Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the Pax-3 paired domain and homeodomain

The Pax-3 protein contains two DNA-binding domains, a paired domain and a homeodomain. Mutations in Pax-3 cause Waardenburg syndrome (WS) in humans and the mouse Splotch (Sp) phenotype. In the Sp-delayed mouse, a mutation in the Pax-3 paired domain (G9R) abrogates the DNA-binding activity of both the paired domain and the homeodomain, suggesting that they may functionally interact. To investigate this possibility further, we have analyzed the DNA-binding properties of additional point mutants in the Pax-3 paired domain and homeodomain that occur in WS patients (F12L, N14H, G15S, P17L, R23L, G48A, S51F and G66D in the paired domain, V47F and R53G in the homeodomain), the Pax-1 un mutation (G15A) and a substitution associated with Peters' anomaly in the PAX-6 gene (R23G). Within the paired domain, seven of 10 mutations were found to abrogate DNA-binding by the paired domain. Remarkably, these seven mutations also affected DNA binding by the homeodomain, causing either a complete loss (P17L and G66D), a reduction (R23G, R23L, G15S and G15A) or an increase in DNA-binding activity (N14H). In addition, the effect of paired domain mutations occurred at the level of monomer formation by the homeodomain, while the dimerization potential of this domain seemed unaffected in mutants where it could be analyzed. Furthermore, while both homeodomain mutations were found to abolish DNA binding by this domain, the R53G mutation also abrogated DNA binding by the paired domain. The important observation that independent mutations in either domain can affect DNA binding by the other in the intact Pax- 3 protein strongly suggests that the two domains are not functionally independent but bind DNA through cooperative interactions. Modeling the deleterlous mutations on the three-dimensional structure of the paired domain of Drosophila Prd shows that these mutations cluster at the DNA interface, thus suggesting that a series of DNA contacts are essential for DNA binding by both the paired domain and the homeodomain of Pax-3.      

Validating self-reported strokes in a longitudinal UK cohort study (Whitehall II): Extracting information from hospital medical records versus the Hospital Episode Statistics database

Background

Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome.

Discussion

In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists.

Summary

The use of quantiles is often inadequate for epidemiologic research with continuous variables.     

左腋动脉和臂丛神经走行变异1例

笔者在标本解剖操作观察腋窝结构时发现1例左侧腋动脉与臂丛神经位置及走行出现变异,既往文献报道的变异多为腋动脉发出的分支与臂丛神经之间的位置与走行之间变异^[1-3],本次解剖观察发现腋动脉与臂丛神经的内侧束、外侧束和后束之间的位置关系出现变异,与既往报道有所不同,现报告如下。     

Does preoperative needle localization lead to an increase in local breast cancer recurrence?

Between 1978 and 1981, 74 women with nonpalpable breast cancer underwent surgery after localization guides were placed. In 72 patients, guides were introduced parallel to the chest wall; in two the needle was positioned anteroposteriorly under computed tomographic guidance. Fifty-six cases (76%) were infiltrating cancer; 13 (17%), intraductal cancers; two (3%), inflammatory; and three (4%), lobular carcinoma in situ. Surgery was not used to treat the latter five patients. In the remaining 69 women, 42 (61%) were treated by means of modified radical mastectomy; six (9%), total mastectomy; 12 (17%), local excision and radiation therapy; and seven (10%), local excision alone; exact therapy for two women (3%) was unknown. At a minimum follow-up of 5 years, none of the 67 women in whom the parallel approach was used had a local recurrence. The authors conclude that preoperative placement of guides parallel to the chest wall does not appear to increase the risk of local breast cancer recurrence.     

Asbestos-related focal lung masses: manifestations on conventional and high-resolution CT scans

In 260 asbestos-exposed individuals evaluated by means of computed tomography (CT), 43 unsuspected pulmonary masses were found in 27 individuals. The masses included fissural pleural plaques (n = 10), dense fibrotic bands (n = 3), round atelectasis (n = 11), carcinomas (n = 3), and other presumed benign masses (n = 16). The most helpful features in the diagnosis of rounded atelectasis with CT were (a) contiguity to areas of diffuse pleural thickening, (b) a lentiform or wedge-shaped outline, (c) evidence of volume loss in the adjacent lung, and (d) a characteristic "comet tail" of vessels and bronchi sweeping into the margins of the mass. Less advanced areas of focal atelectasis had fewer classic features. Intrafissural pleural plaques were readily identified with high-resolution CT. In asbestos-related masses, the demonstration of stability over time is necessary. Careful interpretation of CT and high-resolution CT features and close surveillance can obviate the need for biopsy in the majority of instances.     

MR氢质子波谱成像在神经上皮组织肿瘤分级中的应用

目的研究MR氢质子波谱（^1H-MRS）成像在神经上皮组织肿瘤分级中的价值。方法52例颅内神经上皮组织肿瘤患者，低级别29例，高级别23例，均行MRI及^1H-MRS检查。结果52例中，Ⅱ级9例，Ⅲ级11例，Ⅳ级12例，将Ⅱ级列为低级别组，Ⅲ级、Ⅳ级为高级别组，脂质（Lip）[乳酸（Lac）]／肌酸（Cr）、Lip（Lac）／N-乙酰天门冬氨酸（NAA）、Lip（Lac）／胆碱化合物（Cho），Lip（Lac）在组间差异有统计学意义，低级别组各代谢物比值中位数分别为0．14、0．16、0．09、0．32，高级别组各代谢物中位数分别为1．64、1．24、0．87、1．68。Lip（Lac）／Cr≤0．425为低级别肿瘤，Lip（1ac）／Cr＞0．425为高级别肿瘤，诊断敏感度、特异度、阳性予测值、阴性预测值分别为87．0％、96．6％、95.2％、90．3％。常规MR图像诊断肿瘤级别敏感度、特异度、阳性予测值、阴性预测值分别为87．0％、82．8％、80．0％、88．9％。结论^1H-MRS在神经上皮组织肿瘤分级中有一定的价值，常规MR图像结合MRS可明显提高诊断准确率。     

急性非淋巴细胞性白血病细胞共刺激分子的表达

目的：检测急性非淋巴细胞白血病患者白血病细胞表面MHC—Ⅱ类分子和共刺激分子的表达情况。方法：采集骨髓中白血病细胞大于70％的27例初诊或复发息者骨髓细胞。荧光抗体标记。应用流式细胞仪进行HLA—DR、CD80(B7-1)和CI)和(B7—2)免疫标记检测。结果：27例病人除M3型表达明显低于其他各型外。HLA—DR抗原的表达均较高。其中M2型最高为90％；CD80阳性率很低，最高为M1型只有5％。其余均在l％～3％之间。CD86的表达高于CD80，最高为M5型为48％，最低为M6型为11％。结论：白血病细胞表面共刺激分子表达以CD80缺乏为主。     

Multiple cerebral metastases: detectability with Gd-DTPA-enhanced MR imaging

Sixteen patients with suspected cerebral metastases were studied with magnetic resonance (MR) imaging before and after the intravenous administration of 0.1 mmol/kg of gadolinium diethylenetriaminepenta-acetic acid. The images were interpreted blindly by two neuroradiologists; all clinical, radiologic (computed tomographic and MR imaging), and pathologic data were reviewed to arrive at a final "best diagnosis," which was then compared with the prior blinded interpretations. Of seven patients found to have multiple metastases, six (86%) had at least one tumor nodule depicted by postinfusion MR imaging that was missed by one or both observers on review of preinfusion images alone. Lesions missed on preinfusion studies were usually small nodules hidden by or not detected next to regions of high-signal edema thought to be related to the adjacent tumor nodule. The authors believe that contrast enhancement improves detection of metastatic foci with MR imaging and that the findings indicate broader implications for the detection of multiple lesions from other causes.