A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects

We analysed a Dutch family with autosomal dominant non-syndromic progressive sensorineural hearing loss and mapped the underlying gene defect by genetic linkage analysis to a 11.0 cM region overlapping the DFNA9 interval on chromosome 14q12-q13. Clinically, the Dutch family differs from the original DFNA9 family by a later age at onset and a more clearly established vestibular impairment. A gene that is highly and specifically expressed in the human fetal cochlea and vestibule, COCH (previously described as Coch5B2 ), was mapped to the DFNA9 critical region. Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals. The same mutation was also identified in three apparently unrelated families with a similar phenotype, suggesting the presence of a Dutch founder mutation. The function of COCH is unknown but several characteristics of the protein point to a structural role in the extracellular matrix. The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins.      

异型缝隙连接通道和磷酸化对心脏缝隙连接的调变

目的 检测由缝隙连接蛋白(connexin，Cx)43和Cx45组成的多种异型缝隙连接通道(her—eromultimeric gap junction channels，HGJC)和磷酸化对缝隙连接(gap junction，GJ)的调变作用。方法 将转染了编码为Cx43或Cx45的DNA后的Hela细胞放置在一起共同培养组成双侧和单侧异型GJ通道。显微注射若丹明123(rhodamine123，Rh)检测经200nmol／L十四(烷)酰佛波醇乙酸酯(12-0-tetrade—canoylphorbol-13-acetae，TPA)处理前后，在紫外光显示下由Cx43和Cx45所组成的不同GJ通道对荧光染料的偶联率(coupling ratio)。结果 在不同的GJ中，同型GJ通道Cx43(homotypie Cx43，HoCx43)偶联率最高。从Cx45侧注入荧光染料的单侧异型GJ通道45(mono-heteromeric Cx45-Cx43／45，MH45)偶联率较之从Cx43／45侧注入荧光染料的MH45、双侧异型GJ通道Cx43／45(bi-heteromeric Cx43／45，BH43／45)及同型GJ通道Cx45(homotypic Cx45，HoCx45)等的偶联率是最低的。根据HoCx43或HoCx45通道的偶联率对各型通道偶联率进行标准化处理。BH43／45和MH43通道的偶联率均较HoCx43降低。对MH45通道来说，从Cx43／45侧注射的通道偶联率大于从Cx45侧注射的偶联率。TPA处理后HoCx43的偶联率降低，而当Cx43和Cx45组合成BH43／45和MH43通道后其偶联率下降更显著。结论 Cx43和Cx45共同表达可构成BH43／45、MH43和MH45等异型通道，而这些通道可降低细胞间的通讯并对磷酸化的作用不敏感。单侧异型GJ通道的偶联率取决于染料注射的方向。     

Temporary suppression of Kidd system antigen expression accompanied by transient production of anti-Jk3

This report describes an 85-year-old woman of Russian Jewish extraction whose red cell Kidd system phenotype changed during the 2 years in which her blood was studied. Certainly once, and perhaps twice, the patient's phenotype changed from Jk(a+b-) to Jk(a-b-). On both occasions, it reverted to Jk(a+b-). During the first episode of loss of Jka, she formed anti-Jk3. Although this antibody was weak, it was capable of in vivo destruction of Jk(a+b-) and Jk(a-b+) red cells. A lack of details about the patient's clinical condition precludes speculation as to the cause of suppression of Jka expression. The phenomenon appeared to affect only the Kidd blood group system. This case should alert others that antigen loss can occur in the Kidd system as it has been shown to occur in, at least, the Rh, Kell, and Ge systems.     

云南红豆杉抗肿瘤活性成分的研究

云南红豆杉(Taxus yunnanensis Cheng et L.K.Fu)树皮的乙醇提取物显示较强的抗肿瘤活性,从中分离得到8个紫杉烷类二萜及其生物碱。经光谱分析和化学反应鉴定7个已知物为taxinine E(1),taxinine J(2),1-acetoxy-5-deacetvl baccatin Ⅰ(4),baccatin Ⅲ(5),taxol(6),cephalomannine(7)和7-xylosyl-10-deacetyl taxol(8)。化合物3命名为云南红豆杉甲素(ymlnanxane),为一新的紫杉烷二萜化合物,其结构为taxa-4(20),11-diene-2α,5α,10β,14β-tetraol-2α,5α,10β-triacetate-14β-αmethyl-β-hydroxyl butyrate,并通过X-射线单晶衍射予以证实.经体外筛迭化合物3具有抗肿瘤活性。     

Temporomandibular joint: correlation between single-contrast videoarthrography and postmortem morphology

Arthrography of the temporomandibular joint is widely performed in clinical practice. The diagnostic accuracy of this technique has not been systematically evaluated. Therefore, findings from transcranial single-contrast, lower-compartment videoarthrography of 58 temporomandibular joint autopsy specimens were correlated with postmortem morphology. Arthrographic diagnosis of disk position and perforation was confirmed in 47 joints (81%). Misinterpretations were made in 11 joints; nine concerned disk position and two concerned perforation. Analysis of the misinterpretations revealed that inability of arthrography to allow differentiation of lateral from medial resulted in four false-negative diagnoses and one false-positive diagnosis. Variation of joint anatomy with disk deformation resulted in four false-positive diagnoses of anterior disk position. The number of false diagnoses in clinical practice might be reduced if transcranial single-contrast, lower-compartment videoarthrography is followed by multilayer arthrotomography in cases with an unclear diagnosis.     

Coronoid process hyperplasia: CT studies

Coronoid process hyperplasia is a disorder that causes restricted jaw movement due to enlargement of the coronoid process of the mandible, which impinges on the zygomatic arch with mouth opening. The cause is unclear. Computed tomographic (CT) findings in three patients with this disorder (two bilateral, one unilateral)--including a 3-year-old boy who may be the youngest patient with this disorder ever reported--include an enlarged coronoid process, with sclerosis and erosion of the zygomatic arch. CT is an effective and rapid method for establishing the diagnosis.     

von Hippel-Lindau disease: inadequacy of angiography for identification of renal cancers

Selective renal angiograms were retrospectively evaluated for the identification of renal cell cancers in patients with von Hippel-Lindau disease (VHL). Seven patients underwent angiography and surgery because of solid or complex renal masses identified at cross-sectional imaging. Nine kidneys underwent detailed examination by the surgeon and by a pathologist. There were 31 renal cancers. Angiography had enabled identification of only five cancers (16%), and six others (19%) had been suspected. Cancers detected angiographically were larger than those not detected (P less than .05). Solid tumors tended to appear less hypervascular than expected and occasionally had the angiographic appearance of atypical cysts. There were no false-positive angiograms. Angiography revealed only one cancer not previously suspected and changed the surgeon's approach for only one kidney (11%). The sensitivity and specificity of angiography were 35% and 100%, respectively. In these patients, selective renal angiography is not helpful for the detection or exclusion of cancer in a kidney. It does not have a limited role for vascular mapping prior to partial nephrectomy or tumor enucleation.     

Are phase I studies without drug level determination acceptable?

Summary— Among the main objectives of phase I studies, the definition of the safety profile of the new drug, its pharmacodynamic profile and the relationship between doses, concentrations and effects can be cited. The definition of these correlations is of paramount importance not only for a correct choice of the dose and dosing intervals in patients, but also for a more rational evaluation of the possible risk/benefit ratio at a clinical level. It is hence evident that drug level determination is a "necessary" step during phase I studies in volunteers. These concepts are discussed, with particular emphasis on the possible acceptability of phase I studies without drug level determination.     

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