Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age > 65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene for late-onset AD.      

Evidence for an increased release of proteolytic activity by the eutopic endometrial tissue in women with endometriosis and for involvement of matrix metalloproteinase-9

BACKGROUND: For the implantation of endometrium in ectopic locations, remodelling of the extracellular matrix (ECM) is necessary. Many studies have shown an increased expression of various proteases in the ectopic endometrium of women with endometriosis. Few, however, have addressed possible changes in protease expression in the eutopic endometrium. METHODS AND RESULTS: Herein, we reveal an increased release of proteolytic activity by the eutopic endometrium of women with endometriosis compared with normal women (P < 0.01). Using zymography and western blotting, we identified matrix metalloproteinase (MMP)-2 and MMP-9 in the culture medium, and further found that MMP-9 secretion, as assessed by zymography and enzyme-linked immunosorbent assay (ELISA), was elevated in women with endometriosis compared with normal women (P < 0.05). No statistically significant difference in MMP-2 secretion between women with and without endometriosis was noted. However, a significant difference in the levels of the tissue inhibitor of metalloproteinases (TIMP)-1, a known MMP-9 inhibitor, was found (P < 0.05). CONCLUSION: The endometriosis-associated increase in proteolysis and imbalance between the secretion of MMP-9 and that of its natural inhibitor, TIMP-1, revealed in the culture medium of endometrial tissue may reflect in vivo the enhanced capacity of this tissue to break down the ECM in host tissues, thereby favouring its ectopic implantation and development.     

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.      

Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21- hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.      

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

ABSTRACT: BACKGROUND: Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved. METHODS: We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990--2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation. RESULTS: A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein. CONCLUSION: We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.     

Patterns of femoral head migration in osteoarthritis of the hip: a reappraisal with CT and pathologic correlation

Although medial, superior, and axial patterns of migration of the femoral head in osteoarthritis of the hip have been well described, it is not clear what anatomic and biomechanical factors determine the direction of migration. The authors studied 22 patients with bilateral (11 patients) or unilateral (11 patients) osteoarthritis by means of conventional radiography and computed tomography (CT) to define any relationships between migration in the coronal plane and that in the transverse plane and to determine whether femoral anteversion, acetabular anteversion, femoral neck-shaft angle, or acetabular inclination were related to particular migration patterns. Anterior migration was evident in 14 of the 19 hips with a superior migration pattern, whereas posterior migration was present in five of the seven hips with a medial migration pattern. In the remainder of cases, no migration in the transverse plane was present. Femoral anteversion as determined with CT, femoral neck-shaft angle, angle of acetabular inclination, and acetabular anteversion angle in this relatively small sample were all found to be within normal limits and appeared to have no influence on the occurrence of a specific pattern of femoral head migration.     

Urokinase in gastrointestinal tract bleeding

Selective urokinase infusion into the superior mesenteric artery allowed the accurate determination of the site of small bowel bleeding in a patient with recurrent lower gastrointestinal bleeding who bled despite resective surgery and who had negative findings on four angiograms. Fibrinolytic agents are useful in rare cases in which the need for successful and accurate diagnosis outweighs the risks of reactivating the bleeding.     

Peribursal fat plane of the shoulder: anatomic study and clinical experience

A comprehensive anatomic and radiographic analysis of the peribursal fat plane in 12 cadavers confirmed that the fat plane seen on radiographs represents extrasynovial fat lining the subacromial bursa and documented the anatomic relations of the bursa. A three-part retrospective clinical evaluation of rotator cuff tears, calcific tendinitis, and rheumatoid arthritis was performed. Two osteoradiologists blindly graded the appearance of the peribursal fat plane with the shoulder in external versus internal rotation in 21 patients with arthrographically intact rotator cuffs and 21 patients with disrupted rotator cuffs. The peribursal fat plane was seen better with disrupted rotator cuffs. The peribursal fat plane was seen better with the shoulder in internal rotation and was seen in 60% of control subjects but only 21% of patients with rotator cuff tears. Partial or complete obliteration of this fat plane is a sensitive (79%) but less specific (60%) indicator of rotator cuff tears. Obliteration of the peribursal fat plane by inflammatory processes in adjacent tissues, including calcific tendinitis and rheumatoid arthritis, occurred with a high frequency.     

Multiphasic examinations of the stomach: efficacy of individual techniques and combinations of techniques in detecting 153 lesions

Multiphasic examinations of 153 gastric abnormalities observed radiologically and endoscopically were reviewed to determine the efficacy of four radiologic techniques and of several common combinations of these techniques for examining the stomach. There were 68 gastric ulcers, 12 ulcer scars, 44 cases of gastritis including 27 with erosions, 24 benign neoplasms, and five malignancies. Double-contrast, compression, mucosal relief, and full-column techniques detected 82%, 65%, 62%, and 51%, respectively, of all lesions diagnosed with the complete multiphasic examinations. Results indicate that the greater the number of techniques employed, the more accurate the examination, with biphasic and multiphasic examinations detecting 9%-18% more lesions overall than simple single- or double-contrast studies.