above 36 weeks of gestation undergoing external cephalic version. METHODS: During external cephalic version, the operator wore a pair of pressure-sensing gloves which had thin piezo-resistive sensors positioned on the palmar surface. During each version procedure, real-time pressure readings were recorded from all sensors, and then analysed with a computer program. The amount of pressure applied over time was presented by pressure-time integral. The pulsatility indices of both fetal middle cerebral artery and umbilical artery before and after external cephalic version were measured. The changes of pulsatility indices of both middle cerebral artery and umbilical artery were presented as a ratio of the post-external cephalic version pulsatility indices to pre-external cephalic version pulsatility indices, denoted by middle cerebral artery pulsatility index ratio and umbilical artery pulsatility index ratio, respectively. The statistical correlation between pressure-time integral and middle cerebral artery pulsatility index ratio and umbilical artery pulsatility index ratio are analysed using Pearson's correlation test. MAIN OUTCOME MEASURES: Changes in pulsatility indices of fetal middle cerebral and umbilical arteries and fetal heart rate after external cephalic version. RESULTS: The overall success rate of external cephalic version was 77%. There was a significant negative correlation between pressure-time integral and both middle cerebral artery pulsatility index ratio (P= 0.001) and umbilical artery pulsatility index ratio (P= 0.012). When women were categorised according to placental site, pressure-time integral was negatively correlated with middle cerebral artery pulsatility index ratio only when the placenta was posteriorly located (P= 0.003), and with umbilical artery pulsatility index ratio only when the placenta was laterally located (P= 0.03). CONCLUSIONS: The greater the force applied during external cephalic version, the greater the reduction in pulsatility indices of middle cerebral artery and umbilical artery, indicating an increase in blood flow through these arteries. The increase in cerebral blood flow after external cephalic version is more prominent when the placenta is lying posteriorly, while the increase in umbilical flow is more prominent when the placenta is lying laterally. These findings suggest that the vascular changes probably represent a direct effect of force exerted on the fetal head and the placenta.