Migration of murine intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation

Initiation of adaptive immunity to particulate antigens in lymph nodes largely depends on their presentation by migratory dendritic cells (DCs). DC subsets differ in their capacity to induce specific types of immunity, allowing subset-specific DC-targeting to influence vaccination and therapy outcomes. Faithful drug design, however, requires exact understanding of subset-specific versus global activation mechanisms. cDC1, the subset of DCs that excel in supporting immunity toward viruses, intracellular bacteria, and tumors, express uniquely high levels of the pattern recognition receptor TLR3. Using various murine genetic models, we show here that both, the cDC1 and cDC2 subsets of cDCs are activated and migrate equally well in response to TLR3 stimulation in a cell extrinsic and TNF-α dependent manner, but that cDC1 show a unique requirement for type I interferon signaling. Our findings reveal common and differing pathways regulating DC subset migration, offering important insights for the design of DC-based vaccination and therapy approaches.     

Sex differences in symptomatology of psychosis-risk patients and in prediction of psychosis

Archives of Women's Mental Health - Sex differences may be important for understanding underlying pathophysiological mechanisms and developing effective preventions and treatments of mental...     

Allorecognition of HLA-DP by CD4+ T cells is affected by polymorphism in its alpha chain

Alloreactivity to HLA-DP molecules, class II heterodimers of an oligomorphic alpha and a polymorphic beta chain, is increasingly being studied due to its relevance in clinical transplantation. We hypothesized that not only polymorphisms in the peptide binding groove encoded by exon 2 of HLA-DPB1, but also in other regions of the molecule and the alpha chain, could play a role in CD4+ T cell allorecognition. To test this possibility, we comparatively investigated CD4+ T cell allorecognition, measured by upregulation of the activation marker CD137, against HLA-DPB1*13:01, *05:01, *03:01, *17:01 or their allele counter parts DPB1*107:01, *135:01, *104:01, *131:01, with identical exon 2 sequences but polymorphism in exons 1, 3 or 4, in the context of different HLA-DPA1 (DPA1) polymorphisms (DPA1*01:03 and *02:01). No significant differences in CD4+ T cell allorecognition levels could be demonstrated for any of the beyond exon 2 DPB1 variants studied. Interestingly, however, the mean fold change in CD4+ CD137+ cells was significantly higher when the target shared at least one DPA1 allele with the allogeneic stimulator, compared to a distinct DPA1 background (1.65 vs 0.23, P < 0.005). Structural homology modeling suggested specific amino acid residues in the alpha chain, in particular position 31, to impact CD4+ T cell allorecognition of HLA-DP. Our data argue against a significant role of beyond exon 2 DPB1 polymorphisms for T cell alloreactivity, but show relevance of DPA1 polymorphism in this mechanism. These new findings impact HLA matching strategies in unrelated stem cell transplantation.     

Is there a need for orthodontic plaque indices?—diagnostic accuracy of four plaque indices

Objectives

The aim of this study was to assess the diagnostic performance and accuracy of four plaque indices for orthodontic patients.

Materials and methods

The plaque accumulation of 140 maxillary incisors with bonded brackets was recorded using intra-oral photographs and assessed using four different plaque indices: the orthodontic plaque (OP) index, the modified orthodontic plaque (MOP) index, the Quigley and Hein (QHP) index and the modified Navy plaque (MNP) index. The assessment was performed twice within a time interval of 4 weeks by four different examiner groups: orthodontists, dentists, students and orthodontic assistants.

Results

No significant differences were detected for the OP and MOP indices among the examiner groups. A significant difference was found for the QHP and MNP indices. The inter- and intra-examiner reliability of the OP and MOP indices was good. In contrast, the reliability for the QHP and MNP indices was moderate to poor with few exceptions. The discrimination performance of the OP and MOP indices was excellent. The sum of the sensitivity and specificity was generally lower for the QHP and MNP indices compared with the OP and MOP indices.

Conclusion

OP and MOP indices showed good performance. The QHP and MNP indices are not appropriate for orthodontic purposes.

Clinical relevance

Traditional plaque indices reflect the typical pattern of plaque accumulation for patients without multi-bracket appliances. The performance of these indices for orthodontic patients has never been investigated. Orthodontic plaque indices that focus on the surface along the gingival margin and areas around the bracket exhibit higher diagnostic performance and accuracy compared with traditional indices.     

Invasive Breast Carcinoma with Neuroendocrine Differentiation: A Single-Center Analysis of Clinical Features and Prognosis

Introduction Invasive breast cancer with neuroendocrine differentiation is a rare subtype of breast malignancy. Due to frequent changes in the definition of these lesions, the correct diagnosis, estimation of exact prevalence, and clinical behaviour of this entity may be challenging. The aim of this study was to evaluate the prevalence, clinical features, and outcomes in a large cohort of patients with breast cancer with neuroendocrine differentiation. Patients Twenty-seven cases of breast cancer with neuroendocrine differentiation have been included in this analysis. Twenty-one cases were identified by systematic immunohistochemical re-evaluation of 465 breast cancer specimens using the neuroendocrine markers chromogranin A and synaptophysin, resulting in a prevalence of 4.5%. A further six cases were identified by a review of clinical records. Results Median age at the time of diagnosis was 61 years. 70% of patients had T2 – 4 tumors and 37% were node-positive. The most common immunohistochemical subtype was HR-positive/HER2-negative (85%). 93% were positive for synaptophysin and 48% for chromogranin A. Somatostatin receptor type 2A status was positive in 12 of 24 analyzed tumors (50%). Neuroendocrine-specific treatment with somatostatin analogues was administered in two patients. The 5-year survival rate was 70%. Conclusions Breast cancer with neuroendocrine differentiation is mostly HR-positive/HER2-negative and the diagnosis is made at a higher TNM stage than in patients with conventional invasive breast carcinoma. Moreover, breast cancer with neuroendocrine differentiation was found to be associated with impaired prognosis in several retrospective trials. Due to somatostatin receptor 2A expression, somatostatin receptor-based imaging can be used and somatostatin receptor-targeted therapy can be offered in selected cases. Key words: neuroendocrine neoplasia of the breast, invasive breast cancer with neuroendocrine differentiation, neuroendocrine breast cancer, neuroendocrine markers, somatostatin receptor 2A     

Clinical utility of postprocessed low-dose radiographs in skeletal imaging

Objectives:Radiography remains the mainstay of diagnostic and follow-up imaging. In view of the risks and the increasing use of ionizing radiation, dose reduction is a key issue for research and development. The introduction of digital radiography and the associated access to image postprocessing have opened up new opportunities to minimize the radiation dosage. These advances are contingent upon quality controls to ensure adequate image detail and maintenance of diagnostic confidence. The purpose of this study was to investigate the clinical applicability of postprocessed low-dose images in skeletal radiography.Methods:In our study setting, the median radiation dose for full dose X-rays was 9.61 dGy*cm2 for pelvis, 1.20 dGy*cm2 for shoulder and 18.64 dGy*cm2 for lumbar spine exams. Based on these values, we obtained 200 radiographs for each anatomic region in four consecutive steps, gradually reducing the dose to 84%, 71%, 60% and 50% of the baseline using an automatic exposure control (AEC). 549 patients were enrolled for a total of 600 images. All X-rays were postprocessed with a spatial noise reduction algorithm. Two radiologists assessed the diagnostic value of the radiographs by rating the visualization of anatomical landmarks and image elements on a five-point Likert scale. A mean-sum score was calculated by averaging the two reader’s total scores. Given the non-parametric distribution, we used the Mann-Whitney U test to evaluate the scores.Results:Median dosage at full dose accounted for 38.4%, 48 and 53.2% of the German reference dose area product for shoulder, pelvis and lumbar spine, respectively. The applied radiation was incrementally reduced to 21.5%, 18.4% and 18.7% of the respective reference value for shoulder, pelvis and lumbar spine. Throughout the study, we observed an estimable tendency of superior quality at higher dosage in overall image quality. Statistically significant differences in image quality were restricted to the 50% dose groups in shoulder and lumbar spine images. Regardless of the applied dosage, 598 out of 600 images were of sufficient diagnostic value.Conclusion:In digital radiography image postprocessing allows for extensive reduction of radiation dosage. Despite a trend of superior image detail at higher dose levels, overall quality and, more importantly, diagnostic utility of low-dose images was not significantly affected. Therefore, our results not only confirm the clinical utility of postprocessed low-dose radiographs, but also suggest a widespread deployment of this advanced technology to ensure further dose limitations in clinical practice.Advances in knowledge:The diagnostic image quality of postprocessed skeletal radiographs is not significantly impaired even after extensive dose reduction by up to 20% of the reference value.