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Long COVID is characterized by the emergence of multiple debilitating symptoms following SARS-CoV-2 infection. Its etiology is unclear and it often follows a mild acute illness. Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.

BACKGROUND Intensive insulin therapy (IIT) has been shown to reduce mortality and morbidity in longer stay, critically ill patients. However, this has been demonstrated in a single site, whereas two multicentric studies have been terminated prematurely mainly due to hypoglycemia. Other difficulties with IIT include efficacy of glycemic control. This report describes how IIT can be improved by protocol simplification and removal of glucose supplementation. METHODS A clinical information system established at each bedspace guided staff through the IIT algorithms. Time spent within predefined glycemic ranges was calculated assuming a linear trend between successive measurements. Three groups were investigated retrospectively: IIT1 protocol,(1) an updated IIT2 version, and intuitive nurse dosing of conventional insulin therapy (CIT). RESULTS Fifty consecutive, critically ill patients were included in each study group. Patient characteristics were similar in each group. The frequency of CIT and IIT2 blood glucose measurements were 11.6 and 11.5 measurements per day, respectively, while the IIT1 measurements were more frequent (14.5 measurements per day). The mean proportion of time spent in the target glycemic range (4.4-6.1 mmol/liter) was highest in the IIT2 group (34.9%), as compared to the IIT1 (22.9%) and CIT groups (20.3%) (p

This paper presents a case-report of a young female reporting sudden onset ankle swelling and pain, subcutaneous inflmmation and progressive bilateral pes planus, in the context of no associated co-morbidities or risk factors for autoimmune and infective conditions. We discussed the appropriate imaging techniques which facilitated the diagnosis, which included Xrays, ultrasound and MRI scans used to rule out soft tissue injuries, stress fractures, inflmmatory arthritis, and other causes of peripheral nerve entrapment and tendon pathology. The patient was diagnosed with polyarteritis nodosa based on deep skin biopsy. This is the fist case ever reported showing signifiant peripheral nerve enlargement in the context of small vessel vasculitis. The imaging step-up approach is discussed in relation to the sensitivity and specifiity of different imaging techniques for assessing joint, bone, tendon, ligament and nerve-related pathology. The rarity of this diagnosis in the context of a very common presentation emphasised the need for specialist referral and has signifiant educational value.

Nitric oxide (NO), produced via inducible NO synthase (iNOS), can modulate polarized epithelial processes such as solute transport. Given the high reactivity of NO, we hypothesized that optimal NO regulation of polarized epithelial functions is achieved through compartmentalization of iNOS, allowing local NO delivery to its molecular targets. Here, we show that iNOS localizes to the apical domain of epithelial cells within a submembranous protein complex tightly bound to cortical actin. We further show that iNOS can bind to the apical PDZ protein, EBP50 (ezrin-radixin-moesin-binding phosphoprotein 50), an interaction that is dependent on the last three COOH-terminal amino acids of iNOS, SAL, but requires the presence of additional unknown cellular proteins. Mutation of these three COOH-terminal residues abolishes the iNOS-EBP50 interaction and disrupts the apical association of iNOS in transfected cells, showing that this COOH-terminal motif is essential for the correct localization of iNOS in epithelial cells. Apically localized iNOS directs vectorial NO production at the apical proximal tubule epithelial cell surface. These studies define human epithelial iNOS as an apical EBP50-binding protein and suggest that the physical association of iNOS with EBP50 might allow precise NO modulation of EBP50-associated protein functions.

Background: Lack of knowledge of an NHS trust’s major incident policies by clinical staff may result in poorly coordinated responses during a mass casualty incident (MCI). Aim: To audit knowledge of the major incident policy by clinical staff working in a central London major acute NHS trust designated to receive casualties on a 24-h basis during a MCI. Methods: A 12-question proforma was distributed to 307 nursing and medical staff in the hospital, designed to assess their knowledge of the major incident policy. Completed proformas were collected over a 2-month period between December 2006 and February 2007. Results: A reply rate of 34% was obtained, with a reasonable representation from all disciplines ranging from nurses to consultants. Despite only 41% having read the policy in full, 70% knew the correct immediate action to take if informed of major incident activation. 76% knew the correct stand-down procedure. 56% knew the correct reporting point but less than 25% knew that an action card system was utilised. Nurses had significantly (p Conclusion: In view of the heightened terrorist threat in London, knowledge of major incident policy is essential. The high percentage of positive responses relating to immediate and stand-down actions reflects the rolling trust-wide MCI education programme and the organisational memory of the trust following several previous MCI in the capital. There is still scope for an improvement in awareness, however, particularly concerning knowledge of action cards, which are now displayed routinely throughout clinical areas and will be incorporated into induction packs.

Use of inhaled nitric oxide for treatment of pulmonary hypertension in adult critical illness is limited by its mode of delivery and high costs, prompting evaluation of alternative therapies. We report the use of oral sildenafil in a patient with severe secondary pulmonary hypertension and right ventricular dysfunction. Following reduction in mean pulmonary artery pressure and pulmonary vascular resistance with inhaled nitric oxide, crossover to sildenafil therapy maintained control of pulmonary hypertension, facilitating discontinuation of respiratory and cardiovascular organ support. The relative pulmonary vascular specificity of oral sildenafil, and its low cost, makes it an attractive therapeutic alternative to inhaled nitric oxide, and warrants further study.

Polarized tubule epithelial cell functions are dependent on correct delivery of effector proteins to the target apical or basolateral plasma membrane and associated cortical cytoskeleton. PDZ (Postsynaptic density protein 95/Drosophila Disks large/Zona occludens-1) domain-containing proteins have been identified as playing a critical role in membrane trafficking and sorting of ion transporters, receptors and other signalling proteins. These scaffolding proteins coordinate the assembly of functional plasma membrane multiprotein complexes, through PDZ domain binding to a consensus amino acid motif within the carboxyl-terminus of target proteins. The organization of these proteins into submembranous complexes may facilitate downstream signalling. Although several epithelial PDZ proteins that bind to a number of important mammalian proteins have been isolated, in many cases the significance of these interactions is unclear. However, the epithelial PDZ domain-containing Na+/H+ exchanger regulatory factor tethers the Na+/H+ exchanger and cystic fibrosis transmembrane regulator Cl– channel within an apical plasma membrane signalling complex, and has been shown to regulate the activity of these proteins. This article reviews the current evidence that supports a central role for the PDZ protein in the regulation of polarized tubule cell functions, such as vectorial solute transport.

Bullous dermatoses (BD) are well recognized in patients with end-stage renal disease (ESRD). It is important to distinguish pseudoporphyria (porphyrin accumulation due to decreased clearance) from true porphyrias, particularly those in which acute neurological attacks may occur. Investigation of the dialysis patient poses practical diagnostic difficulties because urinary porphyrin profiles are not available. We describe a patient on continuous ambulatory peritoneal dialysis (CAPD) with several recognized causative factors for porphyria cutanea tarda (PCT). The patient presented with a blistering photosensitive rash. We highlight the importance of investigating anuric patients with fractionation of both fecal and plasma porphyrins. Plasma porphyrins were grossly elevated (345 nmol/L; reference range

Immune thrombocytopenic purpura (ITP) mediated by quinine-dependent platelet reactive antibodies is well recognized. More recently there have been a number of reports of quinine-induced hemolytic-uremic syndrome (HUS). We describe a patient with quinine-induced immune thrombocytopenia who subsequently developed HUS after re-exposure to a single dose of this drug. To our knowledge, this is the first such case reported. Multiple quinine-dependent antibodies have been characterized in the patient's serum. Initially, quinine-dependent antibodies were directed solely against the platelet glycoprotein complex GPIb/IX. After rechallenge with quinine, there was broadening of quinine-dependent antibody specificities, which were now also directed against the platelet glycoprotein complexes GPIb/IX and GPIIb/IIIa, endothelial cells, and leukocytes. We have shown quinine-dependent antibody-mediated endothelial cell activation, which supports an immunopathogenic role for quinine-dependent antibodies in the causation of this disease.

The serum creatinine level was used to determine the incidence of renal dysfunction in 70 adults with acute leukemia who were alive and well one year following autologous bone marrow transplantation (ABMT). Creatinine measurements at the time of ABMT, one year post-ABMT and at the last follow-up (12–128 months, median 35) were recorded, and a level of >120 μmol/l arbitrarily defined as clinically significant renal impairment. The incidence of renal impairment was 2.9% (n = 2) at 1 year, and 4.3% (n = 3) at the last follow-up in continuous remission. Significant renal impairment occurred after relapse in 8 of 12 patients, but was seen in only 3 of 58 patients who remained in remission (p < 0.001, Fisher's exact test), suggesting subclinical renal damage which became obvious with further nephrotoxic therapy. We conclude that clinically significant renal dysfunction is an uncommon long-term complication of ABMT, and should not be a concern in recommending this therapy to eligible patients.

The clinical deterioration of patients is often heralded by a decline in physiological parameters by up to 24 hours [1]. NICE clinical guideline 50 (NCG 50) was published in July 2007 – 'Recognition of and response to acute illness in adults in hospital' – with the aim of improving the care of acutely ill patients. We undertook an audit to determine how our institution currently performed.

Introduction A single centre has reported that implementation of an intensive insulin protocol, aiming for tight glycaemic control (blood glucose 4.4 to 6.1 mmol/l), resulted in significant reduction in mortality in longer stay medical and surgical critically ill patients. Our aim was to determine the degree to which tight glycaemic control can be maintained using an intensive insulin therapy protocol with computerized decision support and to identify factors that may be associated with the degree of control. Methods At a general adult 22-bed intensive care unit, we implemented an intensive insulin therapy protocol in mechanically ventilated patients, aiming for a target glucose range of 4.4 to 6.1 mmol/l. The protocol was integrated into the computerized information management system by way of a decision support program. The time spent in each predefined blood glucose band was estimated, assuming a linear trend between measurements. Results Fifty consecutive patients were investigated, involving analysis of 7,209 blood glucose samples, over 9,214 hours. The target tight glycaemic control band (4.4 to 6.1 mmol/l) was achieved for a median of 23.1% of the time that patients were receiving intensive insulin therapy. Nearly half of the time (median 48.5%), blood glucose was within the band 6.2 to 7.99 mmol/l. Univariate analysis revealed that body mass index (BMI), Acute Physiology and Chronic Health Evaluation (APACHE) II score and previous diabetes each explained approximately 10% of the variability in tight glycaemic control. BMI and APACHE II score explained most (27%) of the variability in tight glycaemic control in the multivariate analysis, after adjusting for age and previous diabetes. Conclusion Use of the computerized decision supported intensive insulin therapy protocol did result in achievement of tight glycaemic control for a substantial percentage of each patient's stay, although it did deliver 'normoglycaemia' (4.4 to about 8 mmol/l) for nearly 75% of the time. Tight glycaemic control was difficult to achieve in critically ill patients using this protocol. More sophisticated methods such as continuous blood glucose monitoring with automated insulin and glucose infusion adjustment may be a more effective way to achieve tight glycaemic control. Glycaemia in patients with high BMI and APACHE II scores may be more difficult to control using intensive insulin therapy protocols. Trial registration number 05/Q0505/1.

In sepsis-induced acute renal failure, actin cytoskeletal alterations result in shedding of proximal tubule epithelial cells (PTEC) and tubular obstruction. This study examined the hypothesis that inflammatory cytokines, released early in sepsis, cause PTEC cytoskeletal damage and alter integrin-dependent cell-matrix adhesion. The question of whether the intermediate nitric oxide (NO) modulates these cytokine effects was also examined. After exposure of human PTEC to tumor necrosis factor-alpha, interleukin-1 alpha, and interferon-gamma, the actin cytoskeleton was disrupted and cells became elongated, with extension of long filopodial processes. Cytokines induced shedding of viable, apoptotic, and necrotic PTEC, which was dependent on NO synthesized by inducible NO synthase (iNOS) produced as a result of cytokine actions on PTEC. Basolateral exposure of polarized PTEC monolayers to cytokines induced maximal NO-dependent cell shedding, mediated in part through NO effects on cGMP. Cell shedding was accompanied by dispersal of basolateral beta(1) integrins and E-cadherin, with corresponding upregulation of integrin expression in clusters of cells elevated above the epithelial monolayer. These cells demonstrated coexpression of iNOS and apically redistributed beta(1) integrins. Attachment studies demonstrated that the major ligand involved in cell anchorage was laminin, probably through interactions with the integrin alpha(3)beta(1). This interaction was downregulated by cytokines but was not dependent on NO. These studies provide a mechanism by which inflammatory cytokines induce PTEC damage in sepsis, in the absence of hypotension and ischemia. Future therapeutic strategies aimed at specific iNOS inhibition might inhibit PTEC shedding after cytokine-induced injury and delay the onset of acute renal failure in sepsis.