Trisomy 18/trisomy 13 mosaicism in an adult with profound mental retardation and multiple malformations

We report on an adult woman with profound mental retardation and multiple anomalies who consists of 3 cell lines: one with trisomy 18, one with trisomy 13, and a normal cell line. Her phenotype includes manifestations of both trisomy syndromes. The origin of these cell lines could have been a doubly aneuploid (48,XX+ 13, + 18) or singly aneuploid (47,XX + 18 or 47,XX, + 13) zygote with subsequent mitotic nondisjunctions, or a normal zygote with multiple mitotic nondisjunctions. There have been four previous reports of mosaicism involving both trisomy D and trisomy E; all died in the first six months of life. Two of these cases had a doubly aneuploid (48,XX, + D + E) cell line. Our patient illustrates the need for study of several tissues in patients with complex aneuploidy syndromes or atypical manifestations of a given syndrome (such as prolonged survival), as well as the need for caution in counseling families about prognosis for survival in autosomal trisomies which usually are lethal.     

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.Subject terms: Genetics research, Polycystic kidney disease, Genetic testing     

Calcium and neuronal cytoskeletal proteins: alterations with aging

Calcium plays a major role in regulating cellular function. Alterations in calcium systems may underlie some of the physiological changes associated with aging. Calcium activates calmodulin-dependent protein kinase, and this enzyme mediates some effects of calcium on cellular function. Calcium/calmodulin-dependent kinase II may play a significant role in specific cytoskeletal abnormalities of normal aging and selected neurodegenerative diseases.     

Mouse model of oral infection with virulent type A Francisella tularensis

Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Little is known about the immunopathogenesis of oral infection with this pathogen. Here, for the first time, we examined the susceptibility of mice to intragastric inoculation with virulent type A F. tularensis and characterized the course of infection and the associated host responses. Both immunocompetent and immunodeficient mice were relatively susceptible to intragastric inoculation of type A F. tularensis with a 50% lethal dose (LD(50)) of 10(6) organisms, which was 100,000-fold higher than the LD(100) for intradermal or respiratory routes of infection. Mice deficient in gamma interferon or tumor necrosis factor receptors 1 and 2 were more susceptible than wild-type controls to oral infection with a high dose of the pathogen. After oral inoculation, F. tularensis appeared first in the mesenteric lymph nodes (MLN) and then rapidly spread to the livers and spleens, where the organism multiplied to high numbers and induced marked neutrophilic infiltration and severe tissue necrosis. Infected mice showed rapid increases in tissue cytokine mRNA expression, which peaked in the MLN at 2 days postinfection (dpi) and in the liver and spleen at 3 dpi. The levels of gamma interferon, interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, KC, interferon-inducible protein 10, and monocyte chemotactic protein 1 were elevated from day 2 postinoculation onward. Moreover, mice intradermally immunized with the live vaccine strain of F. tularensis showed little survival advantage over naive mice after oral challenge with type A F. tularensis. These results suggest that type A F. tularensis is an effective oral pathogen that can cause fatal systemic infection and could pose a public health concern, particularly to immunocompromised individuals, if ingested in contaminated water and food.     

Three-dimensional internal mammary lymphoscintigraphy: implications for radiation therapy treatment planning for breast carcinoma

Conservative surgery combined with radiation therapy for the treatment of early breast carcinoma has been shown to achieve both a high rate of local tumor control and good cosmetic results with a minimum of complications. Whether the internal mammary lymph nodes (IMNs) should be included in the treatment volume is a topic of considerable controversy. Radionuclide internal mammary node lymphoscintigraphy (IMN-LS) can locate these nodes in three dimensions. We have analyzed the results of IMN-LS in 167 patients imaged at the Dana-Farber Cancer Institute and treated at the Joint Center for Radiation Therapy between 1977 and 1980. The location of the IMNs was found variable from patient to patient. At least one IMN was not included within tangential fields arbitrarily arranged to have a medial entrance point 3.0 cm across the midline in 17% of evaluable patients. However, 48% and 66% of patients had IMNs that could be adequately treated with fields positioned only 1.0 cm or 2.0 cm across midline, respectively. We conclude that when treatment of the IMNs is warranted, IMN-LS not only assures their complete coverage in the majority of patients but also may help reduce the amount of heart and lung irradiated.     

The effect of young age on tumor recurrence in the treated breast after conservative surgery and radiotherapy

Prognostic factors for local recurrence following conservative surgery and radiation therapy for patients with early breast cancer have not been fully established. To evaluate the importance of young age as a prognostic factor for local recurrence, we reviewed the results of treatment of 597 patients with 607 UICC-AJCC Stage I or II breast cancers, 47 of which were diagnosed when the patient was less than 35 years old. All were treated with excisional biopsy and a total dose to the site of the primary tumor of 60 Gy or more. The median follow-up in survivors was 63 months. Patient age and the presence of an extensive intraductal component (EIC) were both highly associated with the likelihood of tumor recurrence in the treated breast. Patients under 35 had an actuarial 5-year recurrence rate of 26%, compared to 10% for older patients (p = 0.002). Patients with an EIC had a breast recurrence rate of 25%, compared to 5% when EIC was absent (p less than 0.0001). Although the incidence of an EIC was higher in the younger subgroup (44% vs. 31%), this alone did not account for the difference in in breast recurrence rates, since younger patients had a higher recurrence rate than older patients even when an EIC was absent (22% vs. 3%, p = 0.0003). We conclude that the age of the patient is an important prognostic factor for local recurrence following conservative surgery and radiation therapy. This finding is in part attributed to the observation that younger women are more likely to have tumors with an EIC than older women, but even when an EIC is absent, they may be at an increased risk of local recurrence. However, caution is required in interpreting these findings with regard to selecting among treatment options until further data are available comparing the results of conservative surgery and radiation therapy to those of mastectomy in younger patients.     

开道散合扶正和胃合剂治疗上消化道癌性狭窄疗效观察

目的：观察开道散合扶正和胃合剂治疗上消化道癌性狭窄的临床疗效。方法：对40例患者采用口服开道散、扶正和胃合剂联合胃镜下癌灶内注射5-氟脲嘧啶注射液及鸦胆子乳剂方法治疗上消化道癌性狭窄。结果：治疗后无瘤灶消失病例,34例患者肿瘤缩小达50％以上,完全缓解0例,部分缓解34例,稳定4例,进展2例,有效率为85．0％。治疗后患者吞咽困难有了较明显的改善,显效7例,有效31例,无效2例,总有效率95．0％。治疗后所有患者的卡氏评分均有所升高,与治疗前比较,差异有显著性意义（P〈0．05）,提示治疗后患者的生活质量有所改善。结论：开道散合扶正和胃合剂治疗上消化道癌性狭窄疗效满意,能使实体瘤缩小、吞咽困难改善、生活质量提高。     

Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing,Perceptuomotor Speed,and Executive Functioning in Younger and Older Listeners

Journal of the Association for Research in Otolaryngology - Older adults typically have difficulty identifying speech that is temporally distorted, such as reverberant, accented, time-compressed,...