CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense.

Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases.

Glycaemic control in insulin requiring diabetes patients receiving exclusive enteral tube feeding in an acute hospital setting.

AIMS: Optimising glycaemic control for insulin requiring individuals during enteral feeding is important but difficult. We compare 3 insulin regimens with the aim of improving glucose control and reducing hypoglycaemia. METHODS: Comparison of 3 insulin/feed regimens: (1) A 20 h feed using a 30:70 premixed insulin (2) Three bolus (4 h) feeds combined with short acting analogue insulin and a basal long acting insulin. (3) A 24 h feed combined with a long acting analogue insulin. The study combined a retrospective analysis of regimen (1) with consecutive prospective analyses of (2) and (3). RESULTS: Glucose concentrations were suboptimal with higher values during the feeds (12.6 mmol/L ± 4.4 vs 10.3 ± 4.1 p<0.001). Although there was no overall difference in glucose control between groups there was a reduction in hypoglycaemia during the feed in the bolus group (no hypoglycaemia during intermittent feeds p<0.001). CONCLUSIONS: Glucose concentrations were relatively high overall. Short bolus feeding appears to reduce the frequency of hypoglycaemia. This is of clinical significance for this patient group.

CCR5 deficiency and severe polio infection in the 1984 outbreak in Finland.

CCR5, a leukocyte chemoattractant receptor for chemokines CCL3, CCL4, and CCL5, promotes innate and adaptive immune responses by mediating leukocyte trafficking within lymph nodes and to peripheral tissues and is also known as a co-receptor for HIV cell entry. Homozygous inheritance of a complete loss-of-function mutation in CCR5 (CCR5Δ32/CCR5Δ32) is associated with symptomatic neuroinflammatory disease in humans with West Nile and Tickborne Encephalitis flavivirus infections. This study sought to establish whether CCR5 deficiency could also be a determinant of clinical outcome after infection by poliovirus which results in central nervous system damage in only a small proportion of cases. We analyzed serum samples from seven patients and 79 controls, collected during the 1984-1985 polio outbreak in Finland, where CCR5Δ32 is relatively common in the general population. The results excluded CCR5 deficiency as the sole determinant of severe neurologic disease after poliovirus infection in this population.

An investigation into the current peri-operative nutritional management of oesophageal carcinoma patients in major carcinoma centres in England.

INTRODUCTION: Patients with oesophageal carcinoma are at high risk of malnutrition. The aim of this study was to assess current practice for the nutritional management of patients following surgery for oesophageal carcinoma. PATIENTS AND METHODS: A postal questionnaire was sent to 82 dietetic departments of those hospitals in England identified as major centres for upper gastrointestinal surgery. RESULTS: Of the 66 (80%) responses received, 22 (33%) centres routinely perform pre-operative nutritional screening/assessment on oesophageal carcinoma patients. Centres with dietetic support dedicated to these patients are more likely to perform a pre-operative nutritional assessment (n = 17; 55%) than those without (n = 5; 14%; P < 0.001; chi(2) = 12.17). Pre-operative nutritional support is routinely provided in only 11 (17%) centres with the majority of centres (n = 50; 75%), providing it if patients are considered malnourished only. A total of 47 (70%) centres routinely provide postoperative nutritional support with jejunal feeding being the most commonly chosen route. Dedicated dietetic support is provided at 31 (47%) centres. Those centres with a dedicated dietitian are more likely to provide early postoperative nutritional support (n = 27; 87%) than those without (n = 20; 57%; P = 0.007; chi(2) = 7.195) and more likely to review patients routinely following discharge from hospital (n = 25 [81%] with a dietitian versus n = 17 [49%] without; P = 0.007; chi(2) = 7.2). CONCLUSIONS: The nutritional management of patients following surgery for upper gastrointestinal carcinoma is not uniform with practice varying considerably between centres. Those centres with a dedicated dietitian are more likely to assess patients' nutritional status and provide nutritional support.

Optimizing the dose of intrathecal morphine in older patients undergoing hip arthroplasty.

UNLABELLED: Intrathecal (IT) morphine provides excellent postoperative analgesia but may result in many side effects, including postoperative nausea and vomiting, pruritus, and respiratory depression, particularly at larger doses. Older patients may be at particular risk. The optimal dose of spinal morphine in older patients undergoing hip arthroplasty is not known. We designed this prospective, randomized, controlled, double-blinded study to evaluate the analgesic efficacy and side effect profile of 50-200 microg of IT morphine in older patients undergoing elective hip arthroplasty. Sixty patients older than 65 years undergoing elective hip arthroplasty were enrolled. Patients were randomized to receive spinal anesthesia with 15 mg of bupivacaine and IT morphine in four groups: 1). 0 microg, 2). 50 microg, 3). 100 microg, and 4). 200 microg. IT morphine 100 and 200 microg produced effective pain relief and decreased the postoperative requirement for morphine compared with control. IT morphine 50 microg did not provide effective pain relief. Both 100 and 200 microg of IT morphine provided comparable levels of postoperative analgesia. There were no between-group differences in postoperative nausea and vomiting, sedation, respiratory depression, or urinary retention. Pruritus was significantly more frequent with 200 microg of IT morphine. In conclusion, 100 microg of IT morphine provided the best balance between analgesic efficacy and side effect profile in older patients undergoing hip arthroplasty. IMPLICATIONS: The dosage of intrathecal morphine that provides the best balance between analgesic efficacy and side effect profile in the older patient undergoing hip arthroplasty is not known. This prospective, randomized, controlled, double-blinded clinical trial demonstrates that a dose of 100 microg of intrathecal morphine provides the best balance between efficacy and side effects, compared with doses of 0, 50, and 200 microg of morphine, in this patient population.

The endogenous opioid spinorphin blocks fMet-Leu-Phe-induced neutrophil chemotaxis by acting as a specific antagonist at the N-formylpeptide receptor subtype FPR.

Spinorphin is an endogenous heptapeptide (leucylvalylvalyltyrosylprolyltryptophylthreonine), first isolated from bovine spinal cord, whose sequence matches a conserved region of beta-hemoglobin. Also referred to as LVV-hemorphin-4 and a member of the nonclassical opioid hemorphin family, spinorphin inhibits enkephalin-degrading enzymes and is analgesic. Recently, spinorphin was reported to block neutrophil activation induced by the chemotactic N-formylpeptide N-formylmethionylleucylphenylalanine (fMLF), suggesting a potential role as an endogenous negative regulator of inflammation. Here we use both gain- and loss-of-function genetic tests to identify the specific mechanism of spinorphin action on neutrophils. Spinorphin induced calcium flux in normal mouse neutrophils, but was inactive in neutrophils from mice genetically deficient in the fMLF receptor subtype FPR (N-formylpeptide receptor). Consistent with this, spinorphin induced calcium flux in human embryonic kidney 293 cells transfected with mouse FPR, but had no effect on cells expressing the closely related fMLF receptor subtype FPR2. Despite acting as a calcium-mobilizing agonist at FPR, spinorphin was a weak chemotactic agonist and effectively blocked neutrophil chemotaxis induced by fMLF at concentrations selective for FPR. Spinorphin did not affect mouse neutrophil chemotaxis induced by concentrations of fMLF that selectively activate FPR2. Thus, spinorphin blocks fMLF-induced neutrophil chemotaxis by acting as a specific antagonist at the fMLF receptor subtype FPR.

Contrasting evolution of the human leukocyte N-formylpeptide receptor subtypes FPR and FPRL1R.

N-formylpeptides are phagocyte chemoattractants that act by binding to two structurally related receptors, FPR (formylpeptide receptor) and FPRL1R (FPR-like-1 receptor), which are encoded by the human genes FPR1 and FPRL1. Single nucleotide polymorphisms (SNPs) in the FPR coding region have been reported and two have been associated with the disease juvenile periodontitis; however, their frequency and linkage relationships are unknown. Here we systematically analyzed polymorphism in the open reading frames of FPR1 and FPRL1 by direct sequencing of cloned alleles from random blood donors from North America. For FPR1 we detected five non-synonymous SNPs and two synonymous SNPs in a sample of 26 chromosomes one each from 17 Caucasian and nine black random blood donors. Although all five non-synonymous SNPs were common in Caucasians, Blacks, and Asians, notable differences in allele frequency were found for each SNP in the different racial groups, suggesting differential selective pressures. We found that the FPR1 polymorphisms are linked in 15 common haplotypes. No polymorphisms were detected in FPRL1 after sampling 44 chromosomes from 36 random blood donors from the same three racial groups. Thus FPR1 and FPRL1, though they originated from a common gene, appear to have undergone markedly different evolutionary events.

Suicidal nonfatal impalement injury of the thorax.

We treated an impalement injury of the thorax resulting from a suicide attempt in the form of a road traffic accident. The patient survived and was discharged 5 weeks after his injury. The surgical management of thoracic impalement injuries and the rationale behind a multidisciplinary approach are discussed.