Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps.

Clinical observations implicate a role of eosinophils in cardiovascular diseases because markers of eosinophil activation are elevated in atherosclerosis and thrombosis. However, their contribution to atherosclerotic plaque formation and arterial thrombosis remains unclear. In these settings, we investigated how eosinophils are recruited and activated through an interplay with platelets. Here, we provide evidence for a central importance of eosinophil-platelet interactions in atherosclerosis and thrombosis. We show that eosinophils support atherosclerotic plaque formation involving enhanced von Willebrand factor exposure on endothelial cells and augmented platelet adhesion. During arterial thrombosis, eosinophils are quickly recruited in an integrin-dependent manner and engage in interactions with platelets leading to eosinophil activation as we show by intravital calcium imaging. These direct interactions induce the formation of eosinophil extracellular traps (EETs), which are present in human thrombi and constitute a substantial part of extracellular traps in murine thrombi. EETs are decorated with the granule protein major basic protein, which causes platelet activation by eosinophils. Consequently, targeting of EETs diminished thrombus formation in vivo, which identifies this approach as a novel antithrombotic concept. Finally, in our clinical analysis of coronary artery thrombi, we identified female patients with stent thrombosis as the population that might derive the greatest benefit from an eosinophil-inhibiting strategy. In summary, eosinophils contribute to atherosclerotic plaque formation and thrombosis through an interplay with platelets, resulting in mutual activation. Therefore, eosinophils are a promising new target in the prevention and therapy of atherosclerosis and thrombosis.

A gynaecological examination could have prevented a long and painful diagnostic work-up of a patient with hymen imperforatus.

Haematocolpos, caused by imperforate hymen, is a rare condition where menstrual blood accumulates in the vagina. Adolescent girls presenting with amenorrhoea, cyclical abdominal pain, and pelvis mass should be evaluated for this condition. Diagnosis requires a gynaecological examination. However, myths surrounding the hymen may impede proper medical care. Addressing these misconceptions is essential for promoting gynaecological care and ensuring timely evaluation and treatment. This case report emphasises the significance of effective communication in preventing misdiagnoses and care delays.

Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy.

The therapeutic potential of the mesenchymal stromal cell (MSC) secretome, consisting of all molecules secreted by MSCs, is intensively studied. MSCs can be readily isolated, expanded, and manipulated in culture, and few people argue with the ethics of their collection. Despite promising pre-clinical studies, most MSC secretome-based therapies have not been implemented in human medicine, in part because the complexity of bioactive factors secreted by MSCs is not completely understood. In addition, the MSC secretome is variable, influenced by individual donor, tissue source of origin, culture conditions, and passage. An increased understanding of the factors that make up the secretome and the ability to manipulate MSCs to consistently secrete factors of biologic importance will improve MSC therapy. To aid in this goal, we can draw from the wealth of information available on secreted factors from MSC isolated from veterinary species. These translational animal models will inspire efforts to move human MSC secretome therapy from bench to bedside.

Mesenchymal stromal cell-secreted CCL2 promotes antibacterial defense mechanisms through increased antimicrobial peptide expression in keratinocytes.

Mesenchymal stromal cells (MSCs) from both humans and horses, which represent a clinically relevant translation animal model for human cutaneous wound healing, were recently found to possess antimicrobial properties against planktonic bacteria, and in the case of equine MSCs, also against biofilms. This, together with previous findings that human and equine MSCs promote angiogenesis and wound healing, makes these cells an attractive approach to treat infected cutaneous wounds in both species. The anti-biofilm activities of equine MSC, via secretion of cysteine proteases, have only been demonstrated in vitro, thus lacking information about in vivo relevance. Moreover, the effects of the equine MSC secretome on resident skin cells have not yet been explored. The goals of this study were to (a) test the efficacy of the MSC secretome in a physiologically relevant ex vivo equine skin biofilm explant model and (b) explore the impact of the MSC secretome on the antimicrobial defense mechanisms of resident skin cells. Our salient findings were that secreted factors from equine MSCs significantly decreased viability of methicillin-resistant Staphylococcus aureus bacteria in mature biofilms in this novel skin biofilm explant model. Moreover, we demonstrated that equine MSCs secrete CCL2 that increases the antimicrobial activity of equine keratinocytes by stimulating expression of antimicrobial peptides. Collectively, these data contribute to our understanding of the MSC secretome's antimicrobial properties, both directly by killing bacteria and indirectly by stimulating immune responses of surrounding resident skin cells, thus further supporting the value of MSC secretome-based treatments for infected wounds.

AVP-786 as a promising treatment option for Alzheimer's Disease including agitation.

INTRODUCTION: To date, there is no FDA-approved treatment for agitation in Alzheimer's disease (AD). Medications currently used off-label have modest clinical efficacy and serious side effects. AREAS COVERED: The authors review the pharmacology, mechanism of action, pharmacokinetics, efficacy, safety and tolerability data of AVP-786, for the treatment of agitation in AD. EXPERT OPINION: AVP-786, the deuterated form of dextromethorphan/quinidine (AVP-923) which is an approved treatment for Pseudo-Bulbar Affect, emerges as a promising and safe treatment for agitation in AD. Deuteration is an innovative technology that accelerates drug development by conducting faster and less costly clinical trials. No phase II trial was conducted with AVP-786 for the treatment of agitation in AD; the decision to expedite the development of this drug was based on a successful phase II study with AVP-923. Phase III trials with AVP-786 (TRIAD-1 and TRIAD-2) showed mixed findings probably due to the difference in study design. Future phase III studies should use innovative study designs such as the Sequential Parallel Comparison Design to mitigate high placebo response, and the Cohen-Mansfield Agitation Inventory for agitation assessment. They should also include positron emission tomography studies to assess occupancy of various receptors in the brain after AVP-786 is administered.

The mesenchymal stromal cell secretome impairs methicillin-resistant Staphylococcus aureus biofilms via cysteine protease activity in the equine model.

Mesenchymal stromal cells (MSCs) from various species, such as humans, mice, and horses, were recently found to effectively inhibit the growth of various bacteria associated with chronic infections, such as nonhealing cutaneous wounds, via secretion of antimicrobial peptides. These MSC antimicrobial properties have primarily been studied in the context of the planktonic phenotype, and thus, information on the effects on bacteria in biofilms is largely lacking. The objectives of this study were to evaluate the in vitro efficacy of the MSC secretome against various biofilm-forming wound pathogens, including the methicillin-resistant Staphylococcus aureus (MRSA), and to explore the mechanisms that affect bacterial biofilms. To this end, we used equine MSCs, because the horse represents a physiologically relevant model for human wound healing and offers a readily translatable model for MSC therapies in humans. Our salient findings were that the equine MSC secretome inhibits biofilm formation and mature biofilms of various bacteria, such as Pseudomonas aeruginosa, S. aureus, and Staphylococcus epidermidis. Furthermore, we demonstrated that equine MSC secrete cysteine proteases that destabilize MRSA biofilms, thereby increasing the efficacy of antibiotics that were previously tolerated by the biofilms. In light of the rise of antibiotic-resistant bacterial strains as an increasing global health threat, our results provide the rationale for using the MSC secretome as a complementary treatment for bacterial skin infections in both humans and horses.

Testing the Cognitive Reserve Index Questionnaire in an Alzheimer's Disease Population.

BACKGROUND: Alzheimer's disease (AD) is the 6th leading cause of death in the United States and has no cure or progression prevention. The Cognitive Reserve (CR) theory poses that constant brain activity earlier in life later helps to deter pathological changes in the brain, delaying the onset of disease symptoms. OBJECTIVE: To determine the reliability and validity of the Cognitive Reserve Index questionnaire (CRIq) in AD patients. METHODS: Primary data collection was done using the CRIq to quantify CR in 90 participants. Correlations and multivariable linear regressions were used to assess reliability and validity. RESULTS: Reliability was tested in 34 participants. A Pearson correlation coefficient of 0.89 (p < 0.001) indicated a strong positive correlation. Validity was tested in 33 participants. A Pearson correlation coefficient of 0.30 (p = 0.10) indicated an insignificant weak positive correlation. CONCLUSION: The CRIq was found reliable. Gaining a better understanding of how CR tools can be used in various cognitive populations will help with the establishment of a research tool that is universally accepted as a true CR measure.

Vascular surveillance by haptotactic blood platelets in inflammation and infection.

Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets.

Thymus size at 6 months of age and subsequent child mortality.

OBJECTIVE: To examine determinants of thymus size at age 6 months and investigate whether thymus size at this age is a determinant of subsequent mortality. STUDY DESIGN: Thymus size was measured by transsternal sonography in 923 6-month-old children participating in a measles vaccination trial in Guinea-Bissau. RESULTS: Thymus size was strongly associated with anthropometric measurements. Boys had larger thymuses than girls, controlling for anthropometry. Crying during sonography made the thymus appear smaller. Children who were not vaccinated with Bacille Calmette-Guérin (BCG) or were vaccinated with BCG in the preceding 4 weeks before inclusion into the study had larger thymuses. Children who had malaria or had been treated with chloroquine or Quinimax in the previous week before inclusion had smaller thymuses. Controlled for background factors associated with thymus size and mortality, small thymus size remained a strong and independent risk factor for mortality (hazard ratio = 0.31; 95% confidence interval = 0.18 to 0.52). CONCLUSIONS: Small thymus size at age 6 months is a strong risk factor for mortality. To prevent unnecessary deaths, it is important to identify preventable factors predisposing to small thymus size.

Organisation and quality of primary surgical intervention for ovarian cancer in Denmark.

BACKGROUND: The positive effect on survival of maximal primary cytoreductive surgery for ovarian cancer is well established, and the highest rates of optimal cytoreduction are achieved by gynecological oncologists. Danish women have not only one of the highest incidences of ovarian cancer, but also the highest mortality rate. From 1981 to 1989, the overall Danish optimal debulking rate was 25% in patients with stage III and IV tumors. The primary aim of the present study was, therefore, to evaluate the organisation and quality of current primary surgical intervention for ovarian cancer in Denmark. METHODS: All women diagnosed with epithelial ovarian carcinoma (DC56) were identified through the Danish National Patient Registry during the study period from 1 July 2002 to 31 December 2003, and surgical notes and histopathology were evaluated by a board of 7 gynecological-oncologists, focusing on maximal cytoreduction. RESULTS: For stage III, the nationwide optimal debulking rate was 39%, significantly higher in the major hospitals (49%) versus other hospitals (29%) (p<0.005). In 19% of cases, there was insufficient information to evaluate debulking from the surgical notes, significantly less at the major hospitals versus other hospitals (12 versus 25%, p<0.001). CONCLUSIONS: In Denmark, the quality of the primary surgical intervention for ovarian cancer is not optimal. In order to enhance survival, compliance with international guidelines and improved registration of the surgical procedures in clinical databases are mandatory.

[Ovarian cancer in Denmark. Status of the surgical intervention]. / Ovariekraeft i Danmark. Status for den kirurgiske indsats.

INTRODUCTION: In Denmark women have not only one of the highest risks of ovarian cancer but also the highest mortality rate. The primary surgery is a key factor in the outcome. MATERIALS AND METHODS: Surgery for the treatment of ovarian cancer in Denmark was evaluated for the period from 1 July 2002 to 31 December 2003 using data from the Danish National Patient Registry (Landspatientregisteret, LPR) as well as the letter with the discharge note. The analysis included all primary surgical procedures during this period where information about number of surgical procedures per department, post-operative hospital stay, complications and mortality were obtained. RESULTS: 765 women, mean age 61 years (range 5-96 years), were operated on for ovarian cancer. The operations were distributed among 52 different hospital departments, and the surgery for advanced stage III patients took place in 32 different departments. The mean postoperative hospital stay was 9.0 days; 28% experienced one or more complications, and 8.1% were reoperated. The mortality rate was 4.2%. CONCLUSION: This first nationwide evaluation of surgery for ovarian cancer in Denmark showed that the surgery took place in far more hospital departments than the five recommended by the Danish National Board of Health. There seems to be room for improvement of quality, and a plan for the next five years is presented.

[Accelerated course after operation for ovarian cancer]. / Accelereret forløb efter operation for ovariecancer.

INTRODUCTION: Introduction of principles for postoperative multimodal rehabilitation (fast track surgery) has decreased hospital stay from about 8-10 days to 2-4 days after colonic resection. The aim of this study was to investigate the effect of a similar fast track regimen in patients operated for ovarian cancer. METHOD: 72 consecutive patients operated with a conventional perioperative treatment regimen (group 1) were compared with the initial 69 consecutive patients (group 2) with a multimodal rehabilitation regimen and the next 50 consecutive patients (group 3) where the fast track regimen was implemented as a routine. RESULTS: Patients demographics and surgical characteristics were comparable between groups. Median postoperative hospital stay was reduced from six days in group 1, to five days in group 2, and four days in group 3 (p < 0,05). Surgical complications were similar while medical complications were reduced from 12% to 1% (p < 0,05) and readmissions from 10% to 2% (p < 0,05) with the fast track regimen. CONCLUSION: Principles for postoperative multimodal rehabilitation from colonic surgery lead to faster rehabilitation, decreased risk of medical complications and hospital stay in patients operated for ovarian cancer.

The effect of accelerated rehabilitation on recovery after surgery for ovarian malignancy.

BACKGROUND: In patients undergoing colonic surgery the postoperative hospital stay has been reduced from 8-12 days to 2-4 days with multimodal rehabilitation programs. The aim of this study was to evaluate the postoperative outcome after surgery for ovarian malignancy with conventional care compared to fast-track multimodal rehabilitation. METHODS: Seventy-two consecutive patients receiving conventional care (group 1) were compared with 69 consecutive patients receiving multimodal, fast-track rehabilitation with a planned care program including continuous epidural analgesia, early oral feeding and mobilization (group 2) in the same department. Outcome was postoperative hospital stay and morbidity during the first postoperative month. RESULTS: Median age was 63 years (group 1) and 62 years (group 2). Median postoperative hospital stay was reduced from 6 days in group 1 (mean 7.3) to 5 days in group 2 (mean 5.4) (p < 0.05). There was no difference in the overall complication rate, although severe medical complications were reduced in group 2 (14% versus 2%; p < 0.01). Readmission rate was 10% in group 1 and 3% in group 2 (p > 0.05). CONCLUSIONS: The concept of fast-track multimodal rehabilitation appears to be beneficial in patients operated for ovarian malignancy, as hospital stay and medical morbidity are reduced.