Complications of fibrotic interstitial lung disease for the general radiologist.

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions characterised by non-infective inflammation and scarring of the lung parenchyma. They are not infrequently encountered by the general radiologist in both acute and outpatient reporting settings who may even be the first to make the diagnosis. In the acute setting, patients with ILD can present with respiratory deterioration due to a number of causes and in addition to the common causes of dyspnoea, an acute exacerbation of ILD needs to be considered. An exacerbation can be initiated by common triggers such as infection, pulmonary embolism (PE), and heart failure, and it can also be initiated by an insult to the lung or occur due to an unknown cause. Particular care needs to be taken when interpreting computed tomography (CT) examinations in these patients as the findings of an acute exacerbation are non-specific and patient and technical factors can cause spurious appearances including dependent changes, breathing artefact and contrast medium opacification. In the non-acute setting, patients with ILD are at increased risk of lung cancer and pulmonary hypertension (PH), with lung cancer being a particularly important consideration as treatments carry the risk of triggering an acute exacerbation or deterioration in lung function. Overall, this review aims to provide an overview for the general radiologist of additional factors to consider when interpreting scans in patients with ILD and how the presence of ILD impacts the differential diagnoses and complications that can occur in these patients in both acute and non-acute settings.

A role for cardiopulmonary exercise testing in detecting physiological changes underlying health status in Idiopathic pulmonary fibrosis: a feasibility study.

INTRODUCTION: There is limited data available on the use of CPET as a predictive tool for disease outcomes in the setting of IPF. We investigated the feasibility of undertaking CPET and the relationship between CPET and quality of life measurements in a well-defined population of mild and moderate IPF patients. METHODS: A prospective, single-centre observational study. RESULTS: Thirty-two IPF patients (mild n = 23, moderate n = 9) participated in the study, n = 13 mild patients attended for repeat CPET testing at 12 months. At baseline, total K-BILD scores and total IPF-PROM scores significantly correlated with 6MWT distance, but not with baseline FVC % predicted, TLco % predicted, baseline or minimum SpO2. VO2 peak/kg at AT positively correlated with total scores, breathlessness/activity and chest domains of the K-BILD questionnaire (p < 0.05). VO2 peak significantly correlated with total IPF PROM scores and wellbeing domains (p < 0.05), with a trend towards statistical significance for total IPF-PROM and VO2 peak/kg at anaerobic threshold (p = 0.06). There was a statistically significant reduction in FVC% predicted at 12 months follow up, although the mean absolute decline was < 10% (p < 0.05). During this period VO2 peak significantly reduced (21.6 ml/kg/min ± 2.9 vs 19.1 ± 2.8; p = 0.017), with corresponding reductions in total K-BILD and breathlessness/activity domains that exceeded the MCID for responsiveness. Lower baseline VO2 peak/kg at anaerobic threshold correlated with greater declines in total K-BILD scores (r = - 0.62, 0.024) at 12 months. Whilst baseline FVC% predicted or TLco % predicted did not predict change in health status, CONCLUSION: We have shown that it is feasible to undertake CPET in patients with mild to moderate IPF. CPET measures of VO2 peak correlated with both baseline and change in K-BILD measurements at 1 year, despite relatively stable standard lung function (declines of < 10% in FVC), suggesting its potential sensitivity to detect physiological changes underlying health status.

FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system.

Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.

Vascular endothelial growth factor in acute lung injury and acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, characterised by alveolar oedema and vascular permeability, in part due to disruption of the alveolar capillary membrane integrity. Vascular endothelial growth factor (VEGF) was originally identified as a vascular permeability factor and has been implicated in the pathogenesis of acute lung injury/ARDS. This review describes our current knowledge of VEGF biology and summarises the literature investigating the potential role VEGF may play in normal lung maintenance and in the development of lung injury.

Cognitive therapy for people with a schizophrenia spectrum diagnosis not taking antipsychotic medication: an exploratory trial.

BACKGROUND: Although antipsychotic medication is the first line of treatment for schizophrenia, many service users choose to refuse or discontinue their pharmacological treatment. Cognitive therapy (CT) has been shown to be effective when delivered in combination with antipsychotic medication, but has yet to be formally evaluated in its absence. This study evaluates CT for people with psychotic disorders who have not been taking antipsychotic medication for at least 6 months. METHOD: Twenty participants with schizophrenia spectrum disorders received CT in an open trial. Our primary outcome was psychiatric symptoms measured using the Positive and Negative Syndromes Scale (PANSS), which was administered at baseline, 9 months (end of treatment) and 15 months (follow-up). Secondary outcomes were dimensions of hallucinations and delusions, self-rated recovery and social functioning. RESULTS: T tests and Wilcoxon's signed ranks tests revealed significant beneficial effects on all primary and secondary outcomes at end of treatment and follow-up, with the exception of self-rated recovery at end of treatment. Cohen's d effect sizes were moderate to large [for PANSS total, d=0.85, 95% confidence interval (CI) 0.32-1.35 at end of treatment; d=1.26, 95% CI 0.66-1.84 at follow-up]. A response rate analysis found that 35% and 50% of participants achieved at least a 50% reduction in PANSS total scores by end of therapy and follow-up respectively. No patients deteriorated significantly. CONCLUSIONS: This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.

Prodromal irritable bowel syndrome may be responsible for delays in diagnosis in patients presenting with unrecognized Crohn's disease and celiac disease, but not ulcerative colitis.

INTRODUCTION: We aimed to determine the prevalence and duration of prodromal periods in patients with celiac disease and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Furthermore, we explored to what extent vague abdominal symptoms consistent with both disorders were attributed to irritable bowel syndrome (IBS) and if the presence of prodromal IBS (P-IBS) had an impact on prodrome duration. METHODS: In the study, 683 biopsy-proven patients (celiac n = 225, ulcerative colitis n = 228, Crohn's disease n = 230) completed a postal survey including an assessment of prodromal periods and IBS symptoms during both the prodrome and at present (achieved by completion of the ROME II criteria). Results were compared to age/sex-matched controls (n = 348). RESULTS: Crohn's disease patients had the highest prevalence of prodromes (94%) in comparison to ulcerative colitis (48%) and celiac disease (44%). However, Crohn's disease patients have the lowest prevalence of P-IBS (29%) in comparison to ulcerative colitis (38%) and celiac disease (67%). Prodrome duration in patients with P-IBS Crohn's disease was 4 years in comparison to 2 years without (p = 0.018). Prodrome duration in P-IBS celiac disease was 10 years in comparison to 7 years without (p = 0.046). Prodrome duration in patients with ulcerative colitis was not affected by P-IBS (p ≥ 0.05). Age and sex were not confounding factors. CONCLUSIONS: This is the first study to make direct comparisons of prodrome periods between celiac disease and IBD. Prodrome duration in celiac disease is significantly longer and more often characterized by P-IBS than IBD. In celiac disease and CD, P-IBS increases prodrome duration. This may represent a failure to understand the overlap between IBS and celiac disease/IBD.

Utility of illness severity scores to predict mortality in patients hospitalized with respiratory deterioration of idiopathic pulmonary fibrosis.

INTRODUCTION: In the context of idiopathic pulmonary fibrosis (IPF), respiratory-related admissions to hospital are associated with a high morbidity and short-term mortality with significant burden on secondary care services. It has yet to be determined how to accurately identify patients at risk of acute respiratory deterioration (ARD) or the prognosticating factors. AIM: We sought to define the characteristics of hospitalized ARD-IPF patients in a real-world cohort and investigate factors associated with worse outcomes. Specifically, we wished to determine the association between baseline CURB-65 and NEWS-2 and mortality in IPF, given illness severity scores have not previously been validated in this cohort. METHODS: Single-centre retrospective observational cohort study. RESULTS: Of 172 first hospitalizations for ARD, 27 admissions (15.7%) were due to an acute exacerbation of IPF (AE-IPF), 28 (16.3%) secondary to cardiac failure/fluid overload and 17 due to pneumonia (9.9%). Other admissions related to lower respiratory tract infection, extra-parenchymal causes and those without a specific trigger. Baseline patient characteristics were comparable for all underlying aetiologies of ARD-IPF. Treatment pathways did not differ significantly between AE-IPF and other causes of ARD-IPF. Short-term mortality was high, with ∼22% patients dying within 30 days. Illness severity scores (NEWS-2 and CURB-65) were independent predictors of mortality in multivariable logistic regression modelling. CONCLUSIONS: Our findings suggest significant mortality related to hospitalization with ARD-IPF of any underlying cause. Our data support the use of CURB-65 and NEWS-2 scores as illness severity scores that can provide a simple tool to help future prognostication in IPF. Research should be aimed at refining the management of these episodes, to try to reduce mortality, where possible, or to facilitate palliative care for those with adverse prognostic characteristics.

Pleuroparenchymal sarcoidosis - A recognised but rare manifestation of disease.

Pleural involvement is rare in sarcoidosis. The presence of a large symptomatic effusion in a patient with sarcoidosis should therefore prompt further investigation for an alternate aetiology. Here we present a case of confirmed pleuro-parenchymal sarcoidosis. We discuss the important differential diagnoses and review the current literature.

Visual analogue scales for interstitial lung disease: a prospective validation study.

BACKGROUND: Visual analogue scales (VAS) are simple symptom assessment tools which have not been validated in interstitial lung disease (ILD). Simple measures of ILD disease burden would be valuable for non-specialist clinicians monitoring disease away from ILD specialist centres. OBJECTIVE: To validate VAS to assess change in dyspnoea, cough and fatigue in ILD, and to define the minimal clinically important difference (MCID) for change in these. METHODS: Patients of 64 with ILD completed VAS for dyspnoea, cough and fatigue. Baseline King's Brief ILD questionnaire (K-BILD) scores, lung function and 6-min walk test results were collected. Tests were repeated 3-6 months later, in addition to a seven-point Likert scale. The MCID was estimated using median change in VAS in patients who reported 'small but just worthwhile change' in symptoms at follow-up. Methods were repeated in a validation cohort of 31 ILD patients to confirm findings. RESULTS: VAS scores were significantly higher for patients who reported a 'small but just worthwhile change' in symptoms vs. 'no change' or 'not worthwhile change' (P < 0.01). The MCID for VAS Dyspnoea was estimated as 22.0 mm and 14.5 mm for VAS Fatigue. These results were reproducible in the validation cohort. Results were not significant for VAS Cough. Change in VAS Dyspnoea correlated with change in K-BILD (r = -0.51, P < 0.01), forced vital capacity (r = -0.32, P = 0.01) and 6-min walking distance (r = -0.37, P = 0.01). CONCLUSION: The VAS is valid for assessing change in dyspnoea and fatigue in ILD. The MCID is estimated as 22.0 mm for dyspnoea and 14.5 mm for fatigue. This could be used to monitor disease in settings away from ILD specialist review. MESH DESCRIPTORS: Lung Diseases, Interstitial, Dyspnoea, Fatigue, Cough.

Does growth hormone allow more efficient nitrogen sparing in postoperative patients requiring parenteral nutrition? A double-blind, placebo-controlled randomised trial.

BACKGROUND & AIMS: Growth hormone (GH) has a strong anabolic effect and is thought to be useful in improving the efficacy of parenteral nutrition (PN) to preserve muscle mass (MM) in the postoperative setting. Unfortunately, the negative clinical outcome of GH treatment in intensive care patients limits its use in this setting, but demands answers to the mechanism behind the action of this therapy. METHOD: In a double-blind randomised controlled study consecutive patients after major abdominal surgery were divided into four groups of either 1/2-PN (0.13 g N/kg/day and 52% of calories as lipid) or full-strength PN (Full-PN) (0.3 g N/kg/day and 65% of calories as lipid) receiving daily injections of either GH (8-16 IU) or placebo for a period of 14 days postoperative. Outcome measures included MM derived from measures of total body potassium (40K counting) and total body nitrogen (TBN) (in vivo neutron capture technique); Fat mass from skin folds; serum insulin like growth factor-I (IGF-I) and its binding proteins (IGFBP). RESULTS: From 43 major upper GI surgical patients randomised 35 completed the study (one patient died from sepsis in the half-strength PN (1/2-PN)+GH group). 1/2-PN (n=11) lost TBN (P=0.001), MM (P=0.005) but not fat. Full-PN (n=9) maintained TBN, MM (P=0.056) and fat. 1/2-PN+GH (n=8) maintained TBN and fat but lost MM (P=0.038). Full-PN+GH (n=7) maintained TBN and MM but lost fat (P=0.018). Two-way ANOVA indicated that PN input (P=0.031) and not GH had a significant effect on MM. GH caused a significant rise in IGF-I levels (290+/-67 and 454+/-71 microg/l for 1/2-PN+GH and Full-PN+GH, respectively) and restored serum IGFBP3 and the acid labile subunit to normal, by the postoperative day 9. CONCLUSION: After major gastrointestinal surgery, GH causes a marked hepatic IGF-I response and nitrogen retention but its effect on body composition was more significant with a high PN input. Further, Full-PN alone was sufficient to prevent nitrogen loss and preserved MM and addition of GH does not provide further metabolic advantage.

The in-vitro characterization of induced apoptosis in placental cytotrophoblasts and syncytiotrophoblasts.

Placental trophoblasts undergo apoptosis as part of normal epithelial turnover and placental ageing. Classically, the induction of apoptosis in in vitro preparations has utilized the cytokines TNFalpha and IFNgamma and has been measured using the TUNEL technique. The aim of this study was to compare apoptotic susceptibility of mononucleated and differentiated trophoblasts using a range of cytotoxic agents. To achieve this, an in vitro model of syncytialization was used, along with isolated placental cytotrophoblasts and an extravillous cytotrophoblast derived cell line (SGHPL-4). Cytotrophoblasts from term placentae (n=12), syncytiotrophoblasts (n=12) and SGHPL-4s (n=8) were cultured under reduced oxygen or with TNFalpha/IFNgamma, dexamethasone or staurosporine. Apoptosis assessments were made using TUNEL, Annexin V binding, fluorescence microscopy and ATP/ADP measurements. Each cytotoxic agent increased apoptosis in all three cell populations. For untreated cells, cytotrophoblasts showed the greatest levels of apoptosis in culture. With stimulation, these levels were significantly elevated using dexamethasone, TNFalpha/IFNgamma and staurosporine and further raised under hypoxic conditions. SGHPL-4 cells showed similar trends to those of cytotrophoblasts, however the syncytiotrophoblasts, although responsive to dexamethasone and TNFalpha/IFNgamma, showed lower levels of apoptosis with staurosporine and hypoxia. ADP : ATP measurements gave similar results to the other techniques and ratios of less than 1.0 were correlated with Annexin V measurements on the flow cytometer (P< 0.001). The typical morphological features of apoptosis i.e. chromatin margination, membrane blebbing and apoptotic body formation were detected in cytotrophoblasts and SGHPL-4 cells. However, only chromatin condensation could be recognized in syncytiotrophoblast preparations. Necrotic cell numbers were also increased under all cytotoxic conditions. Although elevated with dexamethasone, staurosporine and hypoxia, these levels were markedly raised in cytotrophoblasts and SGHPL-4 cells following incubations with TNFalpha/IFNgamma. These observations show variations in apoptosis between mononuclear trophoblasts and differentiated multinucleated syncytiotrophoblasts. Differential effects of stimuli may suggest disparate apoptotic pathways. These variations may reflect functional differences between placental cellular and syncytial components and may highlight the importance of exogenous stimulation in various stages of placental development.

An evaluation of blood creatinine measurement by creatinase on the NOVA M7 blood gas analyzer.

This study compared a creatininase method for the analysis at the bedside of creatinine (CR) in whole blood on a NOVA Biomedical M7 analyser, with rate-Jaffe and creatininase-based laboratory methods. Correlation and precision data were obtained and the effect of increased bilirubin concentration was assessed.

Simultaneous recording of tissue PCO2, interstitial pH and potassium activity in the rat cerebral cortex during anoxia and the subsequent recovery period.

Tissue PCO2 (carbon dioxide tension) (PtCO2), interstitial H+ (H+e) and potassium activities (K+e) were monitored in the cerebral cortex of rats during and after 2-3 min of anoxia. Anoxia was associated with systemic hypotension and caused H+e (extracellular hydrogen ion activity) to increase from pH approximately equal to 7.2 to pH approximately equal to 6.5, K+e to rise from approximately equal to 2.4 up to a maximum of approximately equal to 39 mmol/l, and PtCO2 to increase from approximately equal to 52 to approximately equal to 80 mmHg. Lactate increased from 2 to 5 mmol/kg tissue weight during anoxia and did not fall significantly after re-oxygenation for 10 min. A marked relationship existed between changes in PtCO2 and H+e. After re-oxygenation, K+e (extracellular potassium ion activity) and PtCO2 returned to the pre-anoxic level in a few minutes, whereas H+e took approximately equal to 30 min to recover. H+e recovered in a biphasic manner; a rapid decrease lasting approximately equal to 1 min preceded a much slower phase. We propose that the biphasic normalization of H+e after anoxia mainly reflects an initial and rapid washout of CO2 from brain tissue and a subsequent slow elimination of lactic acid occurring via metabolism and removal by the circulation.

Analgesic agents for the postoperative period. Nonopioids.

For many reasons, nonopioid analgesics have proven to be of immense benefit in postoperative pain relief. Consideration of the limitations and side effects of opioids confirms the need for alternative, complementary analgesics. The current understanding of pain pathophysiology recognizes that many tissue and neuronal factors and changes are invoked by tissue damage, producing peripheral and central sensitization, and some of these may be modulated by the use of NSAIDs, NMDA antagonists, and local anesthetic agents. If successful preemptive analgesic techniques are developed, they will likely include the use of NSAIDs and perhaps NMDA antagonists. Nonopioids are of benefit in multimodal analgesia and allow acute rehabilitation of surgical patients. Acetaminophen, NSAIDs, alpha 2-antagonists, and NMDA antagonists are in routine use as components of multimodal analgesia, in combination with opioids or local anesthetic techniques. Tramadol is interesting because it has nonopioid and opioid actions that can be attributed to the two isomers found in the racemic mixture. Spinal neostigmine and the use of adenosine represent completely different mechanisms of nonopioid analgesia being investigated. Nonopioids, including lidocaine, ketamine, the anticonvulsants, and the antidepressants, are necessary for the treatment of patients with the difficult clinical problem of neuropathic pain that can present in the postoperative period.

Lack of secondary hyperalgesia and central sensitization in an acute sheep model.

BACKGROUND AND OBJECTIVES: We aimed to determine the following in an experimental acute pain model in sheep: (1) whether multimodal analgesia with intravenous fentanyl and ketorolac was more effective than fentanyl alone; (2) whether secondary hyperalgesia (central sensitization) occurred in adjacent (foreleg) dermatomes after thoracic surgery; (3) whether ketorolac used preemptively influenced the development of secondary hyperalgesia after surgery. METHODS: Changes in primary nociception were measured by increases to tolerated pressure, applied to the foreleg by a blunt pin, before foreleg withdrawal occurred. Changes to breath-to-breath interval and estimated end-tidal CO2 were used as indices of respiratory effects. Study 1 (n = 6) compared the paired responses to acute nociception after ketorolac (90 mg) or saline (control) pretreatment, followed by fentanyl (graded, 0 mg to 1.5 mg). Study 2 (n = 6) used a cross-over of ketorolac (90 mg) or saline (control) 24 hours and 1 hour, respectively, before a standardized thoracotomy incision, followed by antinociceptive testing with ketorolac (90 mg) and fentanyl (0.6 mg) daily over 4 days. RESULTS: In study 1, fentanyl produced naloxone-antagonizable antinociception and respiratory depression. Ketorolac did not affect fentanyl antinociception, except for prolonging antinociception at the highest dose; it did not affect the respiratory effects. In study 2, preemptive ketorolac had no effect on the postoperative antinociceptive or respiratory effects of fentanyl. The pharmacokinetics of fentanyl were unaltered by ketorolac. CONCLUSIONS: The results obtained in this acute pain model found no significant evidence of a fentanyl-ketorolac interaction, of central sensitization as shown by secondary hyperalgesia, or of a preemptive analgesic effect.

Vascular remodelling in the pathogenesis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial pneumonia of unknown aetiology that usually leads to respiratory failure and death within 5 years of diagnosis. Alveolar epithelial cell injury, disruption of alveolar capillary membrane integrity and abnormal vascular repair and remodelling have all been proposed as possible pathogenic mechanisms. This review summarizes our current knowledge of the abnormalities in vascular remodelling observed in IPF and highlights several of the cytokines thought to play a pathogenic role, which may ultimately prove to be future therapeutic targets.

Central hypoventilation with PHOX2B expansion mutation presenting in adulthood.

Congenital central hypoventilation syndrome most commonly presents in neonates with sleep related hypoventilation; late onset cases have occurred up to the age of 10 years. It is associated with mutations in the PHOX2B gene, encoding a transcription factor involved in autonomic nervous system development. The case history is described of an adult who presented with chronic respiratory failure due to PHOX2B mutation-associated central hypoventilation and an impaired response to hypercapnia.