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Aim: To determine the expression and distribution of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the normal human iris and ciliary body. Methods: Seven postmortem human eyes were fixed [...]

Background: Experiences of end-of-life care and early bereavement during the COVID-19 pandemic are poorly understood. Aim: To identify clinical and demographic risk factors for sub-optimal end-of-life care and pandemic-related challenges prior to death and in early bereavement, to inform clinical practice, policy and bereavement support. Design: Online national survey of adults bereaved in the UK (deaths between 16 March 2020 and 2 January 2021), recruited via media, social media, national associations and organisations. Setting/participants: 711 participants, mean age 49.5 (SD 12.9, range 18–90). 628 (88.6%) were female. Mean age of the deceased was 72.2 (SD 16.1, range miscarriage to 102 years). 311 (43.8%) deaths were from confirmed/suspected COVID-19. Results: Deaths in hospital/care home increased the likelihood of poorer experiences at the end of life; for example, being unable to visit or say goodbye as wanted (p < 0.001). COVID-19 was also associated with worse experiences before and after death; for example, feeling unsupported by healthcare professionals (p < 0.001), social isolation/loneliness (OR = 0.439; 95% CI: 0.261–0.739), and limited contact with relatives/friends (OR = 0.465; 95% CI: 0.254–0.852). Expected deaths were associated with a higher likelihood of positive end-of-life care experiences. The deceased being a partner or child also increased the likelihood of positive experiences, however being a bereaved partner strongly increased odds of social isolation/loneliness, for example, OR = 0.092 (95% CI: 0.028–0.297) partner versus distant family member. Conclusions: Four clear risk factors were found for poorer end-of-life care and pandemic-related challenges in bereavement: place, cause and expectedness of death, and relationship to the deceased. [ABSTRACT FROM AUTHOR]

Background/aim: Anterior uveitis is a common inflammatory ocular disease characterised by protein accumulation and leucocyte infiltration in the anterior chamber. The aim of this study was to determine the expression [...]

Schnitzler syndrome is a rare, auto inflammatory condition known to manifest with bone pain, urticarial rash, fevers, relapsing arthralgia, and fatigue. In this case report, we describe a patient who was diagnosed with Schnitzler Syndrome that had initially presented with a unilateral pressure-type headache with a sensation of a 'dagger' stabbing into the back of the eye. He also had an associated ipsilateral redness of the conjunctiva, eyelid swelling, subtle optic disc elevations bilaterally and facial flushing - but with no visual acuity, pupillary, or lacrimatory changes. Anterior segment, fundoscopy, intraocular pressures and extraocular muscle movements were otherwise normal. [ABSTRACT FROM AUTHOR]

Background: A detailed description of the natural history of acute Q fever, caused by infection with Coxiella burnetii. Aim: To significantly increase understanding of the illness. Design: Subjects with provisional acute Q fever (n=115) were recruited from primary care in rural Australia, and followed prospectively by interview and blood collection including for serological confirmation. A nested series of subjects with prolonged illness (cases), and those without (controls), were investigated in detail. Methods: Total phase I and phase II anti-C. burnetii antibodies were detected by complement fixation test; and IgG, IgM and IgA phase I and phase II titres by immunofluorescence. Flow cytometric analysis was conducted to enumerate circulating T cells subsets, B cells, monocytes and natural killer cells. Results: Serological testing confirmed acute Q fever in 73 subjects (63%). The acute illness featured fever, headache, sweats, fatigue and anorexia; and varied widely in severity, causing an average of 8 days in bed and 15 days out of work or other role in the first month of illness. The illness course varied from 2 days to greater than a year. No cases of chronic, localized Q fever infection, such as endocarditis, were identified. Neither severe nor prolonged illness were associated with persistence of C. burnetii DNA, altered patterns of C. burnetii-specific IgG, IgM or IgA antibody production, or altered leucocyte subsets. Conclusions: The severity of acute Q fever alone predicted prolonged duration. Further studies are warranted to better understand the pathophysiology of prolonged illness after acute Q fever. [ABSTRACT FROM AUTHOR]

Stem cell (SC) division, deployment, and differentiation are processes that contribute to corneal epithelial renewal. Until now studying the destiny of these cells in a living mammal has not been possible. However, the advent of inducible multicolor genetic tagging and powerful imaging technologies has rendered this achievable in the translucent and readily accessible murine cornea. K14CreERT2-Confetti mice that harbor two copies of the Brainbow 2.1 cassette, yielding up to 10 colors from the stochastic recombination of fluorescent proteins, were used to monitor K-14+ progenitor cell dynamics within the corneal epithelium in live animals. Multicolored columns of cells emerged from the basal limbal epithelium as they expanded and migrated linearly at a rate of 10.8 µm/day toward the central cornea. Moreover, the permanent expression of fluorophores, passed on from progenitor to progeny, assisted in discriminating individual clones as spectrally distinct streaks containing more than 1,000 cells within the illuminated area. The centripetal clonal expansion is suggestive that a single progenitor cell is responsible for maintaining a narrow corridor of corneal epithelial cells. Our data are in agreement with the limbus as the repository for SC as opposed to SC being distributed throughout the central cornea. This is the first report describing stem/progenitor cell fate determination in the murine cornea using multicolor genetic tracing. This model represents a powerful new resource to monitor SC kinetics and fate choice under homeostatic conditions, and may assist in assessing clonal evolution during corneal development, aging, wound-healing, disease, and following transplantation. S tem C ells 2015;33:157-169 [ABSTRACT FROM AUTHOR]

Abstract: Stem cell (SC) therapy is the main treatment modality for patients with limbal stem cell deficiency. If limbal epithelial stem cells (LESC) can be more readily identified, isolated and maintained ex vivo, patients could be treated with better quality grafts. With prior knowledge that vitronectin (VN) is present within the LESC niche and that it supports LESC in vitro, we postulated that VN receptors (integrins αvβ3/5) are expressed by, and can be used to identify and isolate LESC. Immunolocalization studies were conducted on human corneas. Corneas were also used to expand limbal epithelial cells from either biopsies or enzyme-dissociated tissue and αvβ3/5 expression determined by flow cytometry. Integrin expressing cells were isolated by magnetic activated cell sorting then assessed by immunocytology, colony forming efficiency, RT-PCR and microarray analysis. Integrin αvβ5+ cells co-localized to N-cadherin+/CK-15+ putative LESC. αvβ5 was restricted to less than 4% of the total limbal epithelial cells, which expressed higher levels of CK-15 and formed more colonies compared to αvβ5− cells. Transcriptional profiling of αvβ5+/− cells by microarray identified several highly expressed interferon-inducible genes, which localize to putative LESC. Integrin αvβ5 is a candidate LESC marker since its expression is restricted to the limbus and αvβ5+ limbal epithelial cells have phenotypic and functional properties of LESC. Knowledge of the niche's molecular composition and the genes expressed by its SC will facilitate isolation and maintenance of these cells for therapeutic purposes. [Copyright &y& Elsevier]

Objective: To examine the role of mast cells (MCs), cytokines, and matrix metalloproteinases (MMPs) following ultraviolet B (UVB) radiation in cutaneous lupus erythematosus (CLE). Methods: Immunohistochemistry was used to determine the presence of MCs and the expression of MMP-1, MMP-9, interleukin (IL)-15, and CCL5//RANTES in skin from patients with CLE. Human keratinocytes were exposed to varying doses of UVB and supernatants were collected and assessed for IL-15, CCL5, MMP-1, and MMP-9 by protein assays. MC migration was determined against supernatants from UVB-treated keratinocytes. Results: MCs in the skin of patients with CLE were significantly increased. MMP-1 and MMP-9 expression was abundant in these lesions. Intense reactivity for IL-15 and CCL5 was found in skin, particularly in epidermal keratinocytes, from patients with CLE. UVB irradiation induced IL-15, CCL5, MMP-1, and MMP-9 production from keratinocytes in a dose- and time-dependent manner. Supernatants obtained from UVB-treated keratinocytes induced MC migration, which was attenuated by anti-IL-15 and anti-CCL5 neutralizing antibodies. IL-15 induced MC-derived MMP production. Conclusions: Our results indicate that MCs and MMPs may play a role in the skin inflammation in CLE. MC recruitment as well as MMP production may be perpetuated by UV irradiation through locally released mediators. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMP) overexpression has been implicated in the pathogenesis of colorectal carcinoma (CRC). Accumulating evidence suggests that MMP promoter single nucleotide polymorphisms (SNPs) effecting gene transcription are associated with enhanced susceptibility for the development of malignant disease, increased tumour invasiveness and poor patient survival. The aim of the current investigation was to determine whether such associations exist in a large CRC patient/control study population. Using an allelic discrimination real-time polymerase chain reaction, polymorphisms in the MMP-1, MMP-2 and MMP-3 gene promoters (−1607, −1306, and −1612 bp, respectively) were assessed in normal blood mononuclear cells from patients with CRC (n=503) and control subjects (n=471). Genotypes corresponding to each MMP SNP were correlated with tumour characteristics and clinical outcome. The frequency of each genotype was not statistically different between patients and control subjects and no significant differences were noted between the genotypes and tumour characteristics for the three MMP SNPs. CRC patients with the 2G/2G genotype for the MMP-1 SNP had significantly better 5-year survival compared to patients with a 1G allele (P<0.05). Our results demonstrate that CRC patients with a 2G/2G genotype in the MMP-1 gene promoter SNP have a favourable prognosis. Although our results were unexpected, given that this genotype is associated with enhanced MMP-1 transcriptional activity, they are consistent with recent data highlighting the anti-tumorigenic properties of MMPs.British Journal of Cancer (2007) 96, 783–792. doi:10.1038/sj.bjc.6603630 www.bjcancer.com Published online 20 February 2007 [ABSTRACT FROM AUTHOR]

BACKGROUND: Primary Epstein-Barr virus (EBV) infection causes a spectrum of characteristics that range from asymptomatic seroconversion to severe infectious mononucleosis (IM), sometimes with prolonged symptoms and disability. We examined the relationships between clinical course, number of viral copies, and immunological parameters in a prospective cohort of subjects with recent IM. METHODS: Eight case patients with at least 6 months of disabling symptoms and 31 matched control subjects who had recovered promptly were included. Symptom scores were recorded at regular intervals over the course of 12 months. Cellular EBV load, EBV-specific antibody responses, lymphocyte subsets, and EBV-specific interferon (IFN)- gamma induction were measured. RESULTS: In case patients with prolonged illness, the severity of acute-phase symptoms was greater, the development of anti-EBV nuclear antigen-1 immunoglobulin G was more rapid, and the time to development of the peak IFN- gamma response to the majority of latent-cycle EBV peptides was generally slower than those in control subjects. However, in both groups, neither viral nor immune parameters correlated with the severity or duration of symptoms. CONCLUSIONS: The resolution of symptomatic IM is not determined by control of viremia, nor is it easily explained by altered host responses to EBV infection. The detailed determinants of delayed recovery remain to be elucidated. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

This study explores the relationships among measures of nurses' perceptions of organizational culture, continuous quality improvement (CQI) implementation, and medication administration error (MAE) reporting. Hospital-based nurses were surveyed using measures of organizational culture and CQI implementation. These data were combined with previously collected data on perceptions of MAE reporting. A group-oriented culture had a significant positive correlation with CQI implementation, whereas hierarchical and rational culture types were negatively correlated with CQI implementation. Higher barriers to reporting MAE were associated with lower perceived reporting rates. A group-oriented culture and a greater extent of CQI implementation were positively (but not significantly) associated with the estimated overall percentage of MAEs reported. We conclude that health care organizations have implemented CQI programs, yet barriers remain relative to MAE reporting. There is a need to assess the reliability, validity, and completeness of key quality assessment and risk management data. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose: To demonstrate the safety and effectiveness of intravenous methylprednisolone (IVMP) in the treatment of uveitis in association with multiple sclerosis (MS). Methods: Uveitis is an unusual manifestation of MS that may be severe, chronic and require systemic immunosuppression therapy. High-dose IVMP has previously been shown to be effective in the treatment of inflammatory eye disease and MS. Eight episodes of uveitis in five patients with MS were treated over a 10-year period in an open, uncontrolled trial. Two patients had chronic anterior uveitis, one patient had bilateral panuveitis and two patients had intermediate uveitis. Results: All patients responded to IVMP with evidence of a decrease in intraocular inflammatory activity and improved visual acuity (VA) within 2 weeks of commencing treatment. There were no severe ocular or systemic steroid side effects. Conclusions: Intravenous methylprednisolone is an effective, well-tolerated form of therapy for uveitis in patients with MS. [ABSTRACT FROM AUTHOR]

Murine studies have demonstrated that the presence of indigenous gut flora is crucial for the induction of systemic immune hyporesponsiveness to antigens initially encountered within the gastrointestinal lumen. This study investigated whether increased titers of such flora, as occur in human small intestinal bacterial overgrowth, may be associated with increased suppression of systemic immune responsiveness and the possible relation between systemic and mucosal immunity in this setting. Serum total immunoglobulin (Ig), immunoglobulin subclass, and soluble interleukin-2 receptor levels and lamina propria IgA plasma cell counts were determined in 50 consecutive subjects with (N = 30) and without (N = 20) small intestinal bacterial overgrowth. Luminal IgA levels were measured in 35 of these subjects. Serum concentrations of IgG3, but not of other immunoglobulin isotypes or soluble interleukin-2 receptors, were significantly reduced in subjects with bacterial overgrowth (P < 0.0005). Small intestinal lamina propria IgA plasma cell counts (P < 0.0005) and luminal IgA concentrations (P = 0.001) were significantly increased in this group. Serum IgG3 levels were significantly inversely correlated with luminal IgA levels (P < 0.01) and fell below the lower limit of normal (0.41 g/liter) in 17/30 (56.7%) subjects with bacterial overgrowth compared to 1/20 (5.0%) subjects without (P < 0.0005). These findings document an association between small intestinal bacterial overgrowth with indigenous gut flora and reduced serum IgG3 reactivity in humans, possibly via an interaction with mucosa-related immunoregulatory mechanisms. The possibility of underlying small intestinal bacterial overgrowth should be considered in patients with serum IgG3 deficiency, especially those with compatible symptoms and/or known predisposition. [ABSTRACT FROM AUTHOR]

Because the identification and reporting of medication administration errors (MAE) is a nonautomated and voluntary process, it is important to understand potential barriers to MAE reporting. This paper describes and analyzes a survey instrument designed to assist in evaluating the relative importance of 15 different potential MAE-reporting barriers. Based on the responses of over 1300 nurses and a confirmatory LISREL analysis, the 15 potential barriers are combined into 4 subscales: Disagreement Over Error, Reporting Effort, Fear, and Administrative Response. The psychometric properties of this instrument and descriptive profiles are presented. Specific suggestions for enhancing MAE reporting are discussed. [ABSTRACT FROM PUBLISHER]

The prevention of medication administration errors (MAEs) represents a central focus of hospitals' quality improvement and risk management initiatives. Because the identification and reporting of MAEs is a nonautomated and voluntary process, it is essential to understand the extent to which errors may not be reported. This study reports the results of 2 multihospital surveys in which over 1300 staff nurses in each survey estimated the extent to which various types of nonintravenous (non-i.v.) and intravenous (i.v.)-related MAEs are actually being reported on their nursing units. Overall, respondents estimated that about 60% of MAEs are actually being reported. Considerable differences in estimated rates of MAE reporting were found between staff and supervisors working on the same patient care units. A simulation based on actual and perceived rates of MAE reporting is presented to estimate the range of errors not being reported. Implications regarding the reliability, validity, and completeness of MAEs actually being reported are discussed. [ABSTRACT FROM AUTHOR]

The relationship between HLA B27 anterior uveitis (AU) and evidence of chlamydia trachomatis infection was investigated in 35 consecutive patients attending a uveitis research clinic, using a complement fixation test and lymphocyte transformation test to chlamydia (ornithosis-psittacosis) group antigen. A significant stimulation index (SI > 2) was found in 73% (11/15) of the HLA B27 positive patients compared with the HLA B27 negative AU patients and controls (P < 0.03). There was no difference between AU patients with and without associated rheumatic disease or in terms of antibody response. The results of the present study indicate a significant relationship between the cell-mediated immune response to chlamydia group antigen and the HLA B27 positive subgroup of patients with AU. [ABSTRACT FROM AUTHOR]

We have previously reported the association of Chlamydia trachomatis with HLA B27+ related diseases. To investigate the possibility that chlamydial antibodies serve to localize the immune response in such diseases, we examined the crossreactivity of chlamydial antibodies (rabbit anti-D and anti-L2serotypcs) with peripheral blood mononuclear cells of patients with ankylosing spondylitis (AS) and anterior uveitis (AU) and with human and bovine ocular tissue and cells in culture. Our results indicate a significantly increased percentage binding of chlamydial antibody (D serotype) lo the mononuclear cells of HLA B27+ patients with AS when compared with HLA B27- patients with AS (12.9% ± 2.2 versus 5.4%±2.2), B27+ controls (5.5% ±1.5) and B27- controls (6.1%±1.0). There was no significant difference between controls and HLA B27- patients with AU (6.6%±1.9) and B27- patients with AU (8.7%±1.1). This crossreactivity could not be blocked by monoclonal HLA B27 antibody. Chlamydial antibodies (D and L2) crossreact with human and bovine conjunctiva but not uvea, tissue culture derived iris fibroblasts or smooth muscle cells. Our results provide additional support for the concept of crossreactivity between antibodies to microbial agents and peripheral blood mononuclear cells of patients with HLA B27+ AS. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this paper is to explore the longitudinal relationships between physical and psychological symptoms and immunological factors following acute infective illnesses. METHOD: Preliminary data from a prospective investigation of patients with serologically proven acute infectious illnesses due to Epstein-Barr virus (EBV), Ross River virus (RRV) or Q fever are reported. Patients were assessed within 4 weeks of onset of symptoms and then reviewed 2 and 4 weeks later. Physical illness data were collected at interview. Psychological and somatic symptom profiles were assessed by standardised self-report questionnaires. Cell-mediated immune (CMI) function was assessed by measurement of delayed-type hypersensitivity (DTH) skin responses. RESULTS: Thirty patients who had been assessed and followed over the 4-week period (including 17 patients with EBV, five with RRV and eight with Q fever) were included in this analysis. During the acute phase, profound fatigue and malaise were the most common symptoms. Classical depressive and anxiety symptoms were not prominent. Initially, 46% of cases had no DTH skin response (i.e. cutaneous anergy) indicative of impaired cellular immunity. Over the 4-week period, there was a marked improvement in both somatic and psychological symptoms, although fatigue remained a prominent feature in 63% of subjects. The reduction in reported fatigue was correlated with improvement in the DTH skin response (p = 0.001) and with improvement in General Health Questionnaire (GHQ) scores (p < 0.01). CONCLUSIONS: Acute infectious illnesses are accompanied by a range of nonspecific somatic and psychological symptoms, particularly fatigue and malaise rather than anxiety and depression. Although improvement in several symptoms occurs rapidly, fatigue commonly remains a prominent complaint at 4 weeks. Resolution of fatigue is associated with improvement in cell-mediated immunity. [ABSTRACT FROM AUTHOR]

Our aim was to determine the relationships between interleukin-6 and immunoglobulin levels within small intestinal luminal secretions. Twenty adult subjects with small intestinal bacterial overgrowth (N = 13), irritable bowel syndrome (N = 4), and nonulcer dyspepsia (N = 3) underwent endoscopic aspiration of secretions from the small intestinal mucosal surface for assessment of IL-6, IgA1, IgA2, IgM, IgG1, IgG2, IgG3, and IgG4 concentrations. Serum immunoglobulin concentrations and small intestinal histology were also determined. IgA2 and IgG3 were the predominant IgA and IgG subclasses in luminal secretions in 19/20 (95%) and 20/20 (100%) subjects, respectively. IgA1 and IgG1 predominated in serum in all subjects. No subject had villous atrophy. Luminal IL-6 concentrations correlated significantly with luminal IgA2, IgM, and IgG3 concentrations but not with IgA1 or any other IgG subclass levels. Conversely, luminal IL-6 or immunoglobulin concentrations did not correlate significantly with levels of any immunoglobulin isotype in serum. These observations suggest that important relationships exist between local IL-6 and IgA2, IgM, and IgG3 responses in human small intestinal luminal secretions. Local investigation is mandatory when assessing intestinal immune activity. [ABSTRACT FROM AUTHOR]

It is unknown whether bacteriolysis due to luminal complement activation contributes to local defense mechanisms against small intestinal bacterial overgrowth, particularly with gram-negative bacteria. This study addressed this issue. Thirty adult subjects were investigated with culture of luminal secretions adherent to proximal small intestinal mucosa. Luminal and plasma concentrations of C3 and C3d and C3d/C3 ratios were determined. Activated terminal complement complex was sought in surface epithelium to which aspirated secretions had been adherent. Small intestinal bacterial overgrowth with gram-negative bacteria was present in 12/30 (40.0%) subjects. C3, C3d, and C3d/C3 profile indicated that increased local but not systemic C3 activation occurs in this group. Conversely, no activation of terminal complement complex was evident in this circumstance. Thus, complement-mediated bacteriolysis is unlike to contribute to local defense mechanisms against small intestinal bacterial overgrowth, even when overgrowth flora includes gram-negative bacteria. Factors preventing full local activation of the complement cascade in this circumstance require investigation. [ABSTRACT FROM AUTHOR]

Objective: To assess whether vital sign measurements could identify internal medicine patients at risk for cardiopulmonary arrest.Design: Retrospective case-control study comparing 72 hours of pre-arrest vital sign measurements with 72 hours of vital sign measurements for patients from the same units who did not experience cardiopulmonary arrest.Setting: Twelve non-intensive care internal medicine units at a large midwestern academic medical center.Patients: Cases included all 59 inpatients who had experienced cardiopulmonary arrest between May 1989 and December 1990; patients who were designated do-not-resuscitate (DNR) or had less than 72 hours of vital sign recordings were excluded. Controls included 91 inpatients without cardiopulmonary arrest who were matched for units and who had 72 hours of vital sign recordings.Results: The occurrence of one or more respiratory rates > 27 breaths per minute over a 72-hour period had a sensitivity of 0.54 and a specificity of 0.83 (odds ratio = 5.56, 95% CL = 2.67-11.49) in predicting cardiopulmonary arrest. Other respiratory rate thresholds were also predictive of arrest. The ability of respiratory rate to predict arrest was stronger in units with high incidences of arrest relative to units with low incidences, for example, in units for the management of gastrointestinal disease (sensitivity = 1.00, specificity = 0.86) and renal disease (sensitivity = 0.69, specificity = 0.87). Respiratory rate remained a significant predictor (p < 0.001) after controlling for patient age and gender. Pulse rate and blood pressure were not predictive of cardiopulmonary arrest.Conclusions: Using elevated respiratory rates as a signal for focused diagnostic studies and therapeutic interventions in internal medicine patients may be useful in reducing the incidence of subsequent cardiopulmonary arrest, and lowering associated morbidity and mortality. [ABSTRACT FROM AUTHOR]

Inflammatory eye disease (IED) is often the most severe manifestation of Behçet's syndrome (BS). This disease is a common cause of uveitis in Mediterranean countries, the Middle East and Japan. In order to ascertain the prevalence of this disease in Australia, we reviewed the aetiology of patients attending our uveitis clinic over a five-year period. Twelve of 426 patients with inflammatory eye disease had definite Behcet's syndrome. Four patients had anterior uveitis, four had posterior uveitis, four had retinal vasculitis and one also had optic neuritis. Although inflammatory eye disease was the initial clinical feature of Behcet's syndrome in only three of our patients, it was the feature that led to a definite diagnosis in all but one patient. The inflammatory eye disease of Behçet's syndrome was characteristically recurrent and severe with significantly decreased vision in 10 eyes, cataracts in six eyes, macula oedema in four eyes and glaucoma in two eyes. We conclude that Behçet's syndrome is a rare cause of inflammatory eye disease in Australia and is unlikely to be recognised as a distinct clinical entity prior to the onset of ocular involvement. The visual prognosis of ocular inflammation in Behçet's syndrome remains guarded despite the use of a variety of immunosuppressive agents. [ABSTRACT FROM AUTHOR]