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11.
Diagnosis of chronic Q fever is difficult. PCR and culture lack sensitivity; hence, diagnosis relies mainly on serologic tests using an immunofluorescence assay (IFA). Optimal phase I IgG cutoff titers are debated but are estimated to be between 1:800 and 1:1,600. In patients with proven, probable, or possible chronic Q fever, we studied phase I IgG antibody titers at the time of positive blood PCR, at diagnosis, and at peak levels during chronic Q fever. We evaluated 200 patients, of whom 93 (46.5%) had proven, 51 (25.5%) had probable, and 56 (28.0%) had possible chronic Q fever. Sixty-five percent of proven cases had positive Coxiella burnetii PCR results for blood, which was associated with high phase I IgG. Median phase I IgG titers at diagnosis and peak titers in patients with proven chronic Q fever were significantly higher than those for patients with probable and possible chronic Q fever. The positive predictive values for proven chronic Q fever, compared to possible chronic Q fever, at titers 1:1,024, 1:2,048, 1:4,096, and ≥1:8,192 were 62.2%, 66.7%, 76.5%, and ≥86.2%, respectively. However, sensitivity dropped to <60% when cutoff titers of ≥1:8,192 were used. Although our study demonstrated a strong association between high phase I IgG titers and proven chronic Q fever, increasing the current diagnostic phase I IgG cutoff to >1:1,024 is not recommended due to increased false-negative findings (sensitivity < 60%) and the high morbidity and mortality of untreated chronic Q fever. Our study emphasizes that serologic results are not diagnostic on their own but should always be interpreted in combination with clinical parameters.  相似文献   
12.
We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis.  相似文献   
13.
Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in five probands with ADCL features and found five de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5), and c.2124del25 (CL-6). Four probands (CL-1,-2,-3,-6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF-β) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF-β signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis.  相似文献   
14.
Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin‐fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter‐laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next‐generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.  相似文献   
15.

Background

Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs).

Methods

A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry.

Results

Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53 = 58, CDKN2A(p16) = 14, HRAS = 10, PIK3CA = 7, PPP2R1A = 3, KRAS = 1, PTEN = 1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P = .035), with a large effect from patients carrying HRAS-mutations.

Conclusion

Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.  相似文献   
16.
17.
The goal of this study was to examine to what extent the conditions of restricted input of L2 and SLI have an additive impact on language acquisition. Therefore, the Dutch language achievement of 6-, 7-, and 8-year-old bilingual children with SLI was compared with that of typically developing monolingual Dutch children, typically developing bilingual children, and monolingual Dutch children with SLI. Assuming that speaking a language in varying environments involves distinct subskills that can be acquired in differential patterns, the achievement of phonological, lexical, morphosyntactic and textual abilities were assessed separately. For each of these abilities, it was determined to what extent the conditions of restricted input (first vs. second language) and language deficit (typically developing vs. SLI) cause stagnation or a delay in language acquisition. Bilingual children with SLI perform at a lower level than the other groups in almost all aspects of achievement in Dutch. For language tasks related to the mental lexicon and grammar, an additional disadvantage was evidenced as a result of the combination of learning Dutch as second language and having SLI.  相似文献   
18.
19.
Background: Patients with rheumatoid arthritis face the challenge of adjusting to adverse health consequences and accompanying emotions. Styles of emotion regulation may affect health.Purpose: The objective is to examine associations between styles of emotion regulation and perceived health, consisting of psychological well-being, social functioning, physical functioning, and disease activity.Methods: Principal component analysis was used to summarize styles of emotion regulation of 335 patients with rheumatoid arthritis. Relationships between emotion regulation and perceived health were examined with structural equation modeling.Results: Four styles of emotion regulation were identified: ambiguity, control, orientation, and expression. Ambiguity and control were mutually correlated, as were orientation and expression. Styles of emotion regulation were not uniquely related to perceived physical functioning and disease activity. Emotional ambiguity and orientation were related to poorer, whereas expression and control were related to more favorable psychological well-being and social functioning.Conclusions: Our cross-sectional study suggests that emotion regulation is not of direct importance for perceived somatic health of patients with rheumatoid arthritis, but it may be of importance for psychological well-being and social functioning, and perhaps through this route for somatic health. The more conscious and controlled aspects of control and expression are positively related to psychosocial health, and the more unconscious automatic aspects of ambiguity and orientation are negatively related. Changing emotion regulation will potentially affect psychosocial health. It would be worthwhile to verify this possibility in prospective research. This study was financially supported by the Dutch Arthritis Association. We thank all rheumatologists and rheumatology nurses of the Arthritis Research Foundation Utrecht (SRU) for recruitment of participants. We also thank Bert Garssen and the reviewers and editor of this journal for their valuable comments and suggestions on previous drafts of the article.  相似文献   
20.
PURPOSE: Recognition of hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial carcinoma from sporadic carcinoma by histologic features as compared with colonic cases. STUDY DESIGN: Case-control study. METHODS AND MATERIALS: From the files of the Nijmegen Hereditary Cancer Clinic, HNPCC-related (n = 6) endometrial and colorectal (n = 18) carcinomas were selected. For every HNPCC-related tumor, 2 sporadic control cases were included. The tumors were evaluated for the following 7 pathologic features: tumor differentiation, T-stage, growth pattern, presence of Crohn-like lymphoid reaction, mucinous differentiation, presence of lymphangioinvasive growth, and the amount of tumor-infiltrating lymphocytes. RESULTS: HNPCC-related endometrial carcinomas were significantly more often poorly differentiated (83% versus 27%), more often showed the presence of a Crohn-like lymphoid reaction (100% versus 13%) and lymphangioinvasive growth (67% versus 0%), and high number of tumor-infiltrating lymphocytes were more often present (100% versus 36%) compared with sporadic endometrial carcinomas. The differences between HNPCC and sporadic colorectal cancer specimens were less discriminating. CONCLUSIONS: HNPCC-related endometrial carcinomas are characterized by poor differentiation, more frequent Crohn-like lymphoid reaction, lymphangioinvasive growth and more tumor-infiltrating lymphocytes. These features therefore might form the basis for selecting patients for counseling in a hereditary cancer clinic or testing for microsatellite instability or mutation analysis of mismatch repair genes, especially when they are of relatively young age.  相似文献   
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