Narrative enhancement and cognitive therapy (NECT) to improve social functioning in people with serious mental illness: study protocol for a stepped-wedge cluster randomized controlled trial.

BACKGROUND: Self-stigma is highly prevalent in serious mental illness (SMI) and is associated with poorer clinical and functional outcomes. Narrative enhancement and cognitive therapy (NECT) is a group-based intervention combining psychoeducation, cognitive restructuring and story-telling exercises to reduce self-stigma and its impact on recovery-related outcomes. Despite evidence of its effectiveness on self-stigma in schizophrenia-related disorders, it is unclear whether NECT can impact social functioning. METHODS: This is a 12-centre stepped-wedge cluster randomized controlled trial of NECT effectiveness on social functioning in SMI, compared to treatment as usual. One hundred and twenty participants diagnosed with schizophrenia, bipolar disorder or borderline personality disorder will be recruited across the 12 sites. The 12 centres participating to the study will be randomized into two groups: one group (group 1) receiving the intervention at the beginning of the study (T0) and one group (group 2) being a control group for the first 6 months and receiving the intervention after (T1). Outcomes will be compared in both groups at T0 and T1, and 6-month and 12-month outcomes for groups 1 and 2 will be measured without a control group at T2 (to evaluate the stability of the effects over time). Evaluations will be conducted by assessors blind to treatment allocation. The primary outcome is personal and social performance compared across randomization groups. Secondary outcomes include self-stigma, self-esteem, wellbeing, quality of life, illness severity, depressive symptoms and personal recovery. DISCUSSION: NECT is a promising intervention for reducing self-stigma and improving recovery-related outcomes in SMI. If shown to be effective in this trial, it is likely that NECT will be implemented in psychiatric rehabilitation services with subsequent implications for routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03972735 . Trial registration date 31 May 2019.

Immunogenicity and Protective Efficacy of an Intranasal Live-attenuated Vaccine Against SARS-CoV-2 in Preclinical Animal Models

The global deployment of an effective and safe vaccine is currently a public health priority to curtail the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a Newcastle disease virus (NDV)-based intranasal vectored-vaccine in mice and hamsters for its immunogenicity, safety and protective efficacy in challenge studies with SARS-CoV-2. The recombinant (r)NDV-S vaccine expressing spike (S) protein of SARS-CoV-2 administrated via intranasal route in mice induced high levels of SARS-CoV-2-specific neutralizing immunoglobulin A (IgA) and IgG2a antibodies and T cell-mediated immunity. Hamsters vaccinated with two doses of vaccine showed complete protection from clinical disease including lung infection, inflammation, and pathological lesions after SARS-CoV-2 challenge. Importantly, a single or double dose of intranasal rNDV-S vaccine completely blocked SARS-CoV-2 shedding in nasal turbinate and lungs within 4 days of vaccine administration in hamsters. Taken together, intranasal administration of rNDV-S has the potential to control infection at the site of inoculation, which should prevent both the clinical disease and transmission to halt the spread of the COVID-19 pandemic.

Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines.

Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.

Splenic Capture and In Vivo Intracellular Biodegradation of Biological-Grade Graphene Oxide Sheets.

Carbon nanomaterials, including 2D graphene-based materials, have shown promising applicability to drug delivery, tissue engineering, diagnostics, and various other biomedical areas. However, to exploit the benefits of these materials in some of the areas mentioned, it is necessary to understand their possible toxicological implications and long-term fate in vivo. We previously demonstrated that following intravenous administration, 2D graphene oxide (GO) nanosheets were largely excreted via the kidneys; however, a small but significant portion of the material was sequestered in the spleen. Herein, we interrogate the potential consequences of this accumulation and the fate of the spleen-residing GO over a period of nine months. We show that our thoroughly characterized GO materials are not associated with any detectable pathological consequences in the spleen. Using confocal Raman mapping of tissue sections, we determine the sub-organ biodistribution of GO at various time points after administration. The cells largely responsible for taking up the material are confirmed using immunohistochemistry coupled with Raman spectroscopy, and transmission electron microscopy (TEM). This combination of techniques identified cells of the splenic marginal zone as the main site of GO bioaccumulation. In addition, through analyses using both bright-field TEM coupled with electron diffraction and Raman spectroscopy, we reveal direct evidence of in vivo intracellular biodegradation of GO sheets with ultrastructural precision. This work offers critical information about biological processing and degradation of thin GO sheets by normal mammalian tissue, indicating that further development and exploitation of GO in biomedicine would be possible.

The use of flow cytometry to examine calcium signalling by TRPV1 in mixed cell populations.

Flow cytometric analysis of calcium mobilisation has been in use for many years in the study of specific receptor engagement or isolated cell:cell communication. However, calcium mobilisation/signaling is key to many cell functions including apoptosis, mobility and immune responses. Here we combine multiplex surface staining of whole spleen with Indo-1 AM to visualise calcium mobilisation and examine calcium signaling in a mixed immune cell culture over time. We demonstrate responses to a TRPV1 agonist in distinct cell subtypes without the need for cell separation. Multi parameter staining alongside Indo-1 AM to demonstrate calcium mobilization allows the study of real time calcium signaling in a complex environment.

Dentinal tubules occluded by bioactive glass-containing toothpaste exhibit high resistance toward acidic soft drink challenge.

BACKGROUND: Dentine hypersensitivity is a common problem attributed by patent dentinal tubules. Ingredients incorporated in toothpastes aim to occlude patent dentinal tubules to minimize the dentine hypersensitivity. However, frequent consumption of acidic soft drinks may reverse the dentinal tubules' occlusion. In this in vitro study, the efficacy of dentinal tubules occluded by commercially available toothpastes to withstand different durations of an acidic soft drink challenge was investigated. METHODS: One hundred and twenty dentine discs were divided into three groups. The discs from each group were brushed with toothpaste containing bioactive glass, arginine and control toothpaste. Each group was then divided into four subgroups and exposed to acidic soft drink over four different time durations. RESULTS: The scoring and the percentage of occluded dentinal tubules by Novamin-containing toothpaste was significantly better compared with arginine or the control toothpaste. Acidic soft drink challenge reduced the extent of dentinal tubules occlusion along with time. Dentinal tubules occluded by Novamin-containing toothpaste withstand the acidic challenge comparatively for a longer period. CONCLUSIONS: The findings demonstrated that occlusion of dentinal tubules is more efficient by the bioactive glass-containing toothpaste and thus may contribute to its better resistance to acidic soft drink challenge.

In vitro expression of Candida albicans alcohol dehydrogenase genes involved in acetaldehyde metabolism.

Alcohol consumption is a risk factor for oral cancer, possibly via its conversion to acetaldehyde, a known carcinogen. The oral commensal yeast Candida albicans may be one of the agents responsible for this conversion intra-orally. The alcohol dehydrogenase (Adh) family of enzymes are involved in acetaldehyde metabolism in yeast but, for C. albicans it is not known which family member is responsible for the conversion of ethanol to acetaldehyde. In this study we determined the expression of mRNAs from three C. albicans Adh genes (CaADH1, CaADH2 and CaCDH3) for cells grown in different culture media at different growth phases by Northern blot analysis and quantitative reverse transcription polymerase chain reaction. CaADH1 was constitutively expressed under all growth conditions but there was differential expression of CaADH2. CaADH3 expression was not detected. To investigate whether CaAdh1p or CaAdh2p can contribute to alcohol catabolism in C. albicans, each gene from the reference strain C. albicans SC5314 was expressed in Saccharomyces cerevisiae. Cell extracts from an CaAdh1p-expressing S. cerevisiae recombinant, but not an CaAdh2p-expressing recombinant, or an empty vector control strain, possessed ethanol-utilizing Adh activity above endogenous S. cerevisiae activity. Furthermore, expression of C. albicans Adh1p in a recombinant S. cerevisiae strain in which the endogenous ScADH2 gene (known to convert ethanol to acetaldehyde in this yeast) had been deleted, conferred an NAD-dependent ethanol-utilizing, and so acetaldehyde-producing, Adh activity. We conclude that CaAdh1p is the enzyme responsible for ethanol use under in vitro growth conditions, and may contribute to the intra-oral production of acetaldehyde.

Detection of Candida albicans ADH1 and ADH2 mRNAs in human archival oral biopsy samples.

OBJECTIVES: The aim of this study was to investigate the relationship between expression of Candida albicans alcohol dehydrogenases (ADH) genes in archival formalin-fixed paraffin-embedded (FFPE) samples from biopsies of leukoplakia. MATERIALS AND METHODS: Archival FFPE samples were obtained from four sample groups: normal oral mucosa, non-dysplastic leukoplakia, chronic hyperplastic candidosis (CHC), and non-CHC dysplastic leukoplakia. The presence of C. albicans was determined by periodic acid Schiff staining and by immunocytochemistry. C. albicans ADH1 and ADH2 mRNAs were detected using reverse transcription PCR. RESULTS: Candida albicans was detected in FFPE samples diagnosed as CHC (the histological diagnoses had been made by specialist oral pathologists, using uniform criteria), but not in any other sample group, including the non-dysplastic leukoplakias. RT-PCR confirmed a significant correlation between the expression of CaADH1 mRNA (P = 0.000), but not for CaADH2 mRNA (P = 0.056) in archival FFPE samples (n = 31) from biopsies of leukoplakia. CONCLUSIONS: Candida albicans was the predominant species in the lesions diagnosed as CHC, and the presence of C. albicans in CHC lesions was associated with a high expression of C. albicans ADH1 mRNA. There was no association between the presence of Candida and malignant transformation in the cases examined; however, the number of cases was limited and further studies are needed to further elucidate the role of C. albicans ADH1 in the pathogenesis of oral squamous cell carcinoma.

Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis.

The question of how the neural and immune systems interact in host defense is important, integrating a system that senses the whole body with one that protects. Understanding the mechanisms and routes of control could produce novel and powerful ways of promoting and enhancing normal functions as well as preventing or treating abnormal functions. Fragmentation of biological research into specialities has resulted in some failures in recognizing and understanding interactions across different systems and this is most striking across immunology, hematology, and neuroscience. This reductionist approach does not allow understanding of the in vivo orchestrated response generated through integration of all systems. However, many factors make the understanding of multisystem cross-talk in response to a threat difficult, for instance the nervous and immune systems share communication molecules and receptors for a wide range of physiological signals. But, it is clear that physical, hard-wired connections exist between the two systems, with the key link involving sensory, unmyelinated nerve fibers (c fibers) containing the neuropeptide calcitonin gene-related peptide (CGRP), and modified macrophages, mast cells and other immune and host defense cells in various locations throughout the body. In this review we will therefore focus on the induction of CGRP and its key role in the neuroimmune axis.

Circulating-water garment or the combination of a circulating-water mattress and forced-air cover to maintain core temperature during major upper-abdominal surgery.

BACKGROUND: A recent heat-balance study in volunteers suggested that greater efficacy of circulating-water garments (CWGs) results largely from increased heat transfer across the posterior skin surface since heat transfer across the anterior skin surface was similar with circulating-water and forced-air. We thus tested the hypothesis that the combination of a circulating-water mattress (CWM) and forced-air warming prevents core temperature reduction during major abdominal surgery no worse than a CWG does. METHODS: Fifty adult patients aged between 18 and 85 yr old, undergoing major abdominal surgery, were randomly assigned to intraoperative warming with a combination of forced-air and a CWM or with a CWG (Allon ThermoWrap). Core temperature was measured in the distal oesophagus. Non-inferiority of the CWM to the CWG on change from baseline to median intraoperative temperature was assessed using a one-tailed Student's t-test with an equivalency buffer of -0.5°C. RESULTS: Data analysis was restricted to 16 CWG and 20 CWM patients who completed the protocol. Core temperature increased in both groups during the initial hours of surgery. We had sufficient evidence (P=0.001), to conclude that the combination of a CWM and forced-air warming was non-inferior to a CWG in preventing temperature reduction, with mean (95% CI) difference in the temperature change between the CWM and the CWG groups (CWM-CWG) of 0.46°C (-0.09°C, 1.00°C). CONCLUSIONS: The combination of a CWM and forced-air warming is significantly non-inferior in maintaining intraoperative core temperature than a CWG. TRIAL REGISTRY: This trial has been registered at clinical trials.gov, identifier: NCT 00651898.

Some aspects in the control of schistosomosis and soil-transmitted helminthosis in Yemeni children.

OBJECTIVE: Prevalence, intensity and incidence of schistosomosis and soil-transmitted helminthosis among school children in an ignored area in Yemen were determined. The study aimed to investigate the impact of single doses of Praziquantel or Albenedazole or both, relating to sanitary, socioeconomic and behavioral practices on the prevalence and intensity of infections. METHODS: Out of a total number of 897 pupils, 453 were randomly selected from AlMahweet town and 444 from rural surrounding areas. Millipore filtration, modified Kato and precipitation techniques were applied for urine and stool analysis. RESULTS: Prevalence rates were 27% for schistosomosis, 61% for ascariosis, 21% for trichuriosis, 2% for fascilosis, 0.3% for entrobiosis, 0.7% for hook worm infection and 0.2% for strongloydiosis. Factors found confounding the relationship between schistosomosis and residence, under logistic regression analysis, were sex and frequency of water contact. Probability of infection by Bilharzia for boys who reside in rural AlMahweet and visit the water source is 0.52, compared to 0.30 for their mates who reside in AlMahweet town. Odds ratio estimates accounted for via residence was 2.5, via water contact 1.7 and via boys 3.2. With regards to other helminthic infections, availability of latrines remained the only significant factor under ANOVA. CONCLUSION: In conclusion, annual campaigns for treatment as a single control measure can reduce the infection rate of S. mansoni by 62.5%, T. trichura by 48% and A. lumbricoides by 24%. Whereas for S. hematobium the appropriate time interval for intervention should be shortened according to the findings of a properly designed intervention study before used as a single control measure. Since 77% of the children were infected by other helminthes, therefore mass treatment should be extended to cover all children. For those boys in rural AlMahweet who visited the water source during the week before the interview, mass treatment for schistosomosis is recommended since the prediction of infection rate reached 52%.

A hepatitis C virus (HCV) core protein derived peptide inhibits HCV specific lymphocyte proliferation.

T helper lymphocytes are important regulatory cells for the immune response in chronic hepatitis C. They recognize peptides, which are generated from the viral proteins by antigen processing and are bound to MHC (major histocompatibility complex) class II molecules. However, antigen processing might also result in non-immunogenic peptide fragments that can modify T cell activation. - To identify such peptide fragments in hepatitis C, we studied binding of 15 synthetic HCV core derived peptides to MHC class II molecules of 9 human homozygous typing B cell lines (HT-BCLs) as well as T cell proliferation in 41 HLA-typed patients with chronic hepatitis C. - We identified a peptide (HCV core aa 59-83) which bound to 7 HT-BCLs, whereas PBMC of only 2 out of 36 patients with the corresponding HLA-DR alleles proliferated in response to this peptide. Competition experiments indicated that small amounts of peptide aa 59-83 specifically inhibited the proliferative response to the recombinant core protein but not to core derived immunogenic peptides. Our data show that a peptide fragment from the HCV core region aa 59-83 can interfere in vitro with immune recognition of the HCV core protein.

Semiquantitative analysis of intrahepatic cytokine mRNAs in chronic hepatitis C.

In order to characterize intrahepatic cytokine production, the mRNA levels of interleukin (IL)-2, -4, and -10 and interferon (IFN)-gamma were semiquantitatively determined by reverse-transcription competitive polymerase chain reaction in liver specimens from patients with chronic hepatitis C (n = 23), chronic hepatitis B (n = 9), or primary biliary cirrhosis (n = 12) and normal liver (control) specimens (n = 12). IL-4 mRNA was undetectable. Similar IL-10 mRNA levels were detected in all samples studied, including the controls. Mean IFN-gamma and IL-2 mRNA levels were elevated in chronic inflammatory liver disease. IL-2 mRNA levels were similar in all 3 patient groups, but intrahepatic IFN-gamma mRNA levels were significantly higher in chronic hepatitis C than in chronic hepatitis B or primary biliary cirrhosis patients. This predominance of IFN-gamma may indicate a lower susceptibility of hepatitis C virus to the antiviral effects of this cytokine. The presence of IL-10 in normal liver may impair the induction of antiviral immune responses.

Racial variations in the extent of tooth root translucency in ageing individuals.

One hundred and ninety-eight single-rooted teeth from individuals aged 21-90 yr of Caucasian, Malay, Chinese Malay and Indian Malay origin were studied. Single or serial longitudinal sections of extracted teeth were cut following dye imbibition of patent dentinal tubules. The extent of sclerosis of apical dentinal tubules was assessed and correlated with the age of the individual. Correlation with age was higher in the Caucasian than the Malay races and within the Malaysian racial groups correlation with age was highest in the Malays and lowest in the Chinese. It is concluded that factors other than age may be important in the formation of sclerotic apical dentine in teeth of different racial origin. The effect of racial origin should be considered when using sclerosis as a means of age determination in forensic cases.

Severe progressive periodontal destruction due to radiation tissue injury.

Cancer radiotherapy to the head and neck region results in short- and long-term radiation tissue injuries. Radiation bone injury is a long-term manifestation which could progress to osteoradionecrosis. A case of radiation tissue injury to the periodontium is presented. The possible pathogenesis of these events is described as they relate to the sequential radiographic changes observed over a period of 6 years until the involved teeth were exfoliated. The post-irradiation management of the teeth with advancing periodontal disease in the path of irradiation was by conservative means, including good personal oral hygiene care, scaling and root planing, periodic chlorhexidine irrigation, and topical fluoride application.

Brequinar sodium inhibits interleukin-6-induced differentiation of a human B-cell line into IgM-secreting plasma cells.

Brequinar sodium (BQR) has been shown recently to be a potent immunosuppressive agent. This property has been attributed to the capacity of BQR to inhibit de novo pyrimidine nucleoside biosynthesis and consequently, to blockade the synthesis both of DNA and RNA. The influence of this new immunosuppressant on lymphocyte function has not been fully characterized. To determine the potential efficacy of BQR for the control of antibody-mediated graft rejection, which is of particular significance in the context of xenotransplantation, we have examined the influence of the drug on interleukin-6-dependent IgM production by the human B-cell line, SKW 6.4. At concentrations up to 10 micrograms/ml, BQR did not affect concanavalin A (Con A)-induced human peripheral blood lymphocyte proliferation or IL-6 production by blood mononuclear leucocytes. In contrast, the drug was very effective in inhibiting IL-6-stimulated IgM production by SKW 6.4 cells, with an optimal inhibitory concentration of 0.3 microgram/ml. As expected, addition of exogenous uridine (0.1 mM), the precursor of uridine triphosphate (UTP), reversed the inhibitory effect of BQR on antibody production, while cytidine (0.1 mM) potentiated the inhibitory activity of the drug. It was further demonstrated that the inhibition of IgM production was unrelated to DNA synthesis, indicating that BQR may affect IL-6 signal transduction and IgM production in SKW 6.4 cells independent of any effect on cell proliferation.

A recording differential respirometer.

A recording differential respirometer capable of micromeasurement of gaseous changes is described. The rate of volume change under constant pressure is recorded directly. Due to the mechanical nature of the volume measurement, the instrument is drift-free. Factors affecting the sensitivity and correction for deviation due to change in total volumes are discussed.