Insulinoma: an uncommon cause of delirium.

We present the case of an 83-year-old woman with recurrent episodes of delirium occurring overnight, associated with hypoglycaemia. Other causes for delirium were excluded. Laboratory findings were in keeping with endogenous insulin production. Computerised tomography imaging revealed a small mass in the pancreas supporting a presumed diagnosis of an insulinoma. Given the patient's frailty and cognitive impairment, a conservative management approach was taken. Diazoxide was commenced with resolution of episodes of delirium. This case highlights hypoglycaemia, and insulinoma, as a rare, but treatable cause of delirium. It demonstrates the importance of blood sugar screening in delirium. It emphasises the holistic modifications to management, which must be taken to ensure patient-centred care when caring for an older adult living with frailty, who may have cognitive impairment.

A prospective study to investigate the role of serial serum mesothelin in monitoring mesothelioma.

BACKGROUND: Radiological monitoring of malignant pleural mesothelioma (MPM) using modified RECIST criteria is limited by low sensitivity and inter-observer variability. Serial serum mesothelin measurement has shown utility in the assessment of treatment response during chemotherapy but has never been assessed in the longer term follow up of patients. METHODS: This is a single centre study of consecutive patients diagnosed with MPM who received chemotherapy or best supportive care (BSC). Serum mesothelin measurements with paired 6 monthly CT scans were performed following the completion of chemotherapy, or from baseline in the BSC group. Changes in mesothelin were correlated with radiological progression and overall survival. RESULTS: Forty-one patients with MPM were recruited and followed up for a minimum of 12 months (range 12-21 months). The majority of patients (n = 23) received chemotherapy with pemetrexed and cisplatin. Across the cohort a 10% rise in serum mesothelin could predict radiological progression with a sensitivity of 96% (IQR; 79-100) and specificity of 74% (IQR; 50-91). Sensitivity fell to 80% in sarcomatoid only disease. Patients with a rising mesothelin at 6 months had significantly worse overall survival (175 days) compared to stable/falling levels (448 days) (p = 0.003). CONCLUSIONS: This is the first study to assess serum mesothelin's ability to detect progression of MPM following chemotherapy or during BSC. A 10% rise in serum mesothelin level showed excellent sensitivity at predicting progressive disease. Mesothelin measurement has several advantages over serial CT imaging including reducing hospital visits and cost.

Acute Kidney Injury After Prophylactic Cefuroxime and Gentamicin in Patients Undergoing Primary Hip and Knee Arthroplasty-A Propensity Score-Matched Study.

BACKGROUND: Perioperative acute kidney injury (AKI) can be associated with lower limb arthroplasty and increases morbidity, length of stay, and mortality. AKI is more prevalent in some antibiotic regimes compared with others. The aim of the present study is to assess the impact of cefuroxime (CEF), with or without gentamicin (±G), on AKI rates. METHODS: A prospective cohort study involving patients undergoing hip or knee arthroplasty was performed, between September 1, 2015 and November 30, 2016. Prophylactic intravenous antibiotics were administered according to local policy. AKI was graded according to the validated Acute Kidney Injury Network criteria based on the changes from baseline serum creatinine values. Propensity score matching was performed to identify risk factors. The local audit department approved the study. Appropriate statistical analyses were performed. RESULTS: A total of 2560 met the inclusion criteria, with a female preponderance (1447/2560; 56.5%). The mean age was 67.5 ± 10.7 years, with males being significantly younger (65.9 ± 10.9 vs 68.7 ± 10.4 years). AKI developed in 32 cases (1.25%). There was no difference in AKI rates between CEF alone and CEF in combination with gentamicin (1.07% vs 1.36%; P = .524). Overall 31/32 cases were Acute Kidney Injury Network stage I. AKI did not affect the length of stay. Postoperative infection rate was 7/2560 (0.27%). There were no incidences of Clostridium difficile-associated diarrhea. Multivariate analysis demonstrated an increased AKI risk with the use of intravenous gentamicin. CONCLUSION: C ± G yields low rates of infection and AKI compared with high-dose penicillin-based regimes. It is a safe and effective choice for lower limb arthroplasty.

Glycosaminoglycan regulation by VEGFA and VEGFC of the glomerular microvascular endothelial cell glycocalyx in vitro.

Damage to endothelial glycocalyx impairs vascular barrier function and may contribute to progression of chronic vascular disease. An early indicator is microalbuminuria resulting from glomerular filtration barrier damage. We investigated the contributions of hyaluronic acid (HA) and chondroitin sulfate (CS) to glomerular microvascular endothelial cell (GEnC) glycocalyx and examined whether these are modified by vascular endothelial growth factors A and C (VEGFA and VEGFC). HA and CS were imaged on GEnCs and their resynthesis was examined. The effect of HA and CS on transendothelial electrical resistance (TEER) and labeled albumin flux across monolayers was assessed. Effects of VEGFA and VEGFC on production and charge characteristics of glycosaminoglycan (GAG) were examined via metabolic labeling and liquid chromatography. GAG shedding was quantified using Alcian Blue. NDST2 expression was examined using real-time PCR. GEnCs expressed HA and CS in the glycocalyx. CS contributed to the barrier to both ion (TEER) and protein flux across the monolayer; HA had only a limited effect. VEGFC promoted HA synthesis and increased the charge density of synthesized GAGs. In contrast, VEGFA induced shedding of charged GAGs. CS plays a role in restriction of macromolecular flux across GEnC monolayers, and VEGFA and VEGFC differentially regulate synthesis, charge, and shedding of GAGs in GEnCs. These observations have important implications for endothelial barrier regulation in glomerular and other microvascular beds.

A rare case of tension pneumoperitoneum secondary to gastric perforation associated with severe aortic compression.

A 36-year-old male was critically unwell with acute central abdominal pain and distension. CT demonstrated severe pneumoperitoneum leading to compression and total occlusion of the inferior vena cava and occlusion of the aorta. At laparotomy, a perforated posterior gastric ulcer was found with four quadrant contamination. A damage control procedure was performed and a re-look laparotomy was carried out 2 days later where bowel ischaemia was found. Despite being supported on the intensive care unit, unfortunately the patient died. Tension pneumoperitoneum leading to occlusion of the aorta is very rare and the severity of this condition should be recognised; it has never been survived in the reported literature. Rapid assessment and investigation is essential to ensure the timely treatment of this disease.

Acute kidney injury following prophylactic flucloxacillin and gentamicin in primary hip and knee arthroplasty.

BACKGROUND: Following concerns regarding the emergence of Clostridium difficile infection in 2010, we changed antibiotic prophylaxis in patients undergoing primary hip and knee arthroplasty from cefuroxime to flucloxacillin and single-dose (SD) gentamicin. A subsequent perceived increase in the incidence of post-operative acute kidney injury (AKI) led us to evaluate the AKI incidence between different prophylactic antibiotic regimes used at our centre. METHODS: We examined the incidence of AKI as defined by Kidney Disease: Improving Global Outcomes criteria in 1588 patients undergoing primary hip or knee arthroplasty from January 2010 to January 2015. Patients received the following prophylactic antibiotic regimes: 8 g flucloxacillin in four divided doses and SD gentamicin 1.5 mg/kg ideal body weight (IBW; maximum dose 120 mg; n = 400), 8 g flucloxacillin alone in four divided doses (n = 400), SD cefuroxime (n = 400), triple-dose (TD) cefuroxime (n = 188) and teicoplanin with SD gentamicin 1.5 mg/kg IBW (n = 200). RESULTS: The incidence of AKI was as follows: flucloxacillin and gentamicin (13%); flucloxacillin alone (8.5%); SD cefuroxime (2%); TD cefuroxime (0.5%); and teicoplanin and gentamicin (3%). Of the six patients who developed Stage 3 AKI, all were in the flucloxacillin and gentamicin group. The odds ratio for the development of AKI derived from a binary logistic regression model was highest in the flucloxacillin and gentamicin group [7.79 (95% confidence interval 3.54-17.14), P < 0.0001]. CONCLUSIONS: Our findings suggest that the use of prophylactic high-dose flucloxacillin and gentamicin should be used with caution in patients undergoing primary hip or knee arthroplasty without a clear advantage in reducing surgical site infections given the association with increased rates of AKI.

Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury.

BACKGROUND: The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells. METHODS: VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay. MEASUREMENTS AND MAIN RESULTS: VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05). CONCLUSION: These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.

Lung Parenchymal Assessment in Primary and Secondary Pneumothorax.

RATIONALE: The definition of primary spontaneous pneumothorax excludes patients with known lung disease; however, the assumption that the underlying lung is normal in these patients is increasingly contentious. OBJECTIVES: The purpose of this study was to assess lung structure and compare the extent of emphysema in patients with primary versus secondary spontaneous pneumothorax and to patients with no pneumothorax in an otherwise comparable control group. METHODS: We identified patients treated for pneumothorax by screening inpatient and outpatient medical records at one medical center in the United Kingdom. From this group, 20 patients had no clinically apparent underlying lung disease and were classified as having a primary spontaneous pneumothorax, and 20 patients were classified as having a secondary spontaneous pneumothorax. We assembled a control group composed of 40 subjects matched for age and smoking history who had a unilateral pleural effusion or were suspected to have a thoracic malignancy and had a chest computed tomography scan suitable for quantitative analysis. Demographics and smoking histories were collected. Quantitative evaluation of low-attenuation areas of the lung on computed tomography imaging was performed using semiautomated software, and the extent of emphysema-like destruction was assessed visually. MEASUREMENTS AND MAIN RESULTS: The extent of emphysema and percentage of low-attenuation areas was greater for patients with primary spontaneous pneumothorax than for control subjects matched for age and smoking history (median, 0.25 vs. 0.00%; P = 0.019) and was also higher for patients with secondary pneumothorax than those with primary spontaneous pneumothorax (16.15 vs. 0.25%, P < 0.001). Patients with primary pneumothorax who smoked had significantly greater low-attenuation area than patients with primary pneumothorax who were nonsmokers (0.7 vs. 0.1%, P = 0.034). CONCLUSIONS: The majority of patients with primary spontaneous pneumothorax had quantifiable evidence of parenchymal destruction and emphysema. The exclusion of patients with underlying lung disease from the definition of primary spontaneous pneumothorax should be reappraised.

Cultured alveolar macrophages from patients with idiopathic pulmonary fibrosis (IPF) show dysregulation of lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) inductions.

Regulation of the pulmonary host defence mechanism is crucial for protection of the lung without pathological consequences. This is exemplified in the normal lung by the induction of both the pro-inflammatory cytokine TNF-alpha, its receptors and the anti-inflammatory cytokine IL-10 by bacterial lipopolysaccharide (LPS). We have evaluated this mechanism in patients with idiopathic pulmonary fibrosis (IPF). Alveolar macrophages (AM) were obtained by bronchoalveolar lavage from 21 subjects with IPF and 12 healthy volunteers. Constitutive and LPS-stimulated AM production of TNF-alpha, TNF soluble receptors CD120a and CD120b, and IL-10 at the protein and mRNA level were measured by bioassay, ELISA and competitive PCR respectively. AM from IPF subjects were more susceptible to LPS induction of TNF-alpha protein (P = 0.03) and transcription of IL-10 mRNA (P = 0.01) and IL-10R1 (P = 0.01) expression in comparison to controls. In contrast, increased CD120b was present as protein and mRNA compared to controls (P = 0.02). AM from IPF subjects were at least as susceptible to down-regulation of LPS-induced TNF-alpha levels by exogenous IL-10 as normal controls (94% versus 63%). These data suggest that there is dysregulation of LPS-induced TNF-alpha and IL-10 in AM from IPF subjects. Further studies are required to elucidate these observations, which may, in turn, give additional insight into the pathogenesis of this disease.

Contribution of TNF-alpha converting enzyme and proteinase-3 to TNF-alpha processing in human alveolar macrophages.

Membrane-associated TNF-alpha cleavage is required to yield the 17.5-kD soluble product. This process is poorly understood in human cells, and no studies have related this process to the alveolar macrophage (AM). TNF-alpha-converting enzyme (TACE) is known to cleave TNF at the Ala-76-Val-77 site. We have evaluated the expression, regulation, and catalytic function of TACE in healthy human AMs. TACE was detected on the surface of AMs using flow cytometry. TACE protein can be upregulated by LPS (P = 0.036) and IFN-gamma. LPS-induced expression is downregulated by IL-10 (P = 0.04) and TNF-alpha. TACE regulation was observed at the mRNA level. TACE catalytic activity as assessed by cleavage of glutathione S-transferase-proTNF fusion protein correlates significantly with TACE protein expression (P = 0.04). However, cleavage and soluble TNF-alpha release by AMs was inhibited by matrix metalloproteinase and serine protease inhibitors, suggesting a role for a serine protease in this process. We confirmed the presence of proteinase-3 (PR-3) on the AM surface that was functionally capable of TNF cleavage. PR-3 mRNA expression was not found in AMs. However, we determined that PR-3 from neutrophil supernatants could bind to the AM membrane, suggesting that AM-derived PR-3 is from an exogenous source, which is important in the context of inflammation.

A role for vascular endothelial growth factor in acute and resolving lung injury.

We have previously reported, in patients with acute respiratory distress syndrome (ARDS), elevated plasma levels of vascular endothelial growth factor (VEGF) that became reduced in those who recovered. To examine the potential effect of VEGF on the epithelial side of the alveolar-capillary membrane, we compared VEGF levels in the epithelial lining fluid (ELF) of the same 40 patients with ARDS, and in 28 patients at risk of ARDS. We measured intrapulmonary VEGF levels in 23 patients on Days 1 and 4 after admission to the intensive therapy unit and related these levels to recovery. ELF from subjects with ARDS contained lower levels of VEGF than did ELF from at-risk subjects (1,076 and 7,674 pg/ml, respectively, p = 0.0004) and increased ELF levels at Day 4 were associated with recovery (p = 0.001). Alveolar macrophages from subjects with ARDS produced significantly less VEGF than those from at-risk subjects (6.3 and 13.0 pg/ml, respectively, p = 0.005). Similarly, alveolar neutrophils from subjects with ARDS produced significantly less VEGF than those at risk (13.9 and 31.5 pg/ml, respectively, p = 0.03). ELF VEGF levels inversely correlated with Lung Injury Score (p = 0.003). These studies suggest that VEGF in the alveolar space may reflect the development of, and recovery from, acute lung injury in a manner opposite to that in plasma.

Interleukin-22: a potential immunomodulatory molecule in the lung.

Interleukin (IL)-22 is a member of the human type I interferon family, which includes IL-10. IL-22 has the potential to interact with IL-10 because it binds to the IL-10R2c chain with IL-22R1 in its receptor complex. Binding can be blocked by the soluble receptor, IL-22 binding protein (IL-22BP). We hypothesize that IL-22 and IL-22BP are involved in inflammatory regulation and its subsequent role in the pathogenesis of inflammatory lung disease. We have demonstrated IL-22 mRNA expression in alveolar macrophages (AM), monocytes, and alveolar epithelial (AE) cells. IL-22BP mRNA is expressed in AM, AE cells, and neutrophils. In contrast, IL-22R1 is expressed in AE only. Immunohistochemistry on normal and interstitial lung disease lung sections has confirmed IL-22 protein expression. Western blotting for IL-22 in bronchoalveolar lavage fluid demonstrated that lower levels of IL-22 were present in patients with acute respiratory distress syndrome and sarcoidosis relative to control subjects (P = 0.0152 and P = 0.0213). Levels of IL-22 in idiopathic pulmonary fibrosis were not different than those of the control subjects (P = 0.5838). IL-22 did not affect IL-10 inhibition of tumor necrosis factor-alpha in monocytes, which do not express IL-22R1. By contrast, we demonstrated synergy between IL-10 and IL-22 in terms of IL-8 inhibition in IL-22R1-expressing A549 cells. These data suggest a role for IL-22 in the regulation of pulmonary inflammation.

Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells.

The recognition of potentially harmful microorganisms involves the specific recognition of pathogen-associated molecular patterns (PAMPs) and the family of Toll-like receptors (TLRs) is known to play a central role in this process. TLR-4 is the major recognition receptor for lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls, whereas TLR-2 responds to bacterial products from gram-positive organisms. Although resident alveolar macrophages are the first line of defense against microbial attack, it is now understood that the alveolar epithelium also plays a pivotal role in the innate immunity of the lung. The purpose of the current study was to determine whether human primary type II alveolar epithelial cells (ATII) express functional TLR-2 and TLR-4 and how they may be regulated by inflammatory mediators. We have used reverse transcriptase-polymerase chain reaction and flow cytometry to determine basal and inducible expression on ATII. We have used highly purified preparations of the gram-positive bacterial product lipoteichoic acid (LTA) and LPS to look at the functional consequences of TLR-2 and TLR-4 ligation, respectively, in terms of interleukin-8 release. We have shown that human primary ATII cells express mRNA and protein for both TLR-2 and TLR-4, which can be modulated by incubation with LPS and tumor necrosis factor. Furthermore, we have demonstrated that these receptors are functional. This suggests that ATII have the potential to contribute significantly to the host defense of the human alveolus against bacteria.