Transitional changes in the structure of C-reactive protein create highly pro-inflammatory molecules: Therapeutic implications for cardiovascular diseases.

C-reactive protein (CRP) is the prototypic acute-phase reactant that has long been recognized almost exclusively as a marker of inflammation and predictor of cardiovascular risk. However, accumulating evidence indicates that CRP is also a direct pathogenic pro-inflammatory mediator in atherosclerosis and cardiovascular diseases. The 'CRP system' consists of at least two protein conformations with distinct pathophysiological functions. The binding of the native, pentameric CRP (pCRP) to activated cell membranes leads to a conformational change resulting in two highly pro-inflammatory isoforms, pCRP* and monomeric CRP (mCRP). The deposition of these pro-inflammatory isoforms has been shown to aggravate the localized tissue injury in a broad range of pathological conditions including atherosclerosis and thrombosis, myocardial infarction, and stroke. Here, we review recent findings on how these structural changes contribute to the inflammatory response and discuss the transitional changes in the structure of CRP as a novel therapeutic target in cardiovascular diseases and overshooting inflammation.

Evaluation of the Suprafascial Thin ALT Flap in Foot and Ankle Reconstruction.

BACKGROUND: Distal lower extremity reconstruction can be challenging in terms of flap design. Bulky flaps result in limited mobility accompanied with the need of customized footwear. Raising the ALT-flap in a superficial fascial plane (thin ALT-flap) can be beneficial. This study evaluates thin ALT-flaps for lower distal extremity reconstruction. METHODS: In a retrospective study, patients that underwent microvascular extremity reconstruction at the level of the ankle and dorsal foot at the University of Freiburg from 2008-2018 were reviewed. RESULTS: 95 patients could be included in the study (35 perforator flaps, 8 fascia flaps and 54 muscle flaps).Among the perforator flaps, 21 ALT-flaps were elevated conventionally and 14 in the superficial fascial plane (thin ALT-flap). Among the conventional ALT-flaps, there was one flap loss (5%) and one successful revision (5%). 5(24%) flaps received secondary thinning. 57%(n = 12) were able to wear conventional footwear. There were 2(15%) successful revisions of thin ALT-flaps. 100% of thin ALT-flaps survived and 85%(n = 11) of the patients wore ordinary footwear after defect coverage.Among fascial flaps, 50%(n = 4) had to be revised with 2(25%) complete and 1 (13%) partial flap loss. All patients achieved mobility in ordinary shoes (n = 8).In muscle flaps, there were 7(13%) revisions and 5(9%) flap losses. 5(9%) flaps received secondary thinning. Only 33%(n = 18) were mobile in ordinary footwear. CONCLUSION: The thin ALT-flap is a save one-stage evolution for lower distal extremity reconstruction with a favorable flap survival rate. Compared with conventional ALT-flaps it might be beneficial in reducing the need for expensive custom fitted shoes and secondary thinning procedures.

Whole blood miRNA expression analysis reveals miR-3613-3p as a potential biomarker for dedifferentiated liposarcoma.

BACKGROUND: Liposarcoma constitute about 13% of all soft tissue sarcoma and are associated with a high risk of metastases. As the preoperative differentiation between benign and malign lipomatous tumors is restricted to magnetic resonance imaging, computed tomography and biopsy, we performed a miRNA array to distinguish dedifferentiated liposarcoma patients from healthy controls and lipoma patients. METHODS: Blood samples of patients with dedifferentiated liposarcoma, healthy controls and lipoma patients were collected. Whole blood RNA was extracted and samples of patients with dedifferentiated liposarcoma (n= 6) and of healthy donors (n= 4) were analyzed using an Affymetrix GeneChip miRNA Array v. 4.0. qRT-PCR was carried out to confirm the most differentially expressed miRNA; being further analyzed in an independent cohort of healthy controls as well as in lipoma patients. RESULTS: As shown by the microarray, two miRNAs (miR-3613-3p, miR-4668-5p) were shown to be significantly upregulated (fold change: > 2.5; p< 0.05) in patients with dedifferentiated liposarcoma (n= 6) as compared to healthy controls (n= 4). miR-3613-3p was further validated by qRT-PCR to be significantly upregulated in dedifferentiated liposarcoma patients compared to an independent cohort of healthy controls (n= 3) and lipoma patients (n= 5). CONCLUSION: We identified a specific whole blood miRNA (miR-3613-3p) that may serve to distinguish between dedifferentiated liposarcoma patients and healthy controls, thus potentially serving as a specific biomarker for dedifferentiated liposarcoma.

Levels of activated platelet-derived microvesicles in patients with soft tissue sarcoma correlate with an increased risk of venous thromboembolism.

BACKGROUND: Microvesicles are small vesicles expressing specific antigens from their cells of origin. Elevated levels of microvesicles have been shown to be associated with coagulation disorders as well as with different types of malignancies. This study aims to evaluate a possible correlation of different microvesicle subpopulations with a positive history of venous thromboembolism (VTE) in patients with soft tissue sarcoma. METHODS: Annexin V - positive microvesicles, leukocyte (CD45-positive), platelet (CD61-positive), activated platelet (CD62P-, CD63-positive), endothelium-derived (CD62E-positive) and tissue-factor (CD142-positive) microvesicles were identified in the peripheral blood of patients with soft tissue sarcoma (n = 39) and healthy controls (n = 17) using fluorescence-activated cell sorting (FACS). RESULTS: Both the total amount of Annexin V-positive microvesicles and levels of endothelium-derived (CD62E-positive) microvesicles were shown to decrease significantly after tumor resection (n = 18, p = 0.0395 and p = 0.0109, respectively). Furthermore, the total amount of Annexin V - positive microvesicles as well as leukocyte (CD45-positive) and endothelium-derived (CD62E-positive) microvesicles were significantly higher in patients with grade 3 (G3) soft tissue sarcoma (n = 9) compared to healthy controls (n = 17) (p = 0.0304, p = 0.0254 and p = 0.0357, respectively). Moreover, patients with G3 soft tissue sarcoma (n = 9) presented higher levels of Annexin V-positive and endothelium-derived (CD62E-positive) microvesicles compared to patients with grade 2 (G2) soft tissue sarcoma (n = 8) (p = 0.0483 and p = 0.0045). Patients with grade 1 (G1) soft tissue sarcoma (n = 3) presented with significantly lower levels of platelet (CD61-positive) microvesicles than patients with G3 soft tissue sarcoma (n = 9) (p = 0.0150). In patients with a positive history of VTE (n = 11), significantly higher levels of activated platelet (CD62P- and CD63-positive) microvesicles (p = 0.0078 and p = 0.0450, respectively) were found compared to patients without a history of VTE (n = 28). CONCLUSION: We found significantly higher levels of Annexin V-positive and endothelium-derived (CD62E-positive) microvesicles to be circulating in the peripheral blood of patients with G3 soft tissue sarcoma compared to patients with G2 soft tissue sarcoma. Furthermore, we showed that high counts of activated platelet-derived microvesicles correlate with the occurrence of VTE. Thus, the detection of these microvesicles might be an interesting new tool for early diagnosis of soft tissue sarcoma patients with increased risk for VTE, possibly facilitating VTE prevention by earlier use of thromboprophylaxis.

Synovial Sarcoma Microvesicles Harbor the SYT-SSX Fusion Gene Transcript: Comparison of Different Methods of Detection and Implications in Biomarker Research.

Background. Synovial sarcoma is an aggressive soft-tissue malignancy. This study examines the presence of the SYT-SSX fusion transcript in synovial sarcoma microvesicles as well as its potential role as a biomarker for synovial sarcoma. Patients and Methods. Microvesicle release of synovial sarcoma cells was examined by transmission electron microscopy. RNA-content was analyzed by qPCR, nested PCR, nested qPCR, and droplet digital PCR to compare their sensitivity for detection of the SYT-SSX fusion gene transcript. Whole blood RNA, RNA of mononuclear cells, and microvesicle RNA of synovial sarcoma patients were analyzed for the presence of the fusion gene transcripts. Results. Electron microscopic analysis revealed synovial sarcoma cells releasing membrane-enclosed microvesicles. In vitro, the SYT-SSX fusion gene transcript was detected in both synovial sarcoma cells and microvesicles. Nested qPCR proved to be the most sensitive in detecting the SYT-SSX fusion gene mRNA. In contrast, the fusion gene transcript was not detected in peripheral blood cells and microvesicles of synovial sarcoma patients. Conclusion. Synovial sarcoma cells release microvesicles harboring the SYT-SSX fusion transcript. Nested qPCR proved to be the most sensitive in detecting the SYT-SSX fusion gene mRNA; however, more sensitive assays are needed to detect cancer-specific microvesicles in the peripheral blood of cancer patients.

Impact of increasing age on breast reduction surgery: A single centre analysis.

BACKGROUND: Women with hypertrophic breasts suffer for physical and psychological reasons. Breast reduction surgery is a safe procedure that can effectively improve symptoms and quality of life. As most studies have been performed in younger women, little is known about complications and long-term patient satisfaction in elderly women. PATIENTS AND METHODS: We analysed complication rates and patient satisfaction in women aged 60 years and older who underwent a bilateral reduction mammaplasty. Patient satisfaction was measured with a validated questionnaire (client satisfaction questionnaire (CSQ)-8). The results obtained were compared to those of a control group including women aged 35 years and younger. RESULTS: Twenty-five women met the inclusion criteria in each group. The mean age in the elderly and young was 65.4 and 23.4 years, respectively. Older women had more comorbidities (35 vs. 9, p < 0.05). The average overall resection weight was 1684.4 g with slightly lower resection weights in younger women (1541 vs. 1828 g; p = 0.34). Eight women in the young group and 11 in the elderly developed minor complications (p = 0.56). Two women in the young group had major complications. Patient satisfaction was significantly higher in older women, with a mean score of 27.3 in the young and 30.3 in the elderly (maximum score of CSQ-8: 32, p < 0.05). CONCLUSIONS: Age is not a contraindication for reduction mammaplasty. Breast reduction surgery is a safe procedure in elderly women and leads to even higher patient satisfaction. Level of evidence: IV.

Comparison of the Rubin dermal suspension sutures and total parenchymal reshaping technique with a traditional inverted T-scar reduction mammaplasty technique using a superior pedicle.

UNLABELLED: Adipose patients, especially after massive weight loss, pose a challenge to the breast surgeon due to the major loss of volume and the inelasticity of the skin. Rubin described a suitable mammaplasty technique for these patients involving dermal suspension sutures and total parenchymal reshaping. With this technique, the tissue of the prominent axillary skin fold typically found in patients with massive weight loss is used to increase the upper pole volume of the breast. To prove the effectiveness of this technique, the current study compared it with a traditional inverted T-scar technique using a superior pedicle, as described by Höhler. This technique usually is used for a different patient clientele that requires reduction mammaplasty. However, because none of the difficult aforementioned preconditions are found in this clientele, it leads to the best possible outcome and represents the authors' internal "gold standard" for mammaplasty against which all other techniques must be compared. This study retrospectively analyzed the complication rate, lift effect, and upper pole fullness by chart analysis and photometric analysis of 21 Höhler and 24 Rubin mammaplasties. Despite the more challenging patient clientele in the Rubin groups, both therapies achieved a similar lift effect without significant differences (Höhler 4.8 ± 3.3 cm vs Rubin 6 ± 4 cm). In both groups, the upper pole area increased significantly. The ratio of upper pole-to-lower pole area increased from 1.31 preoperatively to 2.1 postoperatively in the Rubin group, suggesting a redistribution of tissue in favor of the upper pole, and it increased from 1.18 to 1.69 in the Höhler group, indicating an even greater increase in upper pole volume in the Rubin group. In conclusion, the technique described by Rubin, despite the dramatically more difficult soft tissue condition of the patients with massive weight loss, results in an outcome similar to that of a traditional reduction mammaplasty technique in terms of increased upper pole volume. It is suitable and preferable for patients who have a lateral axillary roll deformity and can be applied safely for these patients without increasing the complication rate. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Linkage of autosomal dominant common variable immunodeficiency to chromosome 5p and evidence for locus heterogeneity.

Common variable immunodeficiency (CVID, OMIM 240500) and selective immunoglobulin A deficiency (IgAD) are the most frequent primary immunodeficiencies in humans. Of the cases with CVID/IgAD, 20%-25% are familial, but the only previous claims of linkage or association are to the HLA region on chromosome 6p. We report the results of a genome-wide scan in three multiplex families with CVID, IgAD, and dysgammaglobulinemia, where affection is inherited in an autosomal dominant pattern. Two of the families are consistent with linkage to the telomeric region of chromosome 5p, whereas the third is consistent with linkage to the HLA region. Using a locus heterogeneity model and a conservative penetrance model, we obtained a LOD score of 3.35 for the 5p region. We sequenced the exons of one promising candidate gene within this region (PDCD6, also known as ALG-2) but found no causative mutation.

Alcohol hangover and managerial effectiveness.

Twenty-one male managers who normally drink moderate amounts of alcohol participated in a placebo-controlled, double-blind, cross-over experiment. Subjects consumed either placebo or alcoholic drinks to attain a breath alcohol level of 0.10 during the evening before participation in Strategic Management Simulations. By the time of arrival at the simultaion laboratory on the following morning, breath alcohol levels were measured at 0.00. Questionnaire responses indicated considerable hangover discomfort. Responses to semantic differential evaluative scales suggested that research participants evaluated their own managerial performance in the simulation setting as impaired. However, multiple (validated) measures of decision-making performance obtained in the simulation task did not show any deterioration of functioning. Previous research had shown considerable performance decrements in the same task setting, while blood/breath alcohol levels ranged from 0.05 through 0.10%. Apparently, complex decision-making competence by persons who normally consume moderate amounts of alcohol may not be impaired by hangover caused by intoxication during the previous evening that remains at or below a blood alcohol level of 0.10.