Cellular models for beta-cell function and diabetes gene therapy.

Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

Transferring patients with Ebola by land and air: the British military experience.

The Ebola epidemic of 2014/2015 led to a multinational response to control the disease outbreak. Assurance for British aid workers included provision of a robust treatment pathway including repatriation back to the UK. This pathway involved the use of both land and air assets to ensure that patients were transferred quickly, and safely, to a high-level isolation unit in the UK. Following a road move in Sierra Leone, an air transportable isolator (ATI) was used to transport patients for the flight and onward transfer to the Royal Free Hospital. There are several unique factors related to managing a patient with Ebola virus disease during prolonged evacuation, including the provision of care inside an ATI. These points are considered here along with an outline of the evacuation pathway.

Impaired brachial artery endothelial function in young healthy women following an acute painful stimulus.

INTRODUCTION: Impaired endothelial function has been observed during and immediately following an acutely painful stimulus. However, the extent to which this persists following pain dissipation is unclear. PURPOSE: To determine whether painful ischemic handgrip exercise (pain task) causes impaired flow-mediated dilation (FMD) after the sensation of pain and hemodynamic responses have abated. A second purpose was to determine whether the response to pain differed with a predisposition to magnify, ruminate, and feel helpless about pain (pain catastrophizing status). METHODS: Brachial artery FMD stimulated by reactive hyperemia was assessed via ultrasound in 18 (9 high catastrophizing) healthy, women (20 ± 1 years) before and 15 min after a 3 min pain task. The shear stress stimulus for FMD was estimated as shear rate (blood velocity/brachial artery diameter). RESULTS (MEAN ± SD): None of the variables were significantly impacted by pain catastrophizing status and are presented pooled across group. The pain task increased pain ratings [1 ± 1-6 ± 3 (0-10 scale) (p < 0.001)], mean arterial pressure (MAP) (p < 0.001) and heart rate (HR) (p < 0.001), all returning to pre-pain levels ≤2-min post-pain task (pre-pain vs. 2-min post-pain: pain rating p = 1.000; MAP p = 0.142; HR p = 0.992). The shear rate stimulus was not different between pre- and post-pain task FMD tests (p = 0.200). FMD decreased post-pain task (10.8 ± 4.6 vs. 7.0 ± 2.7 %, p < 0.001). CONCLUSION: These results indicate that, regardless of pain catastrophizing status, painful ischemic handgrip exercise has a deleterious impact on endothelial function that persists after the pain sensation and hemodynamic responses have abated.

The safety and efficacy, and recommendations for the use of biologic drugs in the UK military rheumatology population.

Inflammatory arthritis is a significant cause of morbidity in the military. In particular the sero-negative spondyloarthritides, which include ankylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory bowel disease related arthritis and undifferentiated spondyloarthritis, are especially prevalent in the young male phenotype, which is common in the Armed Forces. It is estimated that there are more than 1500 patients in the Armed Forces with spondyloarthritis alone, based on the prevalence in the general population of approximately 1%. Inflammatory arthritides are eminently treatable, especially with the development and widespread use of biologic drugs such as anti-Tumour Necrosis Factor (TNF) therapy. The use of these drugs can deliver patients an exceptionally good outcome leading to symptom control and normal function in many cases. Initial concerns regarding safety and side effects of anti-TNF drugs have been allayed by the evidence provided from comprehensive national databases developed over the last 10 years. With early diagnosis and prompt treatment military patients can complete a full career including deployment with only minor limitations. This paper reviews the burden of inflammatory arthritis in the armed services, its management and outcome in this population, the evidence for the safety of anti-TNF treatments and the recommendations for employability and deployability for service personnel.

Recommendations for the practice of travel medicine.

Travel Medicine has emerged as a distinct entity over the last two decades in response to a very substantial increase in international travel and is now forging its own identity, remit and objectives for care of the traveller. Crucial to the formation of any speciality is the definition of recommendations for its practice. This is particularly important and needed for travel medicine as it overlaps with and forms part of day-to-day work in a number of different medical specialities. This document defines a set of recommendations for the practice of travel medicine from the Faculty of Travel Medicine of the Royal College of Physicians and Surgeons of Glasgow. Their objective is to help raise standards of practice and achieve greater uniformity in provision of services, better to protect those who travel. As travel medicine moves towards applying for speciality status, these standards will also contribute to that process.

Plasmodium knowlesi malaria: assessing the risk to the British Armed Forces.

Plasmodium knowlesi is a zoonosis and is now recognised as the fifth commonly occurring form of human malaria. It is endemic in South East Asia, including some areas previously declared malaria free or at low risk for malaria. The epidemiology of the disease is very different to other forms of malaria which are determined by transmission by anthrophilic mosquitoes from human reservoirs. In contrast Plasmodium knowlesi malaria has a monkey reservoir and disease is transmitted to humans by mosquitoes that normally feed on animals. People become accidentally infected when they enter the ranges of the vector mosquitoes and animal hosts. Improved and novel diagnostic methods have indicated that human disease is much more common than previously thought. Although the greatest disease burden falls on local populations living in endemic areas, visitors entering such zones are also at risk. The changing nature of tourism with deep jungle expeditions being more heavily marketed, and short visits to endemic zones now common, mean that new populations are increasingly recognised as being at risk. One such group are military personnel undergoing jungle training or deployed on Operations. The potential for severe disease in areas previously considered at low risk for malaria means that risk assessment needs to be reviewed, coupled with communication strategies to address prevention of a zoonotic form of the disease. The role of chemoprophylaxis in some specific groups may need to be considered.

Undifferentiated febrile illnesses amongst British troops in Helmand, Afghanistan.

OBJECTIVES: Undifferentiated febrile illnesses have been a threat to British expeditionary forces ever since the Crusades. The infections responsible were identified during the Colonial Era, both World Wars and smaller conflicts since, but nearly all remain a significant threat today. Undiagnosed febrile illnesses have occurred amongst British troops in Helmand, Afghanistan since 2006 and so a fever study was performed to identify them. METHODS: From May to October 2008, all undifferentiated fever cases seen at the British field hospital in Helmand, Afghanistan were assessed using a standard protocol. Demographic details, clinical features and laboratory results were recorded and paired serum samples were sent for testing at the UK Special Pathogens Reference Unit (SPRU). RESULTS: Over 6 months, there were 26 cases of"Helmand Fever" assessed and 23 diagnoses were made of which 12 (52%) were sandfly fever, 6 (26%) were acute Qfever and 5 (22%) were rickettsial infections. Four cases had co-infections and 7 cases were not diagnosed (mostly due to inadequate samples). The clinical features and laboratory results available at the British field hospital did not allow these diseases to be distinguished from each other. The exact type of rickettsial infection could not be identified at SPRU. CONCLUSIONS: These cases probably represent the "tip of an iceberg" for British and Allied forces. More resources for diagnostic facilities and follow-up of patients are required to improve the management and surveillance of "Helmand Fever" cases; until then doxycycline 100 mg twice daily for 2 weeks should be given to all troops who present with an undifferentiated febrile illness in Helmand, Afghanistan. Patients with acute Q fever should be followed-up for at least 2 years to exclude chronic Q fever. Prevention of these diseases requires a better understanding of their epidemiology, but prophylaxis with doxycycline and possibly Q fever vaccine should be considered.

Improvements in compliance with medical force protection measures by simplification of the anti-malarial chemoprophylaxis regime.

OBJECTIVES: Medical Force Protection (MFP) is important in keeping service personnel "fit to fight." It is particularly important for overseas deployment, where personnel are exposed to a range of infectious diseases. We report a full audit cycle assessing compliance with medical force protection measures, on an exercise in Belize. METHODS: An anonymous questionnaire was administered to personnel four weeks after returning from an Infantry Overseas Training Exercise (OTX) in Belize in two successive years (OTX 1 & 2). RESULTS: Compliance with physical MFP measures (mosquito nets, insecticide soak of kit and personal insect repellent usage) was excellent on both exercises. Antimalarial chemoprophylaxis compliance with a regime of weekly chloroquine and daily proguanil was poor (30%) during OTX 1. Revision of the regime to weekly chloroquine alone following review of antimalarial policies increased compliance on OTX 2 to 67%. CONCLUSION: Simplification of dosage regimes, consistency of information provided between different medical briefs and emphasis of the threat from malaria in Belize significantly improved compliance with antimalarial chemoprophylaxis.

Infection in conflict wounded.

Although mechanisms of modern military wounding may be distinct from those of ancient conflicts, the infectious sequelae of ballistic trauma and the evolving microbial flora of war wounds remain a considerable burden on both the injured combatant and their deployed medical systems. Battlefield surgeons of ancient times favoured suppuration in war wounding and as such Galenic encouragement of pus formation would hinder progress in wound care for centuries. Napoleonic surgeons eventually abandoned this mantra, embracing radical surgical intervention, primarily by amputation, to prevent infection. Later, microscopy enabled identification of microorganisms and characterization of wound flora. Concurrent advances in sanitation and evacuation enabled improved outcomes and establishment of modern military medical systems. Advances in medical doctrine and technology afford those injured in current conflicts with increasing survivability through rapid evacuation, sophisticated resuscitation and timely surgical intervention. Infectious complications in those that do survive, however, are a major concern. Addressing antibiotic use, nosocomial transmission and infectious sequelae are a current clinical management and research priority and will remain so in an era characterized by a massive burden of combat extremity injury. This paper provides a review of infection in combat wounding from a historical setting through to the modern evidence base.

The relationship between empathy and estimates of observed pain.

OBJECTIVE: Recent research suggests that higher scores on measures of empathy correlate with a stronger response to observed pain, as well as higher estimates of pain intensity. Little work to date has examined the impact of empathy on evaluations of different levels of expressed pain, or how empathy may alter the accuracy of interpreting these painful facial expressions. This study examines the role of empathy in rating the intensity of facial expressions of pain, and the accuracy of these ratings relative to self-reported pain. The potential mediating role of available pain cues or the moderating role of gender on this relationship are also examined. METHODS: Undergraduate participants (observers, N = 130) were shown video clips of facial expressions of individuals from a cold presser pain task (senders), and then asked to estimate that pain experience. This estimate was compared with the video sender's actual pain ratings. RESULTS: Higher empathy was associated with an overall increase in estimates of senders' pain, which was not mediated by video subject or participant gender or the duration of painful facial expressions. Further analyses revealed that high empathy was associated with greater accuracy in inferring pain on only one of three inferential accuracy indices. CONCLUSIONS: While observers with greater empathy may infer greater pain in senders, resulting in a smaller underestimation bias overall, they are not necessarily more accurate in estimating pain on any given stimuli. The importance of these potential differences in perceived pain for clinical assessment and interpersonal relationships are discussed.

Infection in wounds of conflict--old lessons and new challenges.

Infection is an important consideration in war wounds. Improvements in survival and use of increasingly broad-spectrum antibiotics have led to new challenges with novel pathogens and conventional pathogens with multiple drug resistance patterns.. learnt in conflicts centuries ago. The cornerstone remains early, appropriate and repeated surgery. Antimicrobial agents contribute a very minor part to overall patient outcome, but prudent use of antibiotics and good infection control is essential to prevent establishment and spread of hospital-acquired infections. Research in progress will provide an evidence base for antibiotic and infection control policies and baseline data for research into novel wound management strategies.

Viral gastroenteritis outbreaks in deployed British troops during 2002-7.

OBJECTIVES: The aim of this study was to see what lessons could be learnt from the suspected viral gastroenteritis outbreaks that have occurred in deployed British troops during 2002-7. METHOD: Epidemiological and laboratory data from identifiable outbreaks were reviewed, including epidemic curves and the results of PCR testing for enteropathic viruses. RESULTS: The epidemic curves of outbreaks varied predictably in accordance with the size of the population at risk and whether this population was constant or expanding. Of 11 outbreaks identified, 10 (91%) had a proven viral cause and 10 (91%) occurred in Iraq. Of 84 enteropathic viruses identified, 61 (73%) were noroviruses and these included both unknown strains and those that were common in the UK and Europe. Of the 10 viral outbreaks, 3 (30%) occurred in medical units, 5 (50%) were associated with large-scale relief in place (RiP) deployments and 5 (50%) involved >3 different viruses, which is strongly suggestive of food or water contamination. CONCLUSION: These findings can help to predict future viral gastroenteritis outbreaks and target improved prevention strategies appropriately. However, more systematic studies are now required.

Helminth infections in British troops following an operation in Sierra Leone.

One hundred and fifty-three British soldiers and 86 Royal Air Force (RAF) personnel were deployed on a hostage rescue operation in Sierra Leone. For 3 days they were exposed to various infection risks and 6 weeks later some of the soldiers presented with gastrointestinal complaints. Both groups were screened with structured questionnaires, blood investigations and (where indicated) faecal microscopy and charcoal culture for helminths. Definite and probable cases of helminth infection were treated with albendazole and all soldiers were screened again after 3 months. Among the soldiers investigated, 73/145 (50%) reported gastrointestinal symptoms and 70/139 (50%) had eosinophilia. Among these, 17/66 (26%) had hookworm infection, 6/66 (9%) had Strongyloides stercoralis infection and 1/66 (2%) had Giardia lamblia infection. Eosinophilia was most strongly associated with entering the enemy camp and being in the platoon that attacked the area around the camp latrines. Among RAF personnel, who were not involved in activities on the ground, 3/86 (3%) had borderline eosinophilia. Treatment of 105/153 (69%) soldiers with albendazole was well tolerated and, on follow-up screening 3 months later, 23/124 soldiers (19%) had gastrointestinal symptoms and 18/121 (15%) had eosinophilia. Faecal investigations and schistosomiasis serology tests were all negative at this stage.

Detection of multiple enteric virus strains within a foodborne outbreak of gastroenteritis: an indication of the source of contamination.

An outbreak of acute gastroenteritis of suspected viral aetiology occurred in April 2003 in the British Royal Fleet Auxiliary ship (RFA) Argus deployed in the Northern Arabian Gulf. There were 37 cases amongst a crew of 400 personnel. Of 13 samples examined from cases amongst the crew, six enteric viruses were detected by reverse transcriptase polymerase chain reaction (RT-PCR). Five different viruses were identified including, three norovirus genotypes, a sapovirus and a rotavirus. No multiple infections were detected. A common food source was implicated in the outbreak and epidemiological analysis showed a statistically significant association with salad as the source of the outbreak, with a relative risk of 3.41 (95% confidence interval of 1.7-6.81) of eating salad on a particular date prior to the onset of symptoms. Faecal contamination of the salad at source was the most probable explanation for the diversity of viruses detected and characterized.

A malaria outbreak following a British military deployment to Sierra Leone.

OBJECTIVES: To describe a malarial outbreak amongst a British military force deployed to Sierra Leone in May 2000. METHODS: A case-control study was conducted that investigated possible risk or protective factors affecting the population. RESULTS: All bite avoidance measures (use of insecticide-treated bed nets and insecticide-treated clothes and use of thermal fogging/knockdown insecticide sprays) offered some degree of protection, although only use of clothes and nets was significant at the 5% level. Use of 3 or 4 protection measures was significantly protective, as was the cumulative protective effect when using multiple protective measures. CONCLUSION: Professionals giving travel advice must continue to advice travellers that they can significantly improve their levels of malarial protection by using multiple protection measures.