Treatment with a proton pump inhibitor improves glycaemic control in type 2 diabetic patients - a retrospective analysis

We retrospectively studied whether treatment with esomeprazole improved HbA?(c) levels in type 2 diabetic patients. We selected 21 patients who had been treated with esomeprazole for 11 ± 3 months and 21 controls. HbA?(c) levels decreased in the esomeprazole-treated group. Our data indicate that proton pump inhibitors may improve glycaemic control in type 2 diabetic patients.     

Comparison of microarray-based RNA expression with ELISA-based protein determination of HER2, uPA and PAI-1 in tumour tissue of patients with breast cancer and relation to outcome

Purpose  

Prognostic and predictive markers in breast cancer are currently determined by single analysis of protein amounts. If RNA-based multi-gene analyses enter clinical practice, simultaneous determination of currently established markers like human epidermal growth factor receptor 2 (HER2), urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) would represent an elegant simplification. To investigate the correlation between RNA and protein levels, we assessed HER2, uPA and PAI-1 in patients with breast cancer. In addition, we evaluated the influence of these factors on patient outcome.     

Thymosin ��4 has tumor suppressive effects and its decreased expression results in poor prognosis and decreased survival in multiple myeloma

Thymosin β4 (Tβ4) is a polypeptide involved in cellular proliferation, differentiation, and migration, over-expressed in several tumor entities. We evaluated its expression and function in 298 newly diagnosed multiple myeloma patients and the murine 5TMM model. Mean Tβ4 expression was significantly lower in myeloma cells compared to normal plasma cells (P<0.001). The same observation can be made in the 5TMM-mouse model by qRT-PCR and ELISA. Here, Tβ4 overexpression by lentiviral transduction of 5T33MMvt-cells led to significantly decreased proliferative and migratory capacities and increased sensitivity to apoptosis-induction. Mice injected with Tβ4 over-expressing myeloma cells showed a longer survival compared to mice injected with controls (88,9 vs. 65,9 days, P<0.05). In 209 MM patients treated with high-dose therapy and autologous stem cell transplantation, expression of Tβ4 below the median was associated with a significantly shorter event free survival (37.6 vs. 26.2 months, P<0.05). In conclusion, our results indicate a possible tumor suppressive function of Tβ4.     

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Background

Numerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, two such subsets with “stereotyped” B-cell receptors were recently identified, i.e. subset #4 (IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients appear to share biological and clinical features, e.g. young age at diagnosis and indolent disease, whereas little is known about subset #16 at a clinical level.

Design and Methods

We investigated the global gene expression pattern in sorted chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients using Affymetrix gene expression arrays.

Results

Although generally few differences were found when comparing subset to non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed for subset #4 versus subset #16. The differentially expressed genes, predominantly with lower expression in subset #4 patients, are involved in important cell regulatory pathways including cell-cycle control, proliferation and immune response, which may partly explain the low-proliferative disease observed in subset #4 patients.

Conclusions

Our novel data demonstrate distinct gene expression profiles among patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence for biological differences in the pathogenesis of these subsets and underscoring the functional relevance of subset assignment based on B-cell receptor sequence features.     

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

Background

Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.

Design and Methods

We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.

Results

All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8⁺ T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.

Conclusions

Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.     

The diagnostic performance of APC–PCI complex determination compared to <Emphasis Type="SmallCaps">d</Emphasis>-dimer in the diagnosis of deep vein thrombosis

d-dimer testing is widely used as part of the diagnostic algorithm for the exclusion of deep vein thrombosis (DVT) but is considered of limited in value for ruling DVT in. Since d-dimers are poorly defined, there is no standardization of the assays and this makes reliable comparisons between clinical studies difficult. We report on a performance evaluation of a new marker of activated coagulation (Activated Protein-C in complex with Protein-C inhibitor, APC–PCI complex) compared to two quantitative d-dimer assays (Vidas^®d-dimer Exclusion?and Autodimer^®). The post-hoc comparison was made on 350 frozen plasma samples from consecutive outpatients suspected of DVT in a multicenter management study including clinical probability score, d-dimer testing, venous ultrasound and contrast venography as part of the diagnostic algorithm. Results: The APC–PCI complex performed inferior to the d-dimer assays in terms of sensitivity: 74 vs. >93%, negative predictive value: 91 vs. >96% and area under the curve: 0.82 vs. 0.9, but showed a significantly higher specificity: 80 vs. 40–60%. Specificity for the APC–PCI complex did not decrease with higher clinical probability score and the positive predictive value was significantly higher than that of the d-dimer assays in the intermediate/high probability cohort (66 vs. <52%). In this probability cohort, high levels of the APC–PCI complex and to a lesser extent, d-dimers, can give positive predictive values of >90% in up to 20% of the patients which indicates important clinical implications. However, for the exclusion of DVT at the pre-specified cut-off level, the APC–PCI complex perform inferior to the d-dimer assays in this study.     

Current standards in the treatment of breast cancer

Breast cancer is the most frequent malignoma in female individuals: more than 10 out 100 females suffer from the disease. The understanding of breast cancer as a primarily local disease has undergone a fundamental change in the last few decades. While throughout most of the previous century breast cancer was still mainly conceived of as a predominantly local disease, the radical nature of surgery can now be reduced to a minimum by the use of breast conserving procedures and axillary sentinel lymph node excision. The systemic use of cytostatic and endocrine therapeutic modalities has simultaneously provided a major overall survival benefit for patients treated in accordance with current therapeutic standards. The multidisciplinary treatment challenge of breast cancer comprises nowadays surgery, systemic treatment and radiotherapy and aims to a more individualized therapy.     

Controlled release of chlorhexidine antiseptic from microporous amorphous silica applied in open porosity of an implant surface

Amorphous microporous silica (AMS) serving as a reservoir for controlled release of a bioactive agent was applied in the open porosity of a titanium coating on a Ti-6Al-4V metal substrate. The pores of the AMS emptied by calcination were loaded with chlorhexidine diacetate (CHX) via incipient wetness impregnation with CHX solution, followed by solvent evaporation. Using this CHX loaded AMS system on titanium substrate sustained release of CHX into physiological medium was obtained over a 10 day-period. CHX released from the AMS coating was demonstrated to be effective in killing planktonic cultures of the human pathogens Candida albicans and Staphylococcus epidermidis. This surface modification of titanium bodies with AMS controlled release functionality for a bioactive compound potentially can be applied on dental and orthopaedic implants to abate implant-associated microbial infection.     

Mayo clinical Text Analysis and Knowledge Extraction System (cTAKES): architecture,component evaluation and applications

We aim to build and evaluate an open-source natural language processing system for information extraction from electronic medical record clinical free-text. We describe and evaluate our system, the clinical Text Analysis and Knowledge Extraction System (cTAKES), released open-source at http://www.ohnlp.org. The cTAKES builds on existing open-source technologies—the Unstructured Information Management Architecture framework and OpenNLP natural language processing toolkit. Its components, specifically trained for the clinical domain, create rich linguistic and semantic annotations. Performance of individual components: sentence boundary detector accuracy=0.949; tokenizer accuracy=0.949; part-of-speech tagger accuracy=0.936; shallow parser F-score=0.924; named entity recognizer and system-level evaluation F-score=0.715 for exact and 0.824 for overlapping spans, and accuracy for concept mapping, negation, and status attributes for exact and overlapping spans of 0.957, 0.943, 0.859, and 0.580, 0.939, and 0.839, respectively. Overall performance is discussed against five applications. The cTAKES annotations are the foundation for methods and modules for higher-level semantic processing of clinical free-text.