PLP1 gene analysis in 88 patients with leukodystrophy

Pelizaeus–Merzbacher disease (PMD) is caused in most cases by either duplications or point mutations in the PLP1 gene. This disease, a dysmyelinating disorder affecting mainly the central nervous system, has a wide clinical spectrum and its causing mutations act through different molecular mechanisms. Eighty‐eight male patients with leukodystrophy were studied. PLP1 gene analysis was performed by the Multiplex Ligation‐dependent Probe Amplification technique and DNA sequencing, and, in duplicated cases of PLP1, gene dosage was completed by using array‐CGH. We have identified 21 patients with mutations in the PLP1 gene, including duplications, short and large deletions and several point mutations in our cohort. A customized array‐CGH at the Xq22.2 area identified several complex rearrangements within the PLP1 gene region. Mutations found in the PLP1 gene are the cause of PMD in around 20% of the patients in this series.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

Influence of spatial information on responses of tonically active neurons in the monkey striatum

Previous studies have demonstrated that tonically active neurons (TANs) in the primate striatum play an important role in the detection of rewarding events. However, the influence of the spatial features of stimuli or actions required to obtain reward remains unclear. Here, we examined the activity of TANs in the striatum of monkeys trained to make spatially directed movements elicited by visual stimuli presented ipsilaterally or contralaterally to the moving arm. Among 181 neurons responding to the trigger stimulus, 127 (70%) were nonselective for stimulus location and 54 (30%) responded to only one location of the stimulus. Most of the selective responses (63%) occurred when the stimulus was presented contralaterally to the moving arm. To examine whether TAN responses are related to the location of the stimulus or to the direction of the movement, we tested a subset of the trigger-responsive neurons (n = 44) in a condition that elicited reaching toward or away from the stimulus. By comparing TAN activity between the two conditions, we found that half of the responses can be interpreted as being related to the location of the stimulus, one quarter to the direction of movement, and one quarter to the context in which stimulus-movement combination occurs. These results demonstrate that TANs are not limited to motivational processing, but may play a role in the processing of spatial attributes of stimulus and/or movement as well. These response properties suggest that TANs are involved in the flexible shifting of motor responses during spatially directed behavior.     

WHO生存质量评估简表的等价性评价

目的评价WHO生存质量评估简表(WHOQOL-BREF)在13个国家的等价性。方法采用多组验证性因子分析方法,对世界卫生组织生存质量研究小组提供的13个国家的数据进行分析,评价WHOQOL-BREF不同国家的等价性。结果各个国家的各个领域的Cronbachα系数均大于0·7,分布在0·7至0·88之间。除了英国和挪威之外,其它国家的社会关系领域的Cronbachα系数均大于0·65。采用根据世界卫生组织生存质量研究小组研制量表时构建的四因子模型对数据分别进行拟合,拟合优度指数(CFI)均大于0·8,其中德国、西班牙和美国的拟合优度指数大于0·9。多组验证性因子分析发现模型拟合尚可,CFI等于0·88,各个国家的因子负荷不全相等,因子负荷的轮廓相似。结论WHOQOL-BREF在13个国家具有相同的因子结构,且有等价性。     

Overview and update on molecular testing in non-small cell lung carcinoma utilizing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples

Lung carcinoma remains one of the most frequent and aggressive human neoplasms. Fortunately, in the last decades, the increasing knowledge of the molecular mechanisms leading to cancer development has allowed the use of targeted therapies with improvement of prognosis in many patients. Clinical management has also changed after the introduction of endobronchialultrasonographic bronchoscopy that allows a conservative staging of lung tumors, avoiding the need of mediastinoscopy for lymph node staging. Lung pathologists and cytopathologists are facing the challenge of giving the more comprehensive prognostic and predictive information with ever smaller tissue or cytological samples. The aim of this review is to summarize the molecular testing for non-small cell lung carcinoma and how pathologists can contribute to the patient's outcome with a conscious management of biological samples.     

Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis

Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized "good-risk" patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the "good-risk" children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for "good-risk" patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.     

Hysteroscopic Findings in Women With Menorrhagia

Study ObjectiveTo describe the hysteroscopic findings in patients complaining of menorrhagia to establish any significant association between menorrhagia and benign/malignant intrauterine disorders.DesignProspective cohort study (Canadian Task Force classification II).SettingUniversity La Sapienza, Rome, Italy.PatientsOne hundred eighteen premenopausal women undergoing office hysteroscopy for menorrhagia (group A) and 344 premenopausal patients undergoing office hysteroscopy for other indications (noncyclic abnormal uterine bleeding, infertility, ultrasonographic abnormalities, etc) (group B).InterventionsOffice hysteroscopy.Measurement and Main ResultsData on the prevalence of hysteroscopic findings (cervical polyps, endometrial polyps, submucous myomas, low-grade hyperplasia and high-grade hyperplasia/endometrial carcinoma) were compared between group A and group B. The total prevalence, as well as the prevalence of type 0 and type I myomas (totally or >50% intracavitary, respectively), and the mean number per patients with submucous myomas was significantly higher in group A compared with group B (p = .0001, p = .024, and p = .017, respectively). Multivariable logistic regression analysis showed a statistically significant association between age (odds ratio 4.15, 95% confidence interval 1.55–11.1 in the 40- to 49-year age group), presence of submucous myomas (odds ratio 2.76, 95% confidence interval 1.52–5.00), and menorrhagia.ConclusionsMenorrhagia seems to be associated with aging, the presence and number of submucous myomas, and with the degree of their intracavitary development.