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Although among adolescents with psychosocial problems low health literacy may increase the risk of poor treatment outcomes, the contributing mechanisms within treatment remain unclear. A better understanding of these mechanisms could contribute to improved treatment processes and outcomes. This study aims to examine the relationship between functional health literacy, treatment processes (treatment adherence, learning processes), and treatment outcome (level of psychosocial problems) in adolescents in psychosocial care. We used data from a prospective cohort study among adolescents aged 12–18 (N = 390), collected in four successive measurements: at entry into care, and 3, 12, and 24 months thereafter. We used a mixed effect model to investigate the association between level of functional health literacy (adequate vs. inadequate) and treatment processes (treatment adherence, learning processes) and treatment outcome (level of psychosocial problems). Between adolescents with adequate and inadequate functional health literacy, we found no differences or change over time in adherence or learning processes. The level of psychosocial problems significantly declined over time (β = − 1.70, 95% CI [− 2.72, − 0.69], p =.001) to a similar degree in both groups, though, in all measurements, the level was consistently higher for adolescents with inadequate health literacy. We conclude that health literacy levels did not affect change in treatment processes nor in outcomes of psychosocial treatment. However, the consistently higher level of psychosocial problems among adolescents with inadequate health literacy suggests an unaddressed need in psychosocial care. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the prevalence of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (ACEAs) in patients with acute and chronic central serous chorioretinopathy (CSC). We enrolled 28 patients with acute CSC, 42 patients with chronic CSC, and 40 healthy controls. The presence of ARAs was determined by indirect immunofluorescence using monkey retina as an antigen substrate, while the presence of AECAs was determined using cultivated human umbilical vein endothelial cells (HUVECs) and primate skeletal muscle according to the manufacturer's instructions (Euroimmun AG). There were no differences in the prevalence of antibodies against rods, cones, cytoplasmic components of retinal nuclear layer cells, and retinal vessels between the acute and chronic CSC groups and the control group (P = 0.27, P = 0.16, P = 0.71, and P = 0.06, respectively). However, AECAs reactive with HUVECs were observed in 46% of patients with acute CSC, 45% of those with chronic CSC, and 22% of controls, whereas AECAs reactive with the skeletal muscle were present in 46%, 45%, and 15%, respectively (difference between groups: P = 0.045 for HUVECs and P = 0.005 for the skeletal muscle). Furthermore, AECA titers were higher in CSC patients than in controls (P = 0.004). This study provides evidence for the possible involvement of an autoimmune process directed against vessel antigens in the pathogenesis of CSC. AECAs may be more important than ARAs in this disease and may be involved in endothelial damage in the choroidal vessels and choriocapillaris, leading to hyperpermeability, which is central to the pathophysiology of CSC. [ABSTRACT FROM AUTHOR]

Currently, there is a high demand for amaranth due to its ability to withstand harsh climatic conditions, making it an ideal crop in the changing climate. There is also increased awareness and education on its nutritional and overall health benefits, and the availability of improved recipes. However, the presence of hazards can hinder the commercialisation of amaranth, which is in most cases traded informally. Food safety issues along the amaranth value chain should, therefore, be addressed to cope with both production and safety demands. The objective of this study, therefore, was to develop a Hazard Analysis and Critical Control Point (HACCP) plan for hazards in the amaranth value chain in Uganda. The seven principles outlined by Codex Alimentarius were followed to develop the HACCP plan. A tree diagram was further used to identify each potential hazard at each processing stage and Critical Control Points (CCPs) along the chain. For the CCPs identified, reliable control mechanisms and corrective actions were established to fulfil the requirements set by the critical limits to guarantee the safety of the products. Verification and records systems were proposed to determine the effectiveness and traceability of the HACCP plan. For each of the identified CCPs, samples were collected purposively and analysed for chemical and microbial contaminants. From the analysis, fifteen processing stages, starting from the land section to cooking and serving, were identified. Out of these, eight stages were defined as CCPs. These were site selection, land and seedbed preparation, irrigation, market display/humidity control, washing before preparation, chopping, cooking, and holding time and serving. At CCP 1, soils were contaminated with lead and cadmium, mercury and aflatoxins but at considerably low levels. At CCP 2, organic fertilisers were only contaminated with E. coli. At CCP3, E. coli was present in irrigation water. Heavy metals were also present in the irrigation water but were below the critical limits. At CCP4, E. coli was absent in water and display surfaces. E. coli was, however, present on raw amaranth. S. aureus was detected on vendors' hands. At CCP5, water was not contaminated with E. coli. At CCP6, only personnel hands were infected with S. aureus and Enterobacteriaceae. No contamination was detected in CCP7 and CCP8. Strict control of E. coli in manure and water and S. aureus and Enterobacteriaceae on personnel hands is required to ensure the amaranth value chain attains good food safety output. [ABSTRACT FROM AUTHOR]

Common beans (Phaseolus vulgaris L) may be contaminated with heavy metals and aflatoxins. Cooked beans may also be contaminated with micro-organisms due to poor hygiene and sanitation practices. Hazard Analysis and Critical Control Point (HACCP), which is a globally recognised food safety program, was proposed as a suitable program to minimise/eliminate the risk of contamination. Therefore, the objective of this study was to develop a HACCP plan for dry common beans in Uganda and an accompanying food safety toolkit. The seven principles of HACCP as outlined by Codex Alimentarius were followed to develop a HACCP plan for the dry common beans value chain in Uganda. A decision tree diagram was further used to identify each potential hazard at each processing stage and Critical Control Points (CCPs) along the chain. The identification of the CCPs was further supported by an evaluation of the actual risk and severity of the hazard. For the CCP identified, reliable control mechanism and corrective actions were established to fulfill the requirements set by the critical limits to guarantee the safety of the products. Verification and records systems were proposed to determine the effectiveness and traceability of the HACCP plan. For identified CCPs, a co-creation methodology was used to develop the food safety toolkit. This was carried out in four sessions that included a background of the chain actors' ambitions to determine the suitability of the toolkit, assessment of CCPs, expert advice on the CCP and an exercise to develop concepts for each CCP. From the analysis, fourteen processing stages starting from land selection to cooking and serving were identified. Out of these, four stages were CCPs. These were land selection and preparation, storage, post-harvest drying, and cooking and serving. Hazards at the CCPs included heavy metals, mycotoxins, and micro-organisms such as S. aureus, E. coli, and Salmonella spp. A combination of good hygiene and sanitation practices and good agricultural practices were recommended as control measures against the hazards. To further equip the value chain actors with mitigation strategies, a food safety toolkit whose usefulness is to give the actors a systematic means to control identified CCPs was developed. In this regard, the toolkit and HACCP plan will complement each other. From the study results, implementation of the toolkit, followed by an assessment of its uptake and impact on livelihoods and food safety risks is recommended. [ABSTRACT FROM AUTHOR]

Background: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations.Methods: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation.Results: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi.Conclusions: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells. [ABSTRACT FROM AUTHOR]

Streptococcus mutans in dental plaque biofilms play a role in caries development. The biofilm's complex structure enhances the resistance to antimicrobial agents by limiting the transport of active agents inside the biofilm. The authors assessed the ability of high-velocity water microsprays to enhance delivery of antimicrobials into 3-d-old S. mutans biofilms. Biofilms were exposed to a 90° or 30° impact, first using a 1-µm tracer bead solution (109 beads/mL) and, second, a 0.2% chlorhexidine (CHX) or 0.085% cetylpyridinium chloride (CPC) solution. For comparison, a 30-s diffusive transport and simulated mouthwash were also performed. Confocal microscopy was used to determine number and relative bead penetration depth into the biofilm. Assessment of antimicrobial penetration was determined by calculating the killing depth detected by live/dead viability staining. The authors first demonstrated that the microspray was able to deliver significantly more microbeads deeper in the biofilm compared with diffusion and mouthwashing exposures. Next, these experiments revealed that the microspray yielded better antimicrobial penetration evidenced by deeper killing inside the biofilm and a wider killing zone around the zone of clearance than diffusion alone. Interestingly the 30° impact in the distal position delivered approximately 16 times more microbeads and yielded approximately 20% more bacteria killing (for both CHX and CPC) than the 90° impact. These data suggest that high-velocity water microsprays can be used as an effective mechanism to deliver microparticles and antimicrobials inside S. mutans biofilms. High shear stresses generated at the biofilm-burst interface might have enhanced bead and antimicrobial delivery inside the remaining biofilm by combining forced advection into the biofilm matrix and physical restructuring of the biofilm itself. Further, the impact angle has potential to be optimized both for biofilm removal and active agents' delivery inside biofilm in those protected areas where some biofilm might remain. [ABSTRACT FROM AUTHOR]

Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. [ABSTRACT FROM AUTHOR]

Aims Cerebral amyloid angiopathy ( CAA) is a key pathological hallmark of Alzheimer's disease ( AD) characterized by accumulation of amyloid-beta ( Aβ) protein in blood vessel walls. CAA impairs vessel functioning, affects blood brain barrier integrity and accelerates cognitive decline of AD patients. Unfortunately, mechanisms underlying Aβ deposition in the vessel wall remain largely unknown. Factor XIIIa ( FXIIIa) is a blood-derived transglutaminase crucial in blood coagulation by cross-linking fibrin molecules. Evidence is mounting that blood-derived factors are present in CAA and may play a role in protein deposition in the vessel wall. We therefore investigated whether FXIIIa is present in CAA and if FXIIIa cross-link activity affects Aβ aggregation. Methods Using immunohistochemistry, we investigated the distribution of FXIIIa, its activator thrombin and in situ FXIIIa activity in CAA in post-mortem AD tissue. We used surface plasmon resonance and Western blot analysis to study binding of FXIIIa to Aβ and the formation of FXIIIa- Aβ complexes, respectively. In addition, we studied cytotoxicity of FXIIIa- Aβ complexes to cerebrovascular cells. Results FXIIIa, thrombin and in situ FXIIIa activity colocalize with the Aβ deposition in CAA. Furthermore, FXIIIa binds to Aβ with a higher binding affinity for Aβ1-42 compared with Aβ1-40. Moreover, highly stable FXIIIa- Aβ complexes are formed independently of FXIIIa cross-linking activity that protected cerebrovascular cells from Aβ-induced toxicity in vitro. Conclusions Our data showed that FXIIIa colocalizes with Aβ in CAA and that FXIIIa forms unique protein complexes with Aβ that might play an important role in Aβ deposition and persistence in the vessel wall. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. Eighty percent of UMs harbor mutations in the Gαq family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQQ209L-transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model. Our data identify PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and demonstrate that combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone. [ABSTRACT FROM AUTHOR]

The influence of the impact of a high-velocity water microdrop on the detachment of Streptococcus mutans UA159 biofilms from the interproximal (IP) space of teeth in a training typodont was studied experimentally and computationally. Twelve-day-old S. mutans biofilms in the IP space were exposed to a prototype AirFloss delivering 115 µL water at a maximum exit velocity of 60 m/sec in a 30-msec burst. Using confocal microscopy and image analysis, we obtained quantitative measurements of the percentage removal of biofilms from different locations in the IP space. The 3D geometry of the typodont and the IP spaces was obtained by micro-computed tomography (µ-CT) imaging. We performed computational fluid dynamics (CFD) simulations to calculate the wall shear stress (τw ) distribution caused by the drops on the tooth surface. A qualitative agreement and a quantitative relationship between experiments and simulations were achieved. The wall shear stress (τw ) generated by the prototype AirFloss and its spatial distribution on the teeth surface played a key role in dictating the efficacy of biofilm removal in the IP space. [ABSTRACT FROM AUTHOR]

The influence of the impact of a high-velocity water microdrop on the detachment of Streptococcus mutans UA159 biofilms from the interproximal (IP) space of teeth in a training typodont was studied experimentally and computationally. Twelve-day-old S. mutans biofilms in the IP space were exposed to a prototype AirFloss delivering 115 µL water at a maximum exit velocity of 60 m/sec in a 30-msec burst. Using confocal microscopy and image analysis, we obtained quantitative measurements of the percentage removal of biofilms from different locations in the IP space. The 3D geometry of the typodont and the IP spaces was obtained by micro-computed tomography (µ-CT) imaging. We performed computational fluid dynamics (CFD) simulations to calculate the wall shear stress (τw) distribution caused by the drops on the tooth surface. A qualitative agreement and a quantitative relationship between experiments and simulations were achieved. The wall shear stress (τw) generated by the prototype AirFloss and its spatial distribution on the teeth surface played a key role in dictating the efficacy of biofilm removal in the IP space. [ABSTRACT FROM PUBLISHER]

Cytomegalovirus antiviral resistance may occur in up to 17.6% of viremic lung transplant recipients, with viremic kidney transplant recipient risk up to 6.2%. Risk is higher among seronegative recipients of seropositive organs. Diagnostic and therapeutic management strategies are discussed.Despite advances in the prophylaxis and acute treatment of cytomegalovirus (CMV), it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. There is increasing use of antiviral prophylaxis after transplant with little expansion in the range of antiviral agents effective in treatment of CMV. Further understanding is needed of the risk factors for development of CMV antiviral resistance and of therapeutic strategies for treating patients infected with resistant viruses. We review the current status of CMV resistance in solid organ transplant recipients, and provide diagnostic and therapeutic suggestions for the clinician in managing antiviral resistance. [ABSTRACT FROM PUBLISHER]

Leukocytic infiltration is a common feature of human cancers, including those that develop in immunoprivileged sites, such as the eye. The infiltration of myeloid and T cells into tumours is part of the host response against cancer. In uveal melanoma, high densities of immune cells seem to be involved in tumour progression, as they are associated with the loss of one chromosome 3. The nature of this tumour microenvironment might offer therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Leukocytic infiltration is a common feature of human cancers, including those that develop in immunoprivileged sites, such as the eye. The infiltration of myeloid and T cells into tumours is part of the host response against cancer. In uveal melanoma, high densities of immune cells seem to be involved in tumour progression, as they are associated with the loss of one chromosome 3. The nature of this tumour microenvironment might offer therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Objective To determine the most effective induction disease-modifying antirheumatic drug (DMARD) strategy in early rheumatoid arthritis (RA), second to compare one single dose of intramuscular glucocorticoids (GCs) with daily oral GCs during the induction phase. Methods The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis (tREACH) were used. Patients were included who had a high probability (>70%) of progressing to persistent arthritis, based on the prediction model of Visser. Patients were randomised into three induction therapy strategies: (A) combination therapy (methotrexate (MTX) + sulfasalazine + hydroxychloroquine) with GCs intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. A total of 281 patients were randomly assigned to strategy (A) (n=91), (B) (n=93) or (C) (n=97). Results The Disease Activity Score (DAS) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67 to 0.11, 95% CI)). DAS did not differ between the different GC bridging treatments. After 3 months 50% fewer biological agents were prescribed in the combination therapy groups. Although the proportion of patients with medication adjustments differed signifi cantly between the treatment arms, no differences were seen in these adjustments due to adverse events after stratifi cation for drug. Conclusion Triple DMARD induction therapy is better than MTX monotherapy in early RA. Furthermore, no differences were seen in medication adjustments due to adverse events after stratifi cation for drug. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used. [ABSTRACT FROM AUTHOR]

The prognosis of patients with uveal melanoma is poor. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. Because p53 mutations are uncommon in uveal melanoma, reactivation of p53 may be used to achieve tumor regression. We investigated the use of combination therapies for intraocular melanoma, based on the p53 activators Nutlin-3 and reactivation of p53 and induction of tumor cell apoptosis (RITA) and the topoisomerase I inhibitor Topotecan. Nutlin-3 treatment induced p53-dependent growth inhibition in human uveal melanoma cell lines. The sensitivity to Nutlin-3 of the investigated cell lines did not correlate with basal Hdm2 or Hdmx levels. Nutlin-3 synergized with RITA and Topotecan to induce apoptosis in uveal melanoma cell lines and short-term cultures. Drug synergy correlated with enhanced induction of p53-Ser46 phosphorylation, which was attenuated by ATM inhibition. Nutlin-3 and Topotecan also significantly delayed tumor growth in vivo in a murine B16F10 model for ocular melanoma. Combination treatment appeared to inhibit tumor growth slightly more efficient than either drug alone. Nutlin-3, RITA and Topotecan lead to comparable p53 activation and growth inhibition under normoxia and hypoxia. Treatment with Nutlin-3 or RITA had no effect on HIF-1α induction by hypoxia, whereas the combination of these two drugs did inhibit hypoxia-induced HIF-1α. Also Topotecan, alone or in combination with Nutlin-3, reduced HIF-1α protein levels, suggesting that a certain level of DNA damage response is required for p53-mediated downregulation of HIF-1α. In conclusion, combination treatments based on small-molecule-induced p53 activation may have clinical potential for uveal melanoma. [ABSTRACT FROM AUTHOR]

Chronic diseases can have a great influence on health-related quality of life. Nevertheless, only little research has been carried out on childhood psoriasis. The perception of quality of life by adults with psoriasis of their childhood psoriasis has never been investigated. The aims of this study were to (i) investigate retrospectively the influence of psoriasis as experienced in childhood as compared with the current quality of life in adulthood; (ii) assess retrospectively the impact of childhood psoriasis on daily life; and (iii) compare the current quality of life in patients with childhood onset psoriasis (COP) and adult onset psoriasis (AOP). A survey was performed among all members of the Dutch Psoriasis Society. Validated questionnaires on quality of life, impact on daily life and clinical severity were used. Questionnaires of 1762 patients were suitable for analysis. Adults with an onset of psoriasis before the age of 18 years retrospectively rate their quality of life during childhood much less as compared with their current quality of life (intrapatient comparison). Influence of psoriasis in childhood particularly had a high degree of limitations on recreational and social activities in 15-30% of patients. Quality of life in adulthood is not determined by age of onset of psoriasis. In childhood, the quality of life is greatly influenced by psoriasis. The social development domain, which is one of the developmental milestones in a child, is particularly impaired. The current quality of life of patients with COP is equal to that of patients with AOP. [ABSTRACT FROM AUTHOR]

Psoriatic lesions may involve nearly all sites of the body. Involvement of the genital skin is frequently classified as part of intertriginous psoriasis without special awareness and treatment for this presentation of the disease. Gaining knowledge about the frequency of the involvement of genital skin in these patients will improve the overall care for patients with psoriasis. We studied the prevalence of genital psoriasis in the Netherlands and epidemiological characteristics of this specific presentation of the disease. Furthermore, we studied the relation between flexural and genital psoriasis. A self-administered questionnaire was sent to all 5300 members of the Dutch Psoriasis Society. Sociodemographic patient characteristics and disease-related data (such as localization of psoriatic lesions, involvement of the genitalia, age at onset of genital psoriasis and severity of genital psoriatic lesions) were collected and analysed. A response rate of 37% was achieved. Almost 46% of the responding patients with psoriasis, that is 16.5% of all potential responders ( n = 5300), report genital involvement at some time during the course of their disease. The genitalia can become affected at any age. Many patients with current genital involvement (38%) do not have the flexural skin affected. A large part of patients with psoriasis suffer from genital psoriasis, which was not associated with flexural involvement in at least one third of them. More attention to the genital region is required in the current standard treatment of both male and female psoriatic patients at any age. [ABSTRACT FROM AUTHOR]