MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses.

Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.

Incidence and risk factors for alopecia in survivors of critical illness: A multi-centre observational study.

PURPOSE: To investigate the incidence, nature and risk factors for patient-reported alopecia in survivors of critical illness. MATERIALS AND METHODS: A multi-centre, mixed methods observational study in the intensive care units (ICU) of ten hospitals in Wales. All patients with an ICU stay of 5 days or more, able to give consent were included. Demographic variables and risk factors were collected. A pre-designed survey was completed at three months post-ICU discharge. Statistical analysis included numbers and percentages (categorical variables) and medians and interquartile ranges (continuous variables). Comparisons between patients with and without alopecia were made using Fisher's Exact test (categorical variables) and Mann Whitney U test (continuous variables). Multivariate logistic regression analysis was used to determine the risk factors for alopecia. RESULTS: The survey was completed by 123 patients with alopecia reported in 44 (36%) patients. The only risk factor for alopecia on analysis was sepsis / septic shock (p < .001; OR: 5.1, 95%CI: 2.1-12.4). CONCLUSIONS: Limited research exists examining the incidence, nature and risk factors for patient-reported alopecia in adult survivors of critical illness. The results of this study highlight the need to discuss the potential for alopecia with survivors of critical illness, who had sepsis / septic shock.

Facilitation of Vaginal Delivery in an Infant with Complete Heart Block Secondary to Maternal Anti-Ro Antibodies.

Congenital heart block (CHB) is a rare disorder that may be associated with a high morbidity and even mortality, with a risk of death both in utero and during infancy. Women with serum titres of anti-Ro and/or anti-La antibodies carry a risk of CHB of 1-5% in their offspring, with a recurrence risk of approximately 20%. We present a case of a 36-year-old female with a pregnancy complicated by congenital heart block. Autoimmune profiling at booking showed she was positive for lupus anticoagulant and anti-Ro antibodies. A fetal echocardiogram at 21 + 3 showed complete heart block. She was monitored throughout the remainder of her pregnancy with serial growth scans, cardiovascular profiling, and BPP scoring. She had a normal vaginal delivery at term to a female infant.

Poststroke fatigue: the patient perspective.

PURPOSE: Fatigue is reported as a prevalent symptom post stroke. The purpose of this study is to explore the patent perspective of this symptom, how it is experienced, and its subjective impact on the patient. METHOD: The qualitative procedure of interpretative phenomenological analysis (IPA) was used to analyze the narratives of 10 subjects with previous stroke, who each undertook a single, semi-structured interview. RESULTS: Fatigue was a salient symptom for all the patients. Six main themes were identified. Tiredness/sleep was recognized in all the narratives, and themes of restriction, frustration, and determination/coping reflected varying degrees of physical, cognitive, and psychological dimensions to fatigue. Depression/motivation was also identified, reflecting low mood and helplessness. The remaining theme support indicated a social dimension, with patients recognizing the need for professional and familial support. Further subthemes were identified, and the thematic descriptions of the physical and psychosocial aspects indicated the complexity of fatigue and unique patient profiles. A holistic overview of each narrative furthered an understanding of the dynamic interrelationships between these aspects and their impact on the patient. There were prevalent patterns, but these were different for each patient. CONCLUSION: A better understanding of the varied dimensions or themes elaborated for poststroke fatigue, and their interrelationships, should help in mitigating its impact. The analysis cautions against giving any simplistic and unitary advice to patients about dealing with fatigue.

Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients.

Molecular targeted therapies are becoming ubiquitous in cancer treatment. These drugs may cause gastrointestinal toxicities including perforation, pneumatosis, enteritis, colitis and fistula formation. Knowledge of these complications and their management enables early radiological identification and appropriate intervention, reducing patient morbidity and mortality.

Imaging features of primary and secondary malignant tumours of the sacrum.

Malignant tumours of the sacrum may be primary or secondary. While sacral metastases are frequently encountered, a diagnostic dilemma can present when there is a single sacral bone tumour with no history or evidence of malignancy elsewhere in the body. Familiarity with the imaging features and clinical presentations of primary malignant bone tumours is helpful in narrowing the differential. This pictorial review will illustrate with both common and uncommon malignant sacral tumours CT, MRI and positron emission tomography/CT, highlighting the specific features of each.

Few Associations Found between Mold and Other Allergen Concentrations in the Home versus Skin Sensitivity from Children with Asthma after Hurricane Katrina in the Head-Off Environmental Asthma in Louisiana Study.

Mold and other allergen exposures exacerbate asthma symptoms in sensitized individuals. We evaluated allergen concentrations, skin test sensitivities, and asthma morbidity for 182 children, aged 4-12 years, with moderate to severe asthma, enrolled 18 months after Katrina, from the city of New Orleans and the surrounding parishes that were impacted by the storm, into the Head-off Environmental Asthma in Louisiana (HEAL) observational study. Dust (indoor) and air (indoor and outdoor) samples were collected at baseline of 6 and 12 months. Dust samples were evaluated for dust mite, cockroach, mouse, and Alternaria by immunoassay. Air samples were evaluated for airborne mold spore concentrations. Overall, 89% of the children tested positive to ≥1 indoor allergen, with allergen-specific sensitivities ranging from 18% to 67%. Allergen concentration was associated with skin sensitivity for 1 of 10 environmental triggers analyzed (cat). Asthma symptom days did not differ with skin test sensitivity, and surprisingly, increased symptoms were observed in children whose baseline indoor airborne mold concentrations were below median levels. This association was not observed in follow-up assessments. The lack of relationship among allergen levels (including mold), sensitivities, and asthma symptoms points to the complexity of attempting to assess these associations during rapidly changing social and environmental conditions.

Removal of T-fasteners 2 days after gastrostomy is feasible.

T-fastener gastropexy is widely performed as part of gastrostomy insertion. The current literature recommends removal of T-fasteners at 2 weeks. We present a series of patients in whom T-fasteners were removed at 2 days with no major complications. We removed T-fasteners in 109 patients (male-to-female ratio 59:50, age range 18 to 88 years, mean age 62 years) at 2 days after gastrostomy insertion. Indications for gastrostomy included amytrophic lateral sclerosis, cerebrovascular accidents, head and neck carcinoma, multiple sclerosis, and others, including brain tumours and chronic inflammatory demyelinating polyneuropathy. No peritubal leaks or other major complications were seen in the study population. In the study group, 15 minor complications were recorded (14%), including localised infection and pain, both of which resolved on removal of T-fasteners. We conclude that it is feasible and safe to remove T-fasteners at 2 days.

A randomized group intervention trial to enhance mood and self-efficacy in people with multiple sclerosis.

OBJECTIVES: To document mood, self-efficacy, and resiliency in people with multiple sclerosis (MS) following a brief group psychological intervention, and to examine whether benefits were greater than those derived from provision of education or group social interaction. DESIGN: A randomized controlled intervention trial assessing outcomes at five time points over a 1-year follow-up. METHODS: Participants with MS were assigned to one of three groups: one receiving brief group psychological intervention (PG) comprising three 90 minute cognitive behavioural sessions supported by an Information Booklet dealing with mental and emotional issues relating to MS; a group provided only with educational material - the information booklet group (IBG); and a group who not only received the booklet but also participated in non-structured social discussion (SDG) sessions similar in length and number to PG participants. Outcomes were documented using questionnaires. RESULTS: Outcomes were assessed using area under the curve (AUC) analysis: a summary measure that considers individual changes serially over time to provide a more meaningful picture than the one based on single time points. Ninety participants were followed up over the 12-month post-intervention, and their data are included in the analysis. Analyses indicated benefits in all outcome dimensions for the psychotherapeutic (PG) and social discussion groups (SDG) relative to the IBG group, but no differences between PG and SDG. CONCLUSION: The study indicates benefits from psychosocial intervention compared with bibliotherapy, with some additional benefit from psychological intervention compared with a social discussion group. Results suggest that much of the benefit may derive from non-specific therapeutic components. Without psychosocial intervention, the psychological status of people with MS worsened over time.

Worries and concerns of patients with multiple sclerosis: development of an assessment scale.

This study examined the nature of worry in adult patients with multiple sclerosis (MS) in the UK. A measure of worry in MS was developed and the relationship between worry and standard scale measures of anxiety and depression was examined. Thirty-nine patients with MS and 40 controls completed the new worry scale (WQMS) that was psychometrically evaluated, together with the Penn State Worry Questionnaire (PSWQ), the Hospital Anxiety and Depression Scale (HAD) and a previously developed scale to assess self-efficacy in MS (SESMS). The scores for both anxiety (t = 2.34; P < 0.05) and depression (t = 5.52; P <0.01) were higher in MS patients than controls, as was the new scale for worry--the WQMS. A factor analysis (explaining 65.73% of the variance) suggests that the worries of patients may be dichotomized into those concerned with the physical effects of the disease and those relating to the impact on social interaction, family relationships and daily activity in the home and/or work. Worry in patients with MS was associated with a decreased sense of being able to produce positive activities or effect positive outcomes (low self-efficacy). The questionnaire provides a framework for investigation in clinic of specific concerns and level of worry they engender.

The Managed Military Health System for Force Generation-project.

In summary, the Managed Military Health System for Force Generation will: Allow better understanding of health issues and illness patterns in the Armed Forces. Ensure optimum health and medical fitness of service personnel throughout their military careers by: Promoting health. Protecting health. Providing timely, properly co-ordinated, healthcare from military and civilian providers. In conjunction with DMICP, provide a seamless system of patient care and administration involving all healthcare providers. Enable all military personnel to make good health decisions. Ensure a smooth transition to NHS care on completion of Service. Improve the morale of those in the Defence Medical Services through working in a high quality organisation.

A practical synthesis of Nalpha-Fmoc-L-pyrazinylalanine via Schöllkopf's chiral auxiliary.

A practical, gram-scale synthesis of L-pyrazinylalanine (Paa) is described, utilizing Schöllkopf's D-valine-derived bis-lactim ether chiral auxiliary.

Risk factors associated with exertional medial tibial pain: a 12 month prospective clinical study.

OBJECTIVE: To investigate in a military setting the potential role of intrinsic biomechanical and anthropometric risk factors for, and the incidence of, exertional medial tibial pain (EMTP). METHODS: A prospective clinical outcome study in a cohort of 122 men and 36 women at the Australian Defence Force Academy. Each cadet underwent measurements of seven intrinsic variables: hip range of motion, leg length discrepancy, lean calf girth, maximum ankle dorsiflexion range, foot type, rear foot alignment, and tibial alignment. Test-retest reliability was undertaken on each variable. A physician recorded any cadet presenting with diagnostic criteria of EMTP. Records were analysed at 12 months for EMTP presentation and for military fitness test results. RESULTS: 23 cadets (12 men, 11 women) met the criteria for EMTP after 12 months, with a cross gender (F/M) odds ratio of 3.1. In men, both internal and external range of hip motion was greater in those with EMTP: left internal (12 degrees, p = 0.000), right internal (8 degrees, p = 0.014), left external (8 degrees, p = 0.042), right external (9 degrees, p = 0.026). Lean calf girth was lower by 4.2% for the right leg (p = 0.040) but by only 2.9% for the left leg (p = 0.141). No intrinsic risk factor was associated with EMTP in women. EMTP was the major cause for non-completion of the run component of the ADFA fitness test in both men and women. CONCLUSIONS: Greater internal and external hip range of motion and lower lean calf girth were associated with EMTP in male military cadets. Women had high rates of injury, although no intrinsic factor was identified. Reasons for this sex difference need to be identified.

Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale.

The aim of this study is to develop and validate a brief measure of self-efficacy specifically for use with people with multiple sclerosis (MS). Self-efficacy is the subjective belief that one can overcome challenges that one is faced with. In order to incorporate the subjective experiences of individuals with MS, a 'patient-focused' methodology has been adopted. Open-ended interviews were used to generate potential scale items. Items were piloted on an initial sample of individuals with MS and reduced to 14 items on the basis of their perceived relevance to this patient group. The final 14-item scale was then used with a further 142 individuals in order to assess its psychometric properties. The scale demonstrated high internal consistency (Cronbach's alpha = 0.81) and test-retest reliability (r = 0.81, P < 0.001) and acceptable validity. Issues concerning the assessment of validity are discussed in terms of the scale's relevancy to individuals with MS and the theoretical issues around the construct of self-efficacy. The scale has shown sensitivity to detect change following a brief therapeutic intervention, with an effect size of 0.502. This MS Self-efficacy Scale could, therefore, be a useful tool in the assessment of psychological adjustment and quality-of-life of individuals with MS.

Constitutive secretion of the granule chymase mouse mast cell protease-1 and the chemokine, CCL2, by mucosal mast cell homologues.

BACKGROUND: The mucosal mast cell (MMC) granule-specific beta-chymase, mouse mast cell protease-1 (mMCP-1), is released systemically into the bloodstream early in nematode infection before parasite-specific IgE responses develop and TGF-beta1 induces constitutive release of mMCP-1 by homologues of MMC in vitro. Intraepithelial MMC may also express the chemokine CCL2 (monocyte chemotactic protein-1) during nematode infection but the expression of this chemokine by MMC homologues has not been investigated. OBJECTIVE: To investigate the expression and to compare the mechanisms of constitutive release of the chymase, mMCP-1, and the chemokine, CCL2. METHODS: MMC homologues were generated by culturing bone marrow cells in the presence of TGF-beta1, IL-3, IL-9 and stem cell factor (SCF). The intracellular distribution of mMCP-1 and CCL2 was examined by confocal microscopy. The involvement of the Golgi complex and of protein synthesis in the constitutive release of mMCP-1 and CCL2 was investigated using the Golgi-disrupting agent brefeldin A and cycloheximide to block protein synthesis. Secreted analytes were quantified by ELISA. RESULTS: mMCP-1 colocalized with Golgi matrix protein 130 but was most abundant in the granules, whereas CCL2 was not found in the granules but appeared to be located uniquely in the Golgi complex. Extracellular release of mMCP-1 was significantly inhibited ( approximately 40%) by cycloheximide and by the Golgi-disrupting agent brefeldin A, indicating both continuous protein synthesis and transportation via the Golgi complex are required for optimal mMCP-1 secretion. A similar but more marked inhibitory effect with both compounds was demonstrated on the constitutive secretion of CCL2. CONCLUSION: The culture conditions that promote mMCP-1 expression and release by MMC homologues also promote the expression and release of CCL2. Constitutive release involves de novo protein synthesis and requires a functional Golgi complex, suggesting that similar mechanisms of extracellular secretion operate for both mediators.

Predicting blood pressure reactivity and heart rate variability from mood state following coronary artery bypass surgery.

STUDY OBJECTIVES: Coronary Artery Bypass Graft (CABG) surgery is a common and successful procedure for revascularisation. However, the experience can induce emotional reactions prior to and following surgery. This study aimed to document changes in blood pressure (BP) reactivity and heart rate variability (HRV) following CABG surgery, and to determine the impact of mood state, particularly anxiety and depression upon cardiovascular functioning. METHOD: Twenty-two patients preparing to receive elective, first time CABG surgery were recruited from The Cardiothoracic Centre, Liverpool, UK and psychologically assessed using the Hospital Anxiety and Depression Scale (HAD), Global Mood Scale (GMS) and the Dispositional Resilience Scale (DRI). BP and heart rate responses were also measured during four conditions: baseline response; laboratory session; ambulatory monitoring; and self-initialised recordings during the ambulatory period. In addition, HRV was measured for 12 h in conjunction with the ambulatory monitoring period. All measures were assessed 1 week prior to surgery and 2 months following surgery. RESULTS: A significant decrease in negative mood and an increase in positive mood were reported following surgery. Forty percent of patients were clinically anxious and depressed prior to surgery although this was reduced to 27% after surgery. Depression was the strongest independent predictor of pre-operative BP and HRV whilst anxiety was most significantly related to follow-up BP reactivity. DBP was most strongly predicted by mood state. CONCLUSIONS: These results suggest that patients with higher levels of anxiety and depression are at risk of reduced HRV and increased BP reactivity in response to mental stressors. The study also strongly suggests that current patient services should be expanded to acknowledge the role of psychological factors within clinical prognosis after CABG surgery.

Transforming growth factor-beta1 mediates coexpression of the integrin subunit alphaE and the chymase mouse mast cell protease-1 during the early differentiation of bone marrow-derived mucosal mast cell homologues.

BACKGROUND: Mucosal mast cells (MMC) play a central role in gut hypersensitivities and inflammation. They are morphologically, biochemically and functionally distinct from their connective tissue counterparts. Massive hyperplasia of MMC occurs 7-10 days after intestinal infection with nematodes but it has never been possible to replicate this phenomenon in vitro. OBJECTIVE: (1) To determine whether mouse bone marrow-derived mast cells (mBMMC) grown in the presence of transforming growth factor (TGF)-beta1 could develop over the same time frame (7-10 days) as MMC in parasitized mice. (2) To compare the early expression of surface receptors (integrins alphaE and beta7, c-kit and FcepsilonR) with that of the MMC-specific granule chymase mouse mast cell protease-1 (mMCP-1). METHODS: Mouse bone marrow cells were cultured in the presence of IL-9, IL-3 and Stem Cell Factor (SCF) with or without TGF-beta1. mBMMC were quantified after toluidine blue or Leishmans' staining. Expression of MMC-specific mouse mast cell proteases was analysed by ELISA, immunohistochemistry and RT-PCR. Surface antigen expression was characterized by flow cytometry and confocal microscopy. RESULTS: TGF-beta1 promotes the development of abundant MMC-like mBMMC from bone marrow progenitor cells with kinetics, which closely parallel that seen in vivo. mRNA transcripts encoding mMCP-1 and -2 are readily detectable by day 4 ex vivo in cultures grown in the presence of TGF-beta1. Between 30 and 40% and 75-90% of the cells in these cultures on days 4 and 7, respectively, have typical mast cell morphology, are c-kit+, FcepsilonR+, integrin alphaEbeta7+, and express and secrete abundant mMCP-1. The integrin alphaE subunit is coexpressed with mMCP-1. CONCLUSION: The kinetics of mMCP-1+/alphaE+ mBMMC development, regulated by TGF-beta1, are consistent with that seen in vivo in the parasitized intestine. The normally down-regulatory functions of TGF-beta1 in haematopoiesis are superseded in this culture system by its ability to promote the early expression of alphaE and mMCP-1.

Quality of life issues in motor neurone disease: the development and validation of a coping strategies questionnaire, the MND Coping Scale.

A person's ability to cope with having motor neurone disease may be an important factor in determining their quality of life. We have developed a scale to measure coping strategies in people with MND. A disease-specific and patient-focused approach was employed. Open-ended interviews were used to generate initial items. Coping with the condition was an important consideration for all subjects. The final scale was administered to a sample of 44 people with MND. A factor analysis of the results demonstrated subscales comprised of distinct styles of coping. Reliability and validity were demonstrated within individual subscales. Significant correlations were shown between coping styles and psychological well being, disease duration and disability. Although still at a preliminary stage of development, the MND Coping Scale is proposed as a useful tool for further longitudinal study of coping in MND, with the potential to discover cause effect relationships between coping and psychological outcome.

Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain.

Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9-treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9-treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenate-induced excitotoxic brain lesions in mast cell-deficient P5 pups (WBB6F1/J kit(W/W-v)), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9-treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy.