Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study.

BACKGROUND: NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. PATIENTS AND METHODS: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. RESULTS: Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. CONCLUSIONS: Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. CLINCALTRIALS.GOV NUMBER: NCT02122913.

Radiographer training for screening of patients referred for Magnetic Resonance Imaging: A scoping review.

INTRODUCTION: Strict safety practices are essential to ensure the safety of patients and staff in Magnetic Resonance Imaging (MRI). Training regarding the fundamentals of MRI safety is well-established and commonly agreed upon. However, more complex aspect of screening patients, such as image review or screening of unconscious patients/patients with communication difficulties is less well discussed. The current UK and USA guidelines do not suggest the use of communication training for MRI staff nor indicate any training to encourage reviewing images in the screening process. This review aims to map the current guidance regarding safety and patient screening training for MRI diagnostic and therapeutic radiographers. METHODS: A systematic search of PubMed, Trip Medical database and Radiography journal was conducted. Studies were chosen based on the review objectives and pre-determined inclusion/exclusion criteria using the PRISMA-ScR framework. RESULTS: Twenty-four studies were included in the review, which identified some key concepts including MRI safety training and delivery methods, screening and communication, screening of unconscious or non-ambulatory patients and the use of imaging. CONCLUSION: Training gaps lie within the more complex elements of screening such as the inclusiveness of question phrasing, particularly to the neurodivergent population, how we teach radiographers to screen unconscious/unresponsive patients and using imaging to detect implants. IMPLICATIONS FOR PRACTICE: The consequences of incomplete or inaccurate pre-MRI safety screening could be the introduction of unexpected implants into the scanner or forgoing MRI for a less desirable modality. The development of enhanced training programs in implant recognition using imaging and communication could complement existing training.

Differential pulse oximetry readings between ethnic groups and delayed transfer to intensive care units.

BACKGROUND: Pulse oximeters are widely used to monitor blood oxygen saturations, although concerns exist that they are less accurate in individuals with pigmented skin. AIMS: This study aimed to determine if patients with pigmented skin were more severely unwell at the period of transfer to intensive care units (ICUs) than individuals with White skin. METHODS: Using data from a large teaching hospital, measures of clinical severity at the time of transfer of patients with COVID-19 infection to ICUs were assessed, and how this varied by ethnic group. RESULTS: Data were available on 748 adults. Median pulse oximetry demonstrated similar oxygen saturations at the time of transfer to ICUs (Kruskal-Wallis test, P = 0.51), although median oxygen saturation measurements from arterial blood gases at this time demonstrated lower oxygen saturations in patients classified as Indian/Pakistani ethnicity (91.6%) and Black/Mixed ethnicity (93.0%), compared to those classified as a White ethnicity (94.4%, Kruskal-Wallis test, P = 0.005). There were significant differences in mean respiratory rates in these patients (P < 0.0001), ranging from 26 breaths/min in individuals with White ethnicity to 30 breaths/min for those classified as Indian/Pakistani ethnicity and 31 for those who were classified as Black/Mixed ethnicity. CONCLUSIONS: These data are consistent with the hypothesis that differential measurement error for pulse oximeter readings negatively impact on the escalation of clinical care in individuals from other than White ethnic groups. This has implications for healthcare in Africa and South-East Asia and may contribute to differences in health outcomes across ethnic groups globally.

Are radiographers suffering from symptoms of compassion fatigue due to occupational stress: A systematic review.

INTRODUCTION: Repeated exposure to challenging or traumatic situations can lead to a phenomenon called compassion fatigue (CF). This can present as increased stress and anxiety in staff and a reduced patient relationship. If untreated it can lead to sickness and attrition from the profession. This systematic review aims to investigate the evidence of stressors leading to CF in diagnostic radiographers. METHOD: A review protocol was developed and registered on PROSPERO. Database and grey literature searches were carried out. Studies were selected against pre-defined inclusion and exclusion criteria for review. No meta-analysis was possible therefore the data were presented as a narrative. RESULTS: Fifteen studies were selected for review published between 1982 and 2020. Evidence demonstrates that diagnostic radiographers suffer from high levels of occupational stress, however, stress is perceived rather than defined. Common causes of occupational stress were identified as poor patient interactions and a lack of time to spend with patients. There is a lack of evidence to show how this stress affects radiographer health or their ability to provide compassionate care. CONCLUSION: Diagnostic radiographers are prone to suffering from symptoms that can be attributed to CF. This has been present for an extended period, and the main changes have been a decrease in job satisfaction and accomplishment. Patient interaction was identified as a cause, but it is unclear if this affects staff ability to be compassionate. Further work is required to find ways to mitigate these effects and prevent continued deterioration. IMPLICATIONS FOR PRACTICE: This review has highlighted that the issue of CF may be getting worse for some radiographers and that work is required to design and implement workable interventions to try and mitigate these issues.

The psychosocial and emotional experiences of cancer patients during the COVID-19 pandemic: A systematic review.

BACKGROUND: COVID-19 was declared a pandemic by the World Health Organization on March 11th, 2020. Global social lockdowns were instigated to reduce spread and prevent health-services from becoming overwhelmed. People having treatment for cancer are known to have heightened psychological/emotional burden. The combined impact of managing pandemic regulations alongside this may present additional burden. The purpose of this systematic review is to examine current evidence of the psychological and emotional impact of COVID-19 on people with cancer, early in the pandemic. METHODS: Five electronic databases were searched (Embase, Global Health, HMIC, PsychINFO, CINAHL) from September 2019 to October 2021. Qualitative, quantitative and mixed-method primary research studies exploring emotional and psychological impacts of COVID-19 on cancer patients, limited to English language, were included. Quality appraisal was conducted using the MMAT. RESULTS: Fifty-one papers, with 27,356 people from 21 countries treated for cancer, were included. 43 studies were quantitative with a survey method approach, six studies qualitative and four used a mixed methods design. MMAT score was mostly two or three. Four themes were identified: Emotional aspects and Quality of Life; Psychosocial aspects; Impact of COVID-19 on self; Impact of COVID-19 on cancer, with themes overlapping. CONCLUSION: Whilst emotional/psychological impacts such as anxiety, isolation, employment fears, and uncertainty about the future were potentially universal concerns early in the pandemic, they may have been particularly acute for people living with cancer and represent complex, overlapping factors. As COVID-19 continues to impact health-services and society, it is important to focus on any ongoing impact to the experience of cancer patients. Most of the studies reviewed used tools that do not provide deeper understanding of how and why emotional states of people with cancer were affected. Further qualitative work may reveal patterns of what was unique to cancer patients during the pandemic, compared to general populations.

Arginase-1-expressing macrophages are dispensable for resistance to infection with the gastrointestinal helminth Trichuris muris.

Alternatively activated macrophages (AAMs) have key roles in the immune response to a variety of gastrointestinal helminths such as Heligmosomoides bakeri and Nippostrongylus brasiliensis. In addition, AAMs have been implicated in the resolution of infection-induced pathology in Schistosoma mansoni infection. AAMs exert their activity in part via the enzyme arginase-1 (Arg1), which hydrolyses L-arginine into urea and ornithine, and can supply precursor substrate for proline and polyamine production. Trichuris muris is a worm that resides in the large intestine with resistance being characterized by a Th2 T-cell response, which drives alternatively activated macrophage production in the local environment of the infection. To investigate the role of AAMs in T. muris infection, we used independent genetic and pharmacologic models of arginase deficiency. In acute infection and Th2-dominated immunity, arginase-deficient models expelled worms normally. Macrophage-Arg1-deficient mice showed cytokine and antibody levels comparable to wild-type animals in acute and chronic infection. We also found no role for AAMs and Arg1 in infection-induced pathology in the response to T. muris in either chronic (Th1 dominated) or acute (Th2 dominated) infections. Our data demonstrate that, unlike other gastrointestinal helminths, Arg1 expression in AAMs is not essential for resistance to T. muris in effective resolution of helminth-induced inflammation.

A comparison of the moment arms of pelvic limb muscles in horses bred for acceleration (Quarter Horse) and endurance (Arab).

Selective breeding for performance has resulted in distinct breeds of horse, such as the Quarter Horse (bred for acceleration) and the Arab (bred for endurance). Rapid acceleration, seen during Quarter Horse racing, requires fast powerful muscular contraction and the generation of large joint torques, particularly by the hind limb muscles. This study compared hind limb moment arm lengths in the Quarter Horse and Arab. We hypothesized that Quarter Horse hind limb extensor muscles would have longer moment arms when compared to the Arab, conferring a greater potential for torque generation at the hip, stifle and tarsus during limb extension. Six Quarter Horse and six Arab hind limbs were dissected to determine muscle moment arm lengths for the following muscles: gluteus medius, biceps femoris, semitendinosus, vastus lateralis, gastrocnemius (medialis and lateralis) and tibialis cranialis. The moment arms of biceps femoris (acting at the hip) and gastrocnemius lateralis (acting at the stifle) were significantly longer in the Quarter Horse, although the length of the remaining muscle moment arms were similar in both breeds of horse. All the Quarter Horse muscles were capable of generating greater muscle moments owing to their greater physiological cross-sectional area (PCSA) and therefore greater isometric force potential, which suggests that PCSA is a better determinant of muscle torque than moment arm length in these two breeds of horse. With the exception of gastrocnemius and tibialis cranialis, the observed muscle fascicle length to moment arm ratio (MFL : MA ratio) was greater for the Arab horse muscles. It appears that the Arab muscles have the potential to operate at slower velocities of contraction and hence generate greater force outputs when compared to the Quarter Horse muscles working over a similar range of joint motion; this would indicate that Arab hind limb muscles are optimized to function at maximum economy rather than maximum power output.

Comparative anatomy and muscle architecture of selected hind limb muscles in the Quarter Horse and Arab.

The Quarter Horse (bred for acceleration) and the Arab (bred for endurance) are situated at either end of the equine athletic spectrum. Studies into the form and function of the leg muscles in human sprint and endurance runners have demonstrated that differences exist in their muscle architecture. It is not known whether similar differences exist in the horse. Six Quarter Horse and six Arab fresh hind limb cadavers were dissected to gain information on the muscle mass and architecture of the following muscles: gluteus medius; biceps femoris; semitendinosus; vastus lateralis; gastrocnemius; tibialis cranialis and extensor digitorum longus. Specifically, muscle mass, fascicle length and pennation angle were quantified and physiological cross-sectional area (PCSA) and maximum isometric force were estimated. The hind limb muscles of the Quarter Horse were of a significantly greater mass, but had similar fascicle lengths and pennation angles when compared with those of the Arab; this resulted in the Quarter Horse hind limb muscles having greater PCSAs and hence greater isometric force potential. This study suggests that Quarter Horses as a breed inherently possess large strong hind limb muscles, with the potential to accelerate their body mass more rapidly than those of the Arab.

Specialist breast care nurses for supportive care of women with breast cancer.

BACKGROUND: Breast Care Nurses (BCNs) are now established internationally, predominantly in well resourced healthcare systems. The role of BCNs has expanded to reflect the diversity of the population in which they work, and the improvements in survival of women with breast cancer. Interventions by BCNs aim to support women and help them cope with the impact of the disease on their quality of life. OBJECTIVES: To assess the effectiveness of individual interventions carried out by BCN's on quality of life outcomes for women with breast cancer. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (15 January 2007). We also searched MEDLINE (1966 to September 2006), CINAHL (1982 to September 2006), EMBASE (1980 to September 2006), British Nursing Index (1984 to September 2006), CancerLit (1961 to September 2006), PsycInfo (1967 to September 2006), Library and Info Science Abstracts (LISA) (1969 to September 2006), Dissertation Abstracts International (only available 2005 to September 2006). We contacted authors as appropriate. SELECTION CRITERIA: Randomised controlled trials assessing the effects of interventions carried out by BCN's on quality of life outcomes, for women with breast cancer. DATA COLLECTION AND ANALYSIS: Two authors independently assessed relevant studies for inclusion and undertook data extraction and quality assessment of included studies. MAIN RESULTS: We incuded five studies, categorised into three groups. Three studies assessing psychosocial nursing interventions around diagnosis and early treatment found that the BCN could affect some components of quality of life, such as anxiety and early recognition of depressive symptoms. However, their impact on social and functional aspects of the disease trajectory was inconclusive. Supportive care interventions during radiotherapy was assessed by one study which showed that specific BCN interventions can alleviate perceived distress during radiotherapy treatment, but did not improve coping skills, mood or overall quality of life. One study assessed nurse-led follow-up interventions in which no statistically significant difference was identified for main demographic variables, satisfaction with care, access to medical care or anxiety and depression. AUTHORS' CONCLUSIONS: There is limited evidence at this time to support the contention that interventions by BCNs assist in the short-term with the recognition and management of psychological distress for women with breast cancer. Further research is required before the impact of BCNs on aspects of quality of life for women with breast cancer can be known.

Methods of communicating a primary diagnosis of breast cancer to patients.

BACKGROUND: The method of delivering a diagnosis of breast cancer to women has the potential to impact on their level of interpretation, patient recall and satisfaction. OBJECTIVES: To assess the effectiveness of different methods when used to communicate a primary diagnosis of breast cancer to women. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Specialised Register on 7 September 2006, Cochrane Consumers and Communication Group on 27 October 2006, MEDLINE (1966 to present), CINAHL (1982 to present), EMBASE OVID (1980 to present), British Nursing Index (Jan 1984 to present), PsycInfo (1967 to present), Dissertation Abstracts International (2004 to 2006), Library and Info Science Abstracts (LISA) (1969 to present), ISI Web of Knowledge (conference abstracts) and reference lists of articles. SELECTION CRITERIA: We sought randomised controlled trials of women with a histologically confirmed diagnosis of breast cancer being given a diagnosis of primary breast cancer. Trials should also have used one or more of the following methods; face-to-face consultations, written information, telephone consultation, audio or video tapes of consultation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion in the review. Studies were to be assessed using standardised data extraction and quality assessment forms. MAIN RESULTS: The search strategies identified 2847 citations overall. A total of 30 citations appeared relevant however there were three duplicates which left 27 articles for further review. Articles reporting the same primary data accounted for 6 of the publications Brown 1997; Brown 1998; Brown 1999; Brown 2000; Hack 2000; Hack 2003 which left 23 original papers to be reviewed for inclusion. Of these, none met the inclusion criteria. Data extraction and assessment of methodological quality was therefore not possible. AUTHORS' CONCLUSIONS: The review question remains unanswered as there were no randomised trials of methods of communicating a diagnosis of breast cancer to women. The authors have considered the possible reasons for the lack of research studies in this area and have considered that it is perhaps unethical to randomise women at such a vulnerable time such as waiting for a diagnosis. The design of ethically sensitive research to examine this topic needs to be explored to inform future practice. As some papers reviewed by the authors related to the first consultation visit, where treatment options are discussed, perhaps a review which focused on the methods of communication at the first consultation visit would provide more reliable evidence for the effectiveness of methods of communication and overcome the ethical dilemmas previously mentioned.

Stability in metabolic phenotypes and inferred metagenome profiles before the onset of colitis-induced inflammation.

Inflammatory bowel disease (IBD) is associated with altered microbiota composition and metabolism, but it is unclear whether these changes precede inflammation or are the result of it since current studies have mainly focused on changes after the onset of disease. We previously showed differences in mucus gut microbiota composition preceded colitis-induced inflammation and stool microbial differences only became apparent at colitis onset. In the present study, we aimed to investigate whether microbial dysbiosis was associated with differences in both predicted microbial gene content and endogenous metabolite profiles. We examined the functional potential of mucus and stool microbial communities in the mdr1a -/- mouse model of colitis and littermate controls using PICRUSt on 16S rRNA sequencing data. Our findings indicate that despite changes in microbial composition, microbial functional pathways were stable before and during the development of mucosal inflammation. LC-MS-based metabolic phenotyping (metabotyping) in urine samples confirmed that metabolite profiles in mdr1a -/- mice were remarkably unaffected by development of intestinal inflammation and there were no differences in previously published metabolic markers of IBD. Metabolic profiles did, however, discriminate the colitis-prone mdr1a -/- genotype from controls. Our results indicate resilience of the metabolic network irrespective of inflammation. Importantly as metabolites differentiated genotype, genotype-differentiating metabolites could potentially predict IBD risk.

Treatment of chronic hepatitis C virus infection with recombinant consensus interferon.

To assess the safety and efficacy of consensus interferon (IFN-Con-1), 55 patients with chronic hepatitis C infection were treated with either 3, 6, 9, 12, or 15 microg IFN-Con-1 s.c. three times a week for 24 weeks, followed by 24 weeks of observation. There was a dose-response relationship with respect to the number of patients with normalized ALT concentrations or undetectable HCV RNA. At the end of the 24-week treatment period, the serum ALT had normalized in 18% of patients given the 3 microg dose and 42% of patients given the 12 microg or 15 microg doses of IFN-Con-1. At the end of the posttreatment observation period, the serum ALT was still normal in 10% of patients given the 3 microg, 6 microg, or 9 microg doses and in 50% of patients given the 15 microg dose. Also, at the end of the 24-week treatment period, 27% of patients given the 3 microg dose and 75% given the 15 microg dose had undetectable serum HCV RNA. At the end of the posttreatment observation period, the proportion of patients with undetectable HCV RNA ranged from 9% of those given the 3 microg dose to 50% of those given the 15 microg dose. Our study indicates that treatment with IFN-Con-1 appears to be safe and effective. In addition, use of 15 microg of IFN-Con-1 resulted in significantly more patients with sustained ALT normalization and absence of HCV RNA 6 months after cessation of therapy compared with treatment with lower doses of IFN-Con-1. Additional trials are underway to confirm these findings.

Phase 1 study of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in breast cancer patients after autologous peripheral blood progenitor cell (PBPC) transplantation.

Forty-seven patients with stage II, III, or IV breast cancer undergoing autologous peripheral blood progenitor cell (PBPC) transplantation were randomized to placebo (n = 13) or to one of five sequential dose cohorts of pegylated (PEG) recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) (1.0, 2.5, 5.0, 7.5, or 10.0 microg/kg/day) (n= 34). Blinded study drug was started on the day of transplantation and was continued until the platelet count was > or =100 x 109/l or a maximum of 21 days. PBPCs were mobilized with filgrastim (r-metHuG-CSF) and all patients received filgrastim starting on day +2 after transplantation. The nadir platelet count was not affected by treatment. The median time to platelet recovery was 11 and 12 days for the placebo and combined PEG-rHuMGDF groups, respectively. No trends in adverse events suggested dose- or treatment-related toxicity. Two patients withdrew from the study because of an adverse event (allergic reaction in the 7.5 microg/kg group) probably related to study drug, and veno-occlusive disease (VOD) (in the 5 microg/kg group) which was felt not to be related to study drug by the investigator. No patients developed neutralizing antibodies to MGDF. Day +21 and day +28 platelet counts were higher in the group receiving PEG-rHuMGDF (246 vs 148 x 109/l and 299 vs 145 x 109/l, respectively; both P < 0. 05). PEG-rHuMGDF up to 10 microg/kg/day was well tolerated. In this study, there was no effect of study drug on initial platelet engraftment at the doses studied. However, the efficacy of other doses is unknown.

Use of PEG-rHuMGDF in platelet engraftment after autologous stem cell transplantation.

This paper summarizes a pilot, sequential dose-escalation study of PEG-rHuMGDF in patients with advanced malignancies who had delayed platelet recovery after autologous stem cell transplantation (ASCT). Patients were randomized to receive either placebo (n = 11) or PEG-rHuMGDF at 5 (n = 9), 10 (n = 6), or 25 (n = 7) microg/kg/day by subcutaneous injection for 14 days and were monitored for 5 weeks. Across all treatment groups, eight patients had platelet recovery to > or = 20 x 10(9)/l by day 21. The proportion of patients achieving platelet recovery, the median number of days and units of platelet transfusions were similar for the placebo and the PEG-rHuMGDF groups. PEG-rHuMGDF was well tolerated at all dosages. The incidence rates of adverse events in all groups were similar. No deaths on study, no drug-related serious adverse events, and no development of neutralizing antibodies to MGDF occurred.

Expression of CD44 on bile ducts in primary sclerosing cholangitis and primary biliary cirrhosis.

AIM: To examine expression of CD44, a transmembrane glycoprotein involved in lymphocyte homing and activation, in inflammatory liver diseases. METHODS: Formalin fixed, paraffin embedded tissues were obtained from normal, uninvolved liver from patients undergoing partial hepatectomy for metastatic carcinoma (9) and transplant hepatectomy specimens from patients with primary biliary cirrhosis (12), primary sclerosing cholangitis (8), autoimmune hepatitis (3), hepatitis C (3), and secondary sclerosing cholangitis (1). Expression of CD44 (using antibodies to three core epitopes), HLA-DR, and lymphocyte phenotypic markers was studied by immunohistochemistry. RESULTS: CD44 expression was not detected in either hepatocytes or biliary epithelial cells in normal livers. In sections from all 27 transplant hepatectomy specimens, CD44 was positive in bile duct epithelial cells but not in hepatocytes. The proportion of CD44+ ducts was much higher in biliary disease than in chronic hepatitis. By contrast, expression of HLA-DR was detected in a relatively small percentage of bile ducts. Activated, memory phenotype CD4+ T lymphocytes were increased in the parenchyma of all diseased livers and an infiltrate of activated CD8+ cells within the biliary epithelium was evident in inflammatory biliary disease. CONCLUSIONS: CD44 appears to play an important role in the development of autoimmune biliary disease by promoting lymphoepithelial interactions, whereas HLA-DR may be involved in the subsequent progression of these conditions.

A role for the pattern recognition receptor Nod2 in promoting recruitment of CD103+ dendritic cells to the colon in response to Trichuris muris infection.

The ability of the colon to generate an immune response to pathogens, such as the model pathogen Trichuris muris, is a fundamental and critical defense mechanism. Resistance to T. muris infection is associated with the rapid recruitment of dendritic cells (DCs) to the colonic epithelium via epithelial chemokine production. However, the epithelial-pathogen interactions that drive chemokine production are not known. We addressed the role of the cytosolic pattern recognition receptor Nod2. In response to infection, there was a rapid influx of CD103(+)CD11c(+) DCs into the colonic epithelium in wild-type (WT) mice, whereas this was absent in Nod2(-/-) animals. In vitro chemotaxis assays and in vivo experiments using bone marrow chimeras of WT mice reconstituted with Nod2(-/-) bone marrow and infected with T. muris demonstrated that the migratory function of Nod2(-/-) DCs was normal. Investigation of colonic epithelial cell (CEC) innate responses revealed a significant reduction in epithelial production of the chemokines CCL2 and CCL5 but not CCL20 by Nod2-deficient CECs. Collectively, these data demonstrate the importance of Nod2 in CEC responses to infection and the requirement for functional Nod2 in initiating host epithelial chemokine-mediated responses and subsequent DC recruitment and T-cell responses following infection.

Using intranasal lidocaine to reduce food intake.

OBJECTIVE: Develop a dose-response curve for the effect of intranasal lidocaine on food intake. DESIGN: Healthy obese subjects had food intake, ratings of hunger, desire to eat, craving and fullness measured at lunch after an overnight fast. Four treatments were given as nose drops (0.5-0.6 ml per nostril) 5 min before the meal in a double-blind manner with a four period crossover design including a 7-day washout between periods. The treatments were saline, 2.5, 10 and 25 mg lidocaine per nostril. The order of administration was randomly assigned to each subject. Electrocardiograms, vital signs, chemistry panels, complete blood counts (CBC) and nasal inspections were carried out before and after each dose. SUBJECTS: Forty-seven subjects were screened, 34 were randomized and 20 subjects completed all four study periods in the trial. The subjects were 39+/-12.5 (s.d) years of age, had a weight of 91+/-13.0 kg, a height of 167+/-10.3 cm, 56% were women, 47% were African-American and 53% were Caucasian. MEASUREMENTS: Food intake, rating of hunger, desire to eat, craving and fullness are measures of efficacy. Adverse events, electrocardiograms, vital signs, chemistry panels, nasal inspections, CBC and physical exams are measures of safety. RESULTS: The mean reduction in food intake vs saline control in the 20 subjects completing all four study periods was 3.3+/-7% (s.d), 4.2+/-8.5% and 7.4+/-7.3% in the 2.5 mg, 10 and 25 mg per nostril groups, respectively (P=NS). Hunger and desire to eat in subjects who completed at least one study period decreased dose dependently (P<0.03, at the 25 mg per nostril dose). There were no clinically significant changes in safety measures, electrocardiograms, vital signs, chemistry panels, CBC or nasal inspections. CONCLUSION: Intranasal lidocaine reduced hunger and the desire to eat, but this did not translate into a significant reduction in food intake suggesting that intranasal lidocaine will not have value in treating obesity.

Increased natural killer cell activity in patients with an abdominal aortic aneurysm.

BACKGROUND: Natural killer (NK) cells have an emerging role in the development of chronic disease and in the direction and maintenance of inflammatory responses. Abdominal aortic aneurysms (AAA) is a chronic inflammatory disorder of unknown aetiology. The aim was to investigate whether NK cells showed altered function in patients with an AAA. METHODS: The presence, phenotype and function of peripheral blood and tissue NK cells from patients with an AAA, peripheral vascular disease (PVD) and healthy age-sex-matched controls were assessed before and after surgery. RESULTS: Patients with an AAA had significantly higher (P < 0.010) percentages of peripheral blood NK cells (mean (95 per cent c.i.) 23.8 (2.6) per cent) than patients with PVD (17.4 (2.9) per cent) and control subjects (16.2 (2.8) per cent). The NK cells from patients with an AAA had increased cytotoxicity on a per cell basis towards both an NK-sensitive target cell line and human aortic smooth muscle cells. Increased NK cell proportions (22.7 (3.5) per cent) and cytotoxic activity, together with higher C-reactive protein values, persisted after successful AAA repair. CONCLUSION: These data support the hypothesis that increased NK cytotoxicity could be a contributing factor in the generation or potentiation of inflammation in patients with an AAA.