Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases.

Neutrophil extracellular trap (NET) formation, first described in 2004 as a previously unknown strategy of neutrophils to fight microbes, has attracted an increasing interest in the research community. NETs are formed when neutrophils externalize their decondensed chromatin together with content from their azurophilic granules. In addition to their role in defense against microbes, NETs have been implicated as mediators of pathology in sterile inflammation, such as cancer and autoimmunity, and their potential as therapeutic targets is actively explored. However, targeting of NETs is challenging since the beneficial effects of their removal need to be balanced against the potential harmful loss of their function in microbial defense. Moreover, depending on the stimuli or species, NETs can be formed via distinct mechanisms and are not always made up of the same components, making direct comparisons between various studies challenging. This review focuses on the role of NETs in cancer-associated pathology, such as thrombosis, organ dysfunction, and metastasis. Different strategies to target NETs, by either preventing their formation or degrading existing ones, are also discussed.

Adjustments in Interprofessional Communication: A Focus Group Study in Psychiatric Outpatient Units.

Communication in healthcare extends beyond patient care, impacting the work environment and job satisfaction. Interprofessional communication is essential for fostering collaboration, but challenges arise from differences in training, roles, and hierarchies. The study aimed to explore psychiatric outpatient clinicians' experiences of interprofessional communication and their perceptions of how the communication intersects the organizational and social work environment of healthcare. Qualitative research involved focus group interviews with clinicians from five psychiatric outpatient units in Central Sweden, representing diverse professions. The authors analyzed semi-structured interview data thematically to uncover clinicians' perspectives on interprofessional communication. An overarching theme, "Adjustment of communication," with subthemes "Synchronized communication" and "Dislocated communication," emerged. Clinicians adapted communication strategies based on situations and needs, with synchronized communication promoting collaboration and dislocated communication hindering it. Communicating with each other was highly valued, as it contributed to a positive work environment. The study underscores the importance of an open, supportive environment that fosters trust, and respect among healthcare clinicians. Consistent with prior research, collaboration gaps underscore the urgent need to improve interprofessional communication.

Inflammation and neutrophil extracellular traps in cerebral cavernous malformation.

Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3iECKO mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3iECKO mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas  of patients with CCM confirms the clinical relevance of NETs in CCM.

Being an older hospitalized patient during the COVID-19 pandemic - A qualitative interview study.

BACKGROUND: Older people hospitalized for COVID-19 are a vulnerable group due to the disease itself, aging and often loss of hearing and vision. Person-centered care, where patients have opportunities to communicate and participate in their own care, is important. However, because healthcare staff needed to wear personal protective equipment during the pandemic, to protect the patients and themselves, providing person-centered care was often difficult. This study aims to describe older hospitalized patients' experiences both of being cared for, while having COVID-19, and of the care provided by healthcare staff wearing PPE. METHODS: Fourteen older patients, over 65 years of age, were interviewed, and the data were analyzed using qualitative content analysis. The study adhered to Consolidated criteria for reporting qualitative research guidelines. RESULTS: Three subthemes and one overall theme, "The desire for survival overshadows difficulties", emerged in the analysis. The main findings revealed that the older hospitalized patients experienced the care they received from the healthcare staff as satisfactory. The older patients reported understanding and accepting that the pandemic situation meant that their ability to participate in their own care and communicate with healthcare staff were given lower priority. CONCLUSIONS: Older hospitalized patients need to be provided person-centered care, and situations such as a pandemic are no exception. Care tasks that are not acute in nature, e.g., planning for patients' return home, could be conducted by healthcare staff not required to wear PPE.

Identification of the Major Protein Components of Human and Cow Saliva.

Cows produce saliva in very large quantities to lubricate and facilitate food processing. Estimates indicate an amount of 50-150 L per day. Human saliva has previously been found to contain numerous antibacterial components, such as lysozyme, histatins, members of the S-100 family and lactoferrin, to limit pathogen colonization. Cows depend on a complex microbial community in their digestive system for food digestion. Our aim here was to analyze how this would influence the content of their saliva. We therefore sampled saliva from five humans and both nose secretions and saliva from six cows and separated the saliva on SDS-PAGE gradient gels and analyzed the major protein bands with LC-MS/MS. The cow saliva was found to be dominated by a few major proteins only, carbonic anhydrase 6, a pH-stabilizing enzyme and the short palate, lung and nasal epithelium carcinoma-associated protein 2A (SPLUNC2A), also named bovine salivary protein 30 kDa (BSP30) or BPIFA2B. This latter protein has been proposed to play a role in local antibacterial response by binding bacterial lipopolysaccharides (LPSs) and inhibiting bacterial growth but may instead, according to more recent data, primarily have surfactant activity. Numerous peptide fragments of mucin-5B were also detected in different regions of the gel in the MS analysis. Interestingly, no major band on gel was detected representing any of the antibacterial proteins, indicating that cows may produce them at very low levels that do not harm the microbial flora of their digestive system. The nose secretions of the cows primarily contained the odorant protein, a protein thought to be involved in enhancing the sense of smell of the olfactory receptors and the possibility of quickly sensing potential poisonous food components. High levels of secretory IgA were also found in one sample of cow mouth drippings, indicating a strong upregulation during an infection. The human saliva was more complex, containing secretory IgA, amylase, carbonic anhydrase 6, lysozyme, histatins and a number of other less abundant proteins, indicating a major difference to the saliva of cows that show very low levels of antibacterial components, most likely to not harm the microbial flora of the rumen.

Interprofessional communication in a psychiatric outpatient unit - an ethnographic study.

BACKGROUND: Communication in healthcare has been extensively studied, but most research has focused on miscommunication and the importance of communication for patient safety. Previous research on interprofessional communication has mainly focused on relationships between physicians and nurses in non-psychiatric settings. Since communication is one of the core competencies in psychiatric care, more research on interprofessional communication between other clinicians is needed, and should be explored from a broader perspective. This study aimed to explore and describe interprofessional communication in a psychiatric outpatient unit. METHOD: During spring 2022, data consisting of over 100 h of fieldwork were collected from observations, formal semi-structured interviews and informal conversations inspired by the focused ethnography method. Data was collected at an outpatient unit in central Sweden, and various clinicians participated in the study. The data analysis was a back-and-forth process between initial codes and emerging themes, but also cyclical as the data analysis process was ongoing and repeated and took place simultaneously with the data collection. RESULTS: We found that a workplace's history, clinicians´ workload, responsibilities and hierarchies influence interprofessional communication. The results showed that the prerequisites for interprofessional communication were created through the unit's code of conduct, clear and engaging leadership, and trust in the ability of the various clinicians to perform new tasks. CONCLUSION: Our results indicate that leadership, an involving working style, and an environment where speaking up is encouraged and valued can foster interprofessional communication and respect for each other´s professional roles is key to achieving this. Interprofessional communication between different clinicians is an important part of psychiatric outpatient work, where efficiency, insufficient staffing and long patient queues are commonplace. Research can help shed light on these parts by highlighting aspects influencing communication.

Vaccination against galectin-1 promotes cytotoxic T-cell infiltration in melanoma and reduces tumor burden.

Galectin-1 (Gal1) is a glycan-binding protein that promotes tumor progression by several distinct mechanisms. Through direct binding to vascular endothelial growth factor (VEGF)-receptor 2, Gal1 is able to induce VEGF-like signaling, which contributes to tumor angiogenesis. Furthermore, several studies have demonstrated an immunosuppressive function of Gal1 through effects on both effector and regulatory T cells. Elevated Gal1 expression and secretion have been shown in many tumor types, and high Gal1 serum levels have been connected to poor prognosis in cancer patients. These findings suggest that therapeutic strategies directed against Gal1 would enable simultaneous targeting of angiogenesis, immune evasion and metastasis. In the current study, we have analyzed the potential of Gal1 as a cancer vaccine target. We show that it is possible to generate high anti-Gal1 antibody levels in mice immunized with a recombinant vaccine protein consisting of bacterial sequences fused to Gal1. Growth of Gal1 expressing melanomas was significantly impaired in the immunized mice compared to the control group. This was associated with improved perfusion of the tumor vasculature, as well as increased infiltration of macrophages and cytotoxic T cells (CTLs). The level of granzyme B, mainly originating from CTLs in our model, was significantly elevated in Gal1 vaccinated mice and correlated with a decrease in tumor burden. We conclude that vaccination against Gal1 is a promising pro-immunogenic approach for cancer therapy that could potentially enhance the effect of other immunotherapeutic strategies due to its ability to promote CTL influx in tumors.

Quantitative Analysis of the Transcriptome of Two Commonly Used Human Monocytic Cell Lines-THP-1 and Mono Mac 6-Reveals Their Arrest during Early Monocyte/Neutrophil Differentiation.

Cell lines of monocyte/macrophage origin are often used as model systems to study monocyte/macrophage biology. A relevant question is how similar these cell lines are to their in vivo counterparts? To address this issue, we performed a detailed analysis of the transcriptome of two commonly used human monocyte/macrophage cell lines, Mono Mac 6 and THP-1. Both of these cell lines originate from leukemic cells with myelo-monocytic characteristics. We found that both Mono Mac 6 and THP-1 represent cells of very immature origin. Their transcriptomes show more similarities to immature neutrophils than cells of the monocyte/macrophage lineage. They express significant levels of N-elastase, proteinase 3, cathepsin G, and azurocidin but very low levels of CD14, ficolin, and complement factor P. All major MHC class II genes are also expressed at low levels. They show high levels of lysozyme and low levels of one of the immunoglobulin Fc receptors, FCGRIIA, which is characteristic of both neutrophils and monocytes. THP-1, but not Mono Mac 6, also expresses the high-affinity receptor for IgG, FCGRIA. Both cell lines lack the expression of the connective tissue components fibronectin, proteoglycan 4, and syndecan 3, which are characteristics of tissue macrophages but are absent in blood monocytes, indicating that they originate from bone marrow precursors and not yolk sac-derived hematopoietic cells. Both of these cell lines seem, therefore, to represent cells arrested during early myelo-monocytic development, at a branch point between neutrophil and monocyte differentiation. Their very immature phenotype indicates that great care should be taken when using these cell lines as models for normal monocyte/macrophage biology.

The Human Monocyte-A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation.

Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1α, IL-1ß, IL-6 and TNF-α, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response.

Quantitative In-Depth Transcriptome Analysis Implicates Peritoneal Macrophages as Important Players in the Complement and Coagulation Systems.

To obtain a more detailed picture of macrophage (MΦ) biology, in the current study, we analyzed the transcriptome of mouse peritoneal MΦs by RNA-seq and PCR-based transcriptomics. The results show that peritoneal MΦs, based on mRNA content, under non-inflammatory conditions produce large amounts of a number of antimicrobial proteins such as lysozyme and several complement components. They were also found to be potent producers of several chemokines, including platelet factor 4 (PF4), Ccl6, Ccl9, Cxcl13, and Ccl24, and to express high levels of both TGF-ß1 and TGF-ß2. The liver is considered to be the main producer of most complement and coagulation components. However, we can now show that MΦs are also important sources of such compounds including C1qA, C1qB, C1qC, properdin, C4a, factor H, ficolin, and coagulation factor FV. In addition, FX, FVII, and complement factor B were expressed by the MΦs, altogether indicating that MΦs are important local players in both the complement and coagulation systems. For comparison, we analyzed human peripheral blood monocytes. We show that the human monocytes shared many characteristics with the mouse peritoneal MΦs but that there were also many major differences. Similar to the mouse peritoneal MΦs, the most highly expressed transcript in the monocytes was lysozyme, and high levels of both properdin and ficolin were observed. However, with regard to connective tissue components, such as fibronectin, lubricin, syndecan 3, and extracellular matrix protein 1, which were highly expressed by the peritoneal MΦs, the monocytes almost totally lacked transcripts. In contrast, monocytes expressed high levels of MHC Class II, whereas the peritoneal MΦs showed very low levels of these antigen-presenting molecules. Altogether, the present study provides a novel view of the phenotype of the major MΦ subpopulation in the mouse peritoneum and the large peritoneal MΦs and places the transcriptome profile of the peritoneal MΦs in a broader context, including a comparison of the peritoneal MΦ transcriptome with that of human peripheral blood monocytes and the liver.

The Swedish translation of Perceptions of Restraint Use Questionnaire (PRUQ): A test-retest reliability study in two dementia nursing homes.

BACKGROUND: The Perceptions of Restraint Use Questionnaire measures perception of restraint in a 17-item questionnaire. The aim of this study was to assess the test-retest reliability of the PRUQ as a measure of staff attitudes to restraint in elderly older persons care for people with dementia from two different nursing homes, and its ability to produce reliable results. METHODS: Twenty-six staff members from two different nursing homes completed the 17-item PRUQ twice with 14-21 days between time points. As the questionnaire has already been translated in another study, the current study evaluated total item scores, mean, internal consistency, and intraclass correlation for reliability purposes. RESULTS: The internal consistency Cronbach's Alpha were ˃ ≥0.726. The Intraclass correlation (ICC) between test and retest was moderate to good for the three subscales, with ICC (A,1) and ICC (C,1) values approximately equal and in the range 0.480-0.962. A Bland-Altman plot of the PRUQ total mean scores illustrates no systematic change in the mean. CONCLUSIONS: The Swedish version of the PRUQ shows mainly good reliability. Therefore, we suggest that researchers continue to develop the PRUQ to be an even higher reliable questionnaire of health care professionals' perceptions of measure for restraint use in nursing homes for persons with dementia.

Marginal relationship between affective dispositions and neurocognitive function in patients with schizophrenia spectrum disorders.

PURPOSE: Neurocognitive outcomes are frequently used as indicators of real-world functioning in schizophrenia spectrum disorders (SSD). These test results may be influenced by individual differences, such as affective dispositions. Here we investigate the relationship between positive and negative affect and neuropsychological test scores in a large, mixed-gender, population based group of participants without co-morbid substance abuse. MATERIALS AND METHODS: We assessed 129 male and female SSD patients with the Positive and Negative Affect Schedule (PANAS) and a comprehensive neuropsychological test battery. RESULTS AND CONCLUSIONS: The neuropsychological test scores were mainly predicted by age and gender, with small contributions from negative psychosis symptoms. There was a statistically significant relationship between Positive Affect and processing speed and between Negative Affect and verbal memory and executive function. However, the level of neurocognitive function variance explained by these affects was only 5%. Thus, the neurocognitive test results were not associated with trait affect in any clinically significant manner. This adds to previous findings of no relationship between affective dispositions and psychosis symptom variables in our participants. We suggest that affective traits constitute an independent dimension that may influence well-being, coping, and real-life outcome in SSD patients directly, and not through neurocognitive function.

Mast Cells and Basophils in the Defense against Ectoparasites: Efficient Degradation of Parasite Anticoagulants by the Connective Tissue Mast Cell Chymases.

Ticks, lice, flees, mosquitos, leeches and vampire bats need to prevent the host's blood coagulation during their feeding process. This is primarily achieved by injecting potent anticoagulant proteins. Basophils frequently accumulate at the site of tick feeding. However, this occurs only after the second encounter with the parasite involving an adaptive immune response and IgE. To study the potential role of basophils and mast cells in the defense against ticks and other ectoparasites, we produced anticoagulant proteins from three blood-feeding animals; tick, mosquito, and leech. We tested these anticoagulant proteins for their sensitivity to inactivation by a panel of hematopoietic serine proteases. The majority of the connective tissue mast cell proteases tested, originating from humans, dogs, rats, hamsters, and opossums, efficiently cleaved these anticoagulant proteins. Interestingly, the mucosal mast cell proteases that contain closely similar cleavage specificity, had little effect on these anticoagulant proteins. Ticks have been shown to produce serpins, serine protease inhibitors, upon a blood meal that efficiently inhibit the human mast cell chymase and cathepsin G, indicating that ticks have developed a strategy to inactivate these proteases. We show here that one of these tick serpins (IRS-2) shows broad activity against the majority of the mast cell chymotryptic enzymes and the neutrophil proteases from human to opossum. However, it had no effect on the mast cell tryptases or the basophil specific protease mMCP-8. The production of anticoagulants, proteases and anti-proteases by the parasite and the host presents a fascinating example of an arms race between the blood-feeding animals and the mammalian immune system with an apparent and potent role of the connective tissue mast cell chymases in the host defense.

Factors associated with improvement in depressive symptoms among older persons after hospitalisation - a prospective design with two follow-ups.

BACKGROUND: Depression is a common disorder in old age and increases with hospitalisation. The aim was to investigate whether improvement in depressive symptoms after hospitalisation is associated with education level, age, gender, living situation, self-efficacy, activities in daily living and quality of life by (1) examining the prevalence of depressive symptoms at baseline and at 1st and 2nd follow-up (2) examining different factors' association with depressive symptoms at baseline and (3) examining different factors' association with improvement in depressive symptoms at baseline and at 1st and 2nd follow-up. METHODS: The study consisted of 145 patients, 65 years and older. Data were collected between February 2015 and September 2016 through interviews conducted using structured protocols. The instrument used was Katz index of ADL, Geriatric Depression Scale-20, Life Satisfaction Questionnaire and the General Self-Efficacy Scale. The participants were interviewed before discharge from hospital, after 1.5 month and after 3 months. RESULTS: The prevalence of depressive symptoms in older persons was high after hospitalisation. Factors associated with improvement of depressive symptoms after hospitalisation were higher educational level, improvement in activities in daily living and quality of life. Non-significant results were found for improvement of depressive symptoms and gender, age, living situation or self-efficacy. CONCLUSIONS: Depression is a common health problem in older persons, especially after hospitalisation. It is therefore important that healthcare staff screen older persons for depression during hospitalisation, as this allows identification of those in need and a possibility to help them in an appropriate manner. Persons with lower educational level and depressive symptoms need special attention.

TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-κB subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-κB signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

A scoping review of complexity science in nursing.

AIM: To describe how complexity science has been integrated into nursing. DESIGN: A scoping review. DATA SOURCE/REVIEW METHOD: Academic Search Elite, Scopus, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, PubMed and Web of Science were searched November 2016, updated in October 2017 and January 2020. The working process included: problem identification, literature search, data evaluation, synthesizing and presentation. RESULTS: Four categories were found in the included 89 articles: (a) how complexity science is integrated into the nursing literature in relation to nursing education and teaching; (b) patients' symptoms, illness outcome and safety as characteristics of complexity science in nursing; (c) that leaders and managers should see organizations as complex and adaptive systems, rather than as linear machines; and (d) the need for a novel approach to studying complex phenomena such as healthcare organizations. Lastly, the literature explains how complexity science has been incorporated into the discourse in nursing and its development. CONCLUSION: The review provided strong support for use in complexity science in the contemporary nursing literature. Complexity science is also highly applicable and relevant to clinical nursing practice and nursing management from an organizational perspective. The application of complexity science as a tool in the analysis of complex nursing systems could improve our understanding of effective interactions among patients, families, physicians and hospital and skilled nursing facility staff as well as of education. IMPACT: Understanding complexity science in relation to the key role of nurses in the healthcare environment can improve nursing work and nursing theory development. The use of complexity science provides nurses with a language that liberates them from the reductionist view on nursing education, practice and management.

"Longing to be independent again" - A qualitative study on older adults' experiences of life after hospitalization.

It is important to support older adults' independence after hospitalization and, thus, to increase their perceived quality of life. The present descriptive study took a qualitative approach and aimed to describe older adults' experiences of their life situation after hospital discharge. Fifteen individuals (≥65 years) from two regional hospitals in central Sweden were interviewed between October 2015 and January 2016 in their own home following hospital discharge. The interview data were analyzed using manifest and latent qualitative content analysis. The analysis revealed one theme: "Longing to be independent again" based on four categories: `Dependent on other people and aids´, `Obstacles, impediments and limitations in daily life´, Adapt to the situation´ and `Psychological and physical values´. Understanding older adults' experiences of life after hospitalization is also a prerequisite for being able to provide person-centered care.

Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.

With the aim to improve the efficacy of therapeutic vaccines that target self-antigens, we have developed a novel fusion protein vaccine on the basis of the C-terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abs were analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinated mice displayed a 2- to 10-fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX-vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generated Abs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.-Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.-O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.-K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.

Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation.

BACKGROUND: Intra-abdominal adhesions are a major cause of morbidity after abdominal or gynecologic surgery. However, knowledge about the pathogenic mechanism(s) is limited, and there are no effective treatments. Here, we investigated a mouse model of bowel adhesion formation and the effect(s) of an Federal Drug Administration-approved drug (trametinib) in preventing adhesion formation. MATERIALS AND METHODS: C57BL/6 mice were used to develop a consistent model of intra-abdominal adhesion formation by gentle cecal abrasion with mortality rates of <10%. Adhesion formation was analyzed histologically and immunochemically to characterize the expression of pro-fibrotic marker proteins seen in pathologic scaring and included alpha smooth muscle actin (αSMA) and fibronectin EDA (FNEDA) which arises from alternative splicing of the fibronectin messenger RNA resulting in different protein isoforms. Trichrome staining assessed collagen deposition. Quantitative polymerase chain reaction analysis of RNA isolated from adhesions by laser capture microscopy was carried out to assess pro-fibrotic gene expression. To block adhesion formation, trametinib was administered via a subcutaneous osmotic pump. RESULTS: Adhesions were seen as early as post-operative day 1 with extensive adhesions being formed and vascularized by day 5. The expression of the FNEDA isoform occurred first with subsequent expression of αSMA and collagen. The drug trametinib was chosen for in vivo studies because it effectively blocked the mesothelial to mesenchymal transition of rat mesothelium. Trametinib, at the highest dose used (3 mg/kg/d), prevented adhesion formation while at lower doses, adhesions were usually limited, as evidenced by the presence of FNEDA isoform but not αSMA. CONCLUSIONS: Cecal abrasion in mice is a reliable model to study abdominal adhesions, which can be ameliorated using the MEK1/2 inhibitor trametinib. While blocking adhesion formation at the cell and molecular levels, trametinib, at the therapeutic doses utilized, did not impair the wound healing at the laparotomy site.

Atypical sensory processing pattern following median or ulnar nerve injury - a case-control study.

BACKGROUND: Due to brain plasticity a transection of a median or ulnar nerve results in profound changes in the somatosensory areas in the brain. The permanent sensory deprivation after a peripheral nerve injury might influence the interaction between all senses. The aim of the study was to investigate if a median and/or ulnar nerve injury gives rise to a changed sensory processing pattern. In addition we examined if age at injury, injured nerve or time since injury influence the sensory processing pattern. METHODS: Fifty patients (40 men and 10 women, median age 43) operated due to a median and/or ulnar nerve injury were included. The patients completed the Adolescent/Adult Sensory Profile questionnaire, which includes a comprehensive characterization on how sensory information is processed and how an individual responds to multiple sensory modalities. AASP categorizes the results into four possible Quadrants of behavioral profiles (Q1-low registration, Q2-sensory seeking, Q3-sensory sensitivity and Q4-sensory avoiding). The results were compared to 209 healthy age and gender matched controls. Anova Matched Design was used for evaluation of differences between the patient group and the control group. Atypical sensory processing behavior was determined in relation to the normative distribution of the control group. RESULTS: Significant difference was seen in Q1, low registration. 40% in the patient group scored atypically in this Quadrant compared to 16% of the controls. No correlation between atypical sensory processing pattern and age or time since injury was seen. CONCLUSION: A peripheral nerve injury entails altered sensory processing pattern with increased proportion of patients with low registration to sensory stimulus overall. Our results can guide us into more client centered rehabilitation strategies.