Investigation of an outbreak of vomiting in nurseries in South East England, May 2012.

On 30 May 2012, Surrey and Sussex Health Protection Unit was called by five nurseries reporting children and staff with sudden onset vomiting approximately an hour after finishing their lunch that day. Over the following 24 h 50 further nurseries supplied by the same company reported cases of vomiting (182 children, 18 staff affected). Epidemiological investigations were undertaken in order to identify the cause of the outbreak and prevent further cases. Investigations demonstrated a nursery-level attack rate of 55 out of 87 nurseries (63·2%, 95% confidence interval 52·2-73·3). Microbiological tests confirmed the presence of Bacillus cereus in food and environmental samples from the catering company and one nursery. This was considered microbiologically and epidemiologically consistent with toxin from this bacterium causing the outbreak. Laboratory investigations showed that the conditions used by the caterer for soaking of pearl haricot beans (known as navy bean in the USA) used in one of the foods supplied to the nurseries prior to cooking, was likely to have provided sufficient growth and toxin production of B. cereus to cause illness. This large outbreak demonstrates the need for careful temperature control in food preparation.

Offset integrity reduces environmental risk: Using lessons from biodiversity and carbon offsetting to inform water quality offsetting in the catchments of the Great Barrier Reef.

Environmental offsetting has been developed as a mechanism to facilitate the benefits from economic development while avoiding or minimizing environmental harm. This is achieved by compensating for environmental impacts at one location by generating equivalent environmental improvements elsewhere. However, experience with biodiversity and carbon offsetting indicates it can be difficult to ensure the integrity of offsets. Under recent legislation in the catchments of the Great Barrier Reef (GBR), Australia, it is mandatory for water quality emissions from new or expanded point source development to be offset by reducing pollution elsewhere, frequently through reducing non-point source pollution (NPSP). Therefore, informed by experience with biodiversity and carbon offsetting, we summarised sources of uncertainty in NPSP reduction that would influence water quality offset integrity; estimated the maximum potential demand for water quality offsets from sewage treatment plants, the largest point source emitter of total nitrogen (TN) in the GBR catchments, between 2018 and 2050; and discussed the implications of both on the ability of offsetting to counterbalance the impact of economic development in catchments where nitrogen loads have a large influence on the health of important GBR ecosystems. The catchments surrounding the population centres of Cairns and Mackay had both a potentially high future demand for nitrogen water quality offsets and nitrogen loads with a strong influence on the health of the GBR. Consequently, any low integrity water quality offsets in these catchments could jeopardise progress toward the water quality improvements needed to ensure the continued health of the GBR. Water quality offsetting has numerous strengths as a policy instrument however substantial uncertainties remain related to environmental outcomes. Until further research can reduce these uncertainties, water quality offsets that are implemented near increased point source emissions and have a high certainty of effectiveness may provide a balance between scientific rigour and policy workability.

Outcomes associated with a thrice-weekly antimicrobial stewardship programme in a 253-bed community hospital.

WHAT IS KNOWN AND OBJECTIVES: Antimicrobial stewardship programmes (ASPs) have been shown to decrease antimicrobial resistance, reduce hospital-acquired infections and decrease overall antimicrobial expenditures. At St. Joseph Medical Center in Bellingham, WA, a thrice-weekly ASP was initiated in 2010 with the goals of decreasing carbapenem, fluoroquinolone and vancomycin use and tailoring duration of therapy. METHODS: Antibiotic use per 1000 patient-days and carbapenem, fluoroquinolone and vancomycin use were evaluated pre- and post-implementation of the ASP. Total antimicrobial expenditures were evaluated for the 3 years prior to ASP implementation and three years following implementation. RESULTS AND DISCUSSION: Antimicrobial days of therapy per 1000 patient-days declined by 6·4% after implementation of our ASP. There was a 37% reduction in total antimicrobial expenditures after implementation. Carbapenems, vancomycin and levofloxacin use decreased considerably. Ciprofloxacin use increased during the same time period. WHAT IS NEW AND CONCLUSION: A thrice-weekly, pharmacist-driven ASP can decrease antimicrobial expenditure, shorten duration of therapy and decrease the utilization of carbapenems, vancomycin and levofloxacin.

Does organic farming benefit farmland birds in winter?

The generally higher biodiversity on organic farms may be influenced by management features such as no synthetic pesticide and fertilizer inputs and/or by differences in uncropped habitat at the site and landscape scale. We analysed bird and habitat data collected on 48 paired organic and conventional farms over two winters to determine the extent to which broad-scale habitat differences between systems could explain overall differences in farmland bird abundance. Density was significantly higher on organic farms for six out of 16 species, and none on conventional. Total abundance of all species combined was higher on organic farms in both years. Analyses using an information-theoretic approach suggested that both habitat extent and farm type were important predictors only for starling and greenfinch. Organic farming as currently practised may not provide significant benefits to those bird species that are limited by winter food resources, in particular, several declining granivores.

A national scheme for public access defibrillation in England and Wales: early results.

BACKGROUND: Automated external defibrillators (AEDs) operated by lay persons are used in the UK in a National Defibrillator Programme promoting public access defibrillation (PAD). METHODS: Two strategies are used: (1) Static AEDs installed permanently in busy public places operated by those working nearby. (2) Mobile AEDs operated by community first responders (CFRs) who travel to the casualty. RESULTS: One thousand five hundred and thirty resuscitation attempts. With static AEDs, return of spontaneous circulation (ROSC) was achieved in 170/437 (39%) patients, hospital discharge in 113/437 (26%). With mobile AEDs, ROSC was achieved in 110/1093 (10%), hospital discharge in 32 (2.9%) (P<0.001 for both variables). More shocks were administered with static AEDS 347/437 (79%) than mobile AEDs 388/1093 (35.5%) P<0.001. Highly significant advantages existed for witnessed arrests, administration of shocks, bystander CPR before arrival of AED and short delays to start CPR and attach AED. These factors were more common with static AEDs. For CFRs, patients at home did less well than those at other locations for ROSC (P<0.001) and survival (P=.006). Patients at home were older, more arrests were unwitnessed, fewer shocks were given, delays to start CPR and attach electrodes were longer. CONCLUSIONS: PAD is a highly effective strategy for patients with sudden cardiac arrest due to ventricular fibrillation who arrest in public places where AEDs are installed. Community responders who travel with an AED are less effective, but offer some prospect of resuscitation for many patients who would otherwise receive no treatment. Both strategies merit continuing development.

Bibliotherapy and information prescriptions: a summary of the published evidence-base and recommendations from past and ongoing Books on Prescription projects.

This paper summarizes the published evidence and reports from ongoing and completed projects that used Bibliotherapy and Information Prescription to deliver patient care. A literature search was conducted and relevant papers were summarized into: type of study, type of Bibliotherapy, client group and recommendations. In total, 65 papers were considered with 57 reviewed. A survey was also sent to Library Authorities subscribing to national survey standards asking for details about delivery of Information Prescription projects. There were 21 returned surveys. The experiences and recommendations were then summarized. The aim of the paper is to collate the evidence-base of written research and the experience and recommendations of projects into an easy format so that practitioners interested in using Bibliotherapy/Information Prescription/Books on Prescription have an understanding what they are, the extent of the evidence-base to inform practice, and highlight gaps in the research.

Intrinsic stability and functional properties of disulfide bond-stabilized coagulation factor VIIIa variants.

BACKGROUND: The utility of purified coagulation factor (F)VIII for treatment of hemophilia A is limited in part by its instability following activation by thrombin, which is caused by spontaneous dissociation of the A2 domain from the activated FVIII (FVIIIa) heterotrimer. To prevent this A2 domain dissociation in FVIIIa, we previously engineered a cysteine pair (C664-C1826) in recombinant FVIII that formed a disulfide bond cross-linking the A2 domain in the heavy chain to the A3 domain in the light chain. This engineered disulfide bond resulted in a more stable FVIIIa. AIMS: Here, we characterize the functional parameters of C664-C1828 FVIII and of a new disulfide bond-stabilized FVIII (C662-C1828 FVIII). METHODS: In order to assess whether these FVIII variants might be good candidates for a new therapeutic agent to treat hemophilia A, we investigated a variety of functional parameters that might affect the in vivo properties of the variants, including half-life of disulfide bond-stabilized FVIII and FVIIIa and the potency of these FVIIIa molecules in the FXase complex. RESULTS: Both disulfide bond-stabilized variants had improved affinity for von Willebrand factor (VWF). In studies of FX activation by purified FIXa and FVIIIa, C662-C1828 FVIIIa had normal activity while C664-C1826 FVIIIa had reduced activity. Both C664-C1826 FVIIIa and C662-C1828 FVIIIa were inactivated by activated protein C (APC) but the rates of inactivation were different. CONCLUSION: Overall, the specific location of the disulfide bridge between the A2 and A3 domains appears to affect functional properties of FVIIIa. In summary, introduction of engineered interdomain disulfides results in FVIIIa variants that resist spontaneous loss of activity while retaining susceptibility to APC proteolytic inactivation and maintaining VWF binding.

Multicenter, randomized, controlled trial of 150-J biphasic shocks compared with 200- to 360-J monophasic shocks in the resuscitation of out-of-hospital cardiac arrest victims. Optimized Response to Cardiac Arrest (ORCA) Investigators.

BACKGROUND: In the present study, we compared an automatic external defibrillator (AED) that delivers 150-J biphasic shocks with traditional high-energy (200- to 360-J) monophasic AEDs. METHODS AND RESULTS: AEDs were prospectively randomized according to defibrillation waveform on a daily basis in 4 emergency medical services systems. Defibrillation efficacy, survival to hospital admission and discharge, return of spontaneous circulation, and neurological status at discharge (cerebral performance category) were compared. Of 338 patients with out-of-hospital cardiac arrest, 115 had a cardiac etiology, presented with ventricular fibrillation, and were shocked with an AED. The time from the emergency call to the first shock was 8.9+/-3.0 (mean+/-SD) minutes. CONCLUSIONS: The 150-J biphasic waveform defibrillated at higher rates, resulting in more patients who achieved a return of spontaneous circulation. Although survival rates to hospital admission and discharge did not differ, discharged patients who had been resuscitated with biphasic shocks were more likely to have good cerebral performance.

Lung cancer practice guidelines: lessons learned and issues addressed by the Ontario Lung Cancer Disease Site Group.

PURPOSE: The primary objective was to identify the lessons learned and issues addressed by the Disease Site Group (DSG) developing guidelines on lung cancer for practitioners in the province of Ontario. METHODS: The minutes of the Ontario Lung Cancer Disease Site Group (LCDSG) and the meeting notes of a medical sociologist who attended all LCDSG meetings were reviewed to identify the disease-specific and generic issues addressed by the LCDSG during guideline development. RESULTS AND CONCLUSION: The Ontario LCDSG has completed three practice guidelines and has five evidence-based recommendations (EBRs) in production. Topics for guideline development were selected on the basis of known practice variability (eg, advanced-stage non-small-cell lung cancer [NSCLC]); the size of the patient population that could potentially be affected by the guideline; results of phase II trials of new and potentially expensive agents (vinorelbine, paclitaxel, and docetaxel); and randomized controlled clinical trials that support new practice standards (combined modality therapy for unresectable stage III NSCLC). The wording of each EBR reflects the strength and quality of the evidence in support of the treatment option, the primary outcome(s), and the individual physician and discipline values concerning treatment outcomes in the absence of known patient values.

Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer.

PURPOSE: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in tumor development and progression. MMP expression has been correlated with advanced clinical stage and poor survival in some tumors, but data for small-cell lung cancer (SCLC) are lacking. The aim of this study was to assess the expression of MMPs and TIMPs in SCLC and to evaluate their importance relative to standard prognostic factors. PATIENTS AND METHODS: Expression of MMP-1, -2, -3, -9, -11, -13, and -14 and TIMP-1, -2, -3, and -4 was evaluated by immunohistochemistry (IHC). In situ hybridization was used to confirm expression of specific mRNAs. Clinical data collected included sex, tumor stage, performance status, weight loss, hematology (hemoglobin, WBC, platelets) and biochemistry (sodium, albumin, alkaline phosphatase, lactate dehydrogenase), treatment, and survival. RESULTS: Samples from 46 patients were evaluated: 30 males, 16 females; 29 limited, 17 extensive stage; 35 Eastern Cooperative Oncology Group performance status 0-1. Positive IHC staining was evident for MMP-1 and -9 in 60% to 70% of tumor cells, and for MMP-11, -13, and -14 and TIMP-2 and -3 in 70% to 100% of tumor cells. Stromal staining of TIMP-1 to -3 was present in less than 30% of specimens. On multivariate analysis, only stage and decreased tumoral expression of TIMP-1 were significant for response (P =.043). Significant factors for survival were tumor stage (P =.0021); weight loss (P =. 013); and high tumor cell expression of MMP-3 (P =.077), MMP-11 (P =. 031), and MMP-14 (P =.019). MMP and TIMP expression did not differ significantly between stages. CONCLUSION: MMPs and TIMPs are widely expressed in SCLC. Increased tumoral expression of MMP-3, -11, and -14 were independent negative prognostic factors for survival. The results support the evaluation of synthetic MMP inhibitors in patients with SCLC.

Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung.

One hundred fifty-three patients with limited and 167 with extensive small cell carcinoma of the lung (SCCL) were evaluable for response to treatment with six courses of chemotherapy (cyclophosphamide, doxorubicin, and vincristine), irradiation to intrathoracic disease, and prophylactic cranial irradiation (PCI). No maintenance chemotherapy was given. Fifty-two percent of patients with limited disease (LD) and 10% of extensive disease patients (ED) achieved a complete response. The median survival times for LD and ED patients were 49 and 34 weeks, respectively. These results were compared to a previous experience with 147 patients who were treated with three courses of similar induction chemotherapy and thoracic irradiation, as well as one year of maintenance chemotherapy (CCNU, procarbazine, and methotrexate) but without PCI. Although the use of PCI was found to reduce the frequency of brain metastases as the site of first relapse, detailed comparisons of response rates and survival showed no significant differences between the two study populations. Prolonged maintenance chemotherapy of the type used in the first study does not favorably influence outcome after intensive induction therapy for SCCL.

Quality of life after coronary angioplasty or continued medical treatment for angina: three-year follow-up in the RITA-2 trial. Randomized Intervention Treatment of Angina.

OBJECTIVES: We sought to evaluate the impact of percutaneous transluminal coronary angioplasty (PTCA) and medical treatment on self-perceived quality of life among patients with angina. BACKGROUND: The second Randomized Intervention Treatment of Angina trial (RITA-2) implemented initial policies of PTCA or continued medical treatment in patients with angina, allowing assessment of long-term health consequences. METHODS: A total of 1,018 patients were randomly assigned (504 to PTCA and 514 to medical treatment). The short form 36 (SF-36) self-administered quality-of-life questionnaire was completed at randomization and three months, one year and three years later. To date, 98% of patients reached one year and 67% reached three years. RESULTS: The PTCA group had significantly greater improvements in physical functioning, vitality and general health at both three months and one year, but not at three years. These quality-of-life scores were strongly related to breathlessness, angina grade and treadmill exercise time both at baseline and at one year. The treatment differences in quality of life are explained by the PTCA group's improvements in breathlessness, angina and exercise time. The attenuation of treatment difference at three years is partly attributed to 27% of medically treated patients receiving nonrandomized interventions in the interim. For both groups, there were also improvements in ratings of physical role functioning, emotional role functioning, social functioning, pain and mental health, but for these the superiority of PTCA over medical treatment was less pronounced. After one year, 33% and 22% of the PTCA and medical groups, respectively, rated their health much better. CONCLUSIONS: Coronary angioplasty substantially improves patient-perceived quality of life, especially physical functioning and vitality, as compared with continued medical treatment. These differences are attributed to alleviation of cardiac symptoms (specifically, breathlessness and angina), but must be balanced against the small procedure-related risks of PTCA.

Prospective comparison of unstable angina versus non-Q wave myocardial infarction during antithrombotic therapy. Antithrombotic Therapy in Acute Coronary Syndromes Research Group.

OBJECTIVES: This study was designed to compare the response of unstable angina and non-Q wave myocardial infarction during treatment with antithrombotic therapy. BACKGROUND: Antithrombotic therapy is beneficial in patients with these two coronary syndromes. METHODS: In a multicenter trial of antithrombotic therapy in unstable angina or non-Q wave myocardial infarction, 358 patients admitted within 48 h of chest pain were randomized to antithrombotic therapy with either 1) aspirin alone, or 2) aspirin plus heparin followed by aspirin plus warfarin, and were prospectively followed up for 12 weeks. Admission cardiac enzyme analyses revealed unstable angina in 268 patients and non-Q wave myocardial infarction in 62. Given an event rate of about 25%, this study has a power of 80% to detect a 50% difference between the two groups. RESULTS: Patients with unstable angina and non-Q wave myocardial infarction were similar with regard to age, gender, coronary risk factors and prior antianginal medication. Primary end points at 12 weeks were recurrent ischemia, infarction and death. [table: see text] In the non-Q wave group, all infarctions and death occurred within the 1st week. CONCLUSIONS: Patients with unstable angina or non-Q wave myocardial infarction on antithrombotic therapy have a similar total number of ischemic events by 12 weeks. However, despite maximal medical therapy with antianginal and antithrombotic medication, patients with non-Q wave infarction have a significantly higher rate of reinfarction and death.

A synthetic holliday junction is sandwiched between two tetrameric Mycobacterium leprae RuvA structures in solution: new insights from neutron scattering contrast variation and modelling.

The interaction between homologous DNA molecules in recombination and DNA repair leads to the formation of crossover intermediates known as Holliday junctions. Their enzymatic processing by the RuvABC system in bacteria involves the formation of a complex between RuvA and the Holliday junction. To study the solution structure of this complex, contrast variation by neutron scattering was applied to Mycobacterium leprae RuvA (MleRuvA), a synthetic analogue of a Holliday junction with 16 base-pairs in each arm, and their stable complex. Unbound MleRuvA was octameric in solution, and formed an octameric complex with the DNA junction. The radii of gyration at infinite contrast were determined to be 3.65 nm, 2.74 nm and 4.15 nm for MleRuvA, DNA junction and their complex, respectively, showing that the complex was structurally more extended than MleRuvA. No difference was observed in the presence or absence of Mg2+. The large difference in RG values for the free and complexed protein in 65% 2H2O, where the DNA component is "invisible", showed that a substantial structural change had occurred in complexed MleRuvA. The slopes of the Stuhrmann plots for MleRuvA and the complex were 19 and 15 or less (x10(-5)), respectively, indicating that DNA passed through the centre of the complex. Automated constrained molecular modelling based on the Escherichia coli RuvA crystal structure demonstrated that the scattering curve of octameric MleRuvA in 65% and 100% 2H2O is explained by a face-to-face association of two MleRuvA tetramers stabilised by salt-bridges. The corresponding modelling of the complex in 65% 2H2O showed that the two tetramers are separated by a void space of about 1-2 nm, which can accommodate the width of B-form DNA. Minor conformational changes between unbound and complexed MleRuvA may occur. These observations show that RuvA plays a more complex role in homologous recombination than previously thought.

Primary pleural epithelioid haemangioendothelioma with metastases to the skin. A case report and literature review.

Epithelioid haemangioendothelioma (EHE) is a rare vascular tumour of intermediate behaviour. It can arise from various sites including the liver, spleen, pleura, or lung. Cutaneous EHE can be primary or secondary. This report describes the case of a 51 year old man who presented with a history of dry cough, shortness of breath, and pleural effusion, and who developed two cutaneous nodules in the anterior abdominal wall a few weeks later. He had a previous history of asbestos exposure. Computed tomography scan showed a left sided pleural effusion and nodular pleural mass. Histology of both the pleural and cutaneous lesions was compatible with EHE. Electron microscopic examination demonstrated the presence of Weibel-Palade bodies. The patient underwent elliptical excision of the metastatic cutaneous nodules after decortication of the primary pleural tumour and adjuvant treatment. A few reports have described metastasis of intrathoracic EHE to the skin. Despite treatment with interferon, the patient developed more cutaneous lesions two years after the initial diagnosis. Even though the tumour has the classic light histological and ultrastructural features of EHE, it behaved in an aggressive manner.

Human complement factor I: its expression by insect cells and its biochemical and structural characterisation.

Factor I is a five-domain plasma serine protease which is essential for the regulation of the complement system. In order to express this, the factor I coding sequence was cloned into a recombinant baculovirus system, which was used to infect Trichoplusia ni cells. Using the native factor I leader sequence, recombinant factor I (rFI) was secreted into the culture medium. Purified rFI was recognised by polyclonal antisera and by the factor I-specific monoclonal antibody MRC-OX21. SDS PAGE showed that rFI was processed into two chains with molecular weights of 48,000 and 36,000. Amino acid sequence analysis showed that the N-terminal sequences of the rFI chains were the same as those of serum-derived factor I (sFI), confirming that processing was correct. Since both molecular weights were less than those observed for sFI, this is attributed to the replacement of complex-type oligosaccharides by high mannose ones in rFI. C3(NH,) cleavage assays showed that rFI had 55% the activity of sFI. Circular dichroism and Fourier transform infrared spectroscopy showed that the protein folding of rFI and sFI were very similar. Both had a secondary structure low in alpha-helix and high in beta-sheet, as expected from crystal structure and multiple sequence alignment analyses. It is inferred that the reduced activity of rFI is attributable to its changed glycosylation. The availability of rFI and structures for the domains in factor I makes possible new approaches to determine the molecular basis of its interactions with factor H and C3b.

High-dose ranibizumab monotherapy for neovascular polypoidal choroidal vasculopathy in a predominantly non-Asian population.

PURPOSE: To determine safety and efficacy of intravitreal high-dose ranibizumab in the treatment of active neovascular polypoidal choroidal vasculopathy (PCV). METHODS: In this Phase I/II, single-center, randomized, controlled, double-masked study, predominantly non-Asian, previously treated or treatment-naive, male and female adult patients were randomized to receive high-dose (1.0/0.1 ml or 2.0 mg/0.05 ml; n=15) or standard-dose (0.5 mg/0.05 ml; n=5) ranibizumab in 3 monthly loading doses, followed by 9 months of criteria-based, as-needed retreatment. Safety was evaluated by a descriptive analysis of all non-serious and serious adverse events, angiographic assessments, physical examinations, vital signs, ocular examinations, and visual acuity measurements. Visual acuity and anatomic outcomes are described for the high-dose group. RESULTS: Twenty patients (aged 35-76 years; 8 Black, 11 White, 1 Asian) were enrolled. At baseline, in the high-dose group, mean best-corrected visual acuity (BCVA) was 63.5 letters (Snellen equivalent ~20/50), and mean baseline central foveal thickness (CFT) was 253.7 µm. High-dose ranibizumab was generally well tolerated without evidence of ocular or systemic severe adverse events, including arterial thromboembolic events. At month 12, in the high-dose group, the mean overall change from baseline in BCVA was +6.7 letters and in CFT was -49.7 µm. CONCLUSION: High-dose ranibizumab monotherapy is safe and efficacious for treating patients with PCV.

Adenovirus-mediated interleukin-10 gene transfer inhibits post-transplant fibrous airway obliteration in an animal model of bronchiolitis obliterans.

Bronchiolitis obliterans, a form of chronic allograft rejection characterized by progressive fibrous obliteration of the airways, is the major obstacle limiting prolonged survival of lung transplant recipients. To date, no effective therapy against this fatal complication exists. Interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, inhibits various T cell and antigen-presenting cell functions. We examined the effect of IL-10 in an animal model for bronchiolitis obliterans. A heterotopic tracheal transplant model was used. IL-10 was administered to the recipient either in its recombinant form by osmotic minipump or by adenoviral-mediated IL-10 gene transfer (Ad5E1mIL-10). Successful gene transfection and expression was confirmed by measuring circulating IL-10 protein. Tracheal allografts were assessed histologically based on a scoring system. IL-10 administration (in recombinant form or by gene transfer) inhibited the development of fibrous airway obliteration 3 weeks after transplantation in comparison to untreated controls (p < 0.05). This was demonstrated only if the delivery was initiated 5 days after transplantation and not if it was started at the time of transplantation. A single administration of the gene construct was sufficient to achieve the desired effect. We have shown that IL-10 can prevent the development of airway fibro-obliteration in this model. Gene transfection at a site distant from a graft can be used to produce a desired effect on the graft. IL-10 may be of major importance in the control of post-transplant bronchiolitis obliterans. The timing of its administration is critical and further studies are required to determine the mechanisms underlying the observed effects of IL-10.

Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans.

BACKGROUND: Bronchiolitis obliterans is the most significant complication adversely affecting prolonged survival of lung allograft recipients. The evolution from the initial insult to the final pathologic entity is largely unknown. The aim of this study was to characterize the evolution of transplant-induced fibrous airway obliteration in a rat tracheal transplant model of bronchiolitis obliterans. METHODS: Tracheal segments were transplanted from Brown Norway rats to Brown Norway rats (isografts) or to Lewis rats (allografts). Grafts were implanted into a subcutaneous pouch and an abdominal omental wrap. They were harvested at 14 different time points (from 1 day to 1 year after transplantation) and assessed histologically. RESULTS: The fibrous airway obliteration developed only in allografts showing a triphasic time course: an initial ischemic phase (observed in both isografts and allografts) was followed by a marked lymphocytic infiltrative phase with complete epithelial loss (observed only in allografts, P<0.01), and finally by an obliterative phase with fibrous obliteration of the allograft airway lumen (P<0.01). CONCLUSIONS: This animal model shows a distinct and reproducible triphasic time course in the development of obliterative airway lesions in allografts. It confirms that the mechanism leading to airway obliteration is immune mediated as only allografts showed this lesion and that lymphocytic infiltration is a precursor of the lesion in this model. The insights into the different phases demonstrated may lead to novel approaches regarding the type and timing of therapeutic interventions.

Improved functional recovery of denervated skeletal muscle after temporary sensory nerve innervation.

Prolonged muscle denervation results in poor functional recovery after nerve repair. The possible protective effect of temporary sensory innervation of denervated muscle, prior to motor nerve repair, has been examined in the rat. Soleus and gastrocnemius muscles were denervated by cutting the tibial nerve, and the peroneal nerve was then sutured to the transected distal tibial nerve stump either immediately or after two, four or six months. In half of the animals with delayed repair, the saphenous (sensory) nerve was temporarily attached to the distal nerve stump. Muscles were evaluated three months after the peroneal-to-tibial union, and were compared with each other, with unoperated control muscles and with untreated denervated muscles. After four to six months of sensory "protection", gastrocnemius muscles weighed significantly more than unprotected muscles, and both gastrocnemius and soleus muscles exhibited better preservation of their structure, with less fiber atrophy and connective tissue hyperplasia. The maximum compound action potentials were significantly larger in gastrocnemius and soleus muscles following sensory protection, irrespective of the delay in motor nerve union. Isometric force, although less than in control animals and in those with immediate nerve repair, remained reasonably constant after sensory protection, while in unprotected muscles there was a progressive and significant decline as the period of denervation lengthened. We interpret these results as showing that, although incapable of forming excitable neuromuscular junctions, sensory nerves can nevertheless exert powerful trophic effects on denervated muscle fibers. We propose that these findings indicate a useful strategy for improving the outcome of peripheral nerve surgery.