A systematic review of models of patient engagement in the development and life cycle management of medicines.

There is currently no universally agreed code of practice for patient engagement (PE), and existing guidelines do not fully cover the scope across medicine development and subsequent life cycle management. This review conceptualises the meaning and summarises the current models of PE. A systematic literature review was conducted and analysed by thematic synthesis. Eight themes were identified as components of how to achieve meaningful PE, and five were identified for where to engage with patients in drug development. This review provides summative guidance for stakeholders intending to introduce PE and establishes a starting point for the development of a universal code of practice.

Dental and Temporomandibular Joint Pathology of the American Black Bear (Ursus americanus).

Museum specimens (maxillae and/or mandibles) from 371 American black bears (Ursus americanus) acquired between 1889 and 2006 were examined macroscopically according to predefined criteria, and 348 were included in this study. Of the 348 specimens, 126 (36.2%) were from male animals, 106 (30.5%) were from female animals and 116 (33.3%) were from animals of unknown sex. Specimen ages ranged from young adult (n = 63, 18.1%) to adult (n = 285, 81.9%), with juveniles excluded from the study. The number of teeth available for examination was 12,019 (82.2%); 7.0% of teeth were absent artefactually, 0.4% were deemed absent due to acquired tooth loss and 9.7% were absent congenitally. In 43 specimens (12.3%), 82 teeth (0.68%) were small vestigial structures with crowns that were flush with the level of surrounding alveolar bone. The remaining teeth (99.3%) were of normal morphology. Only three supernumerary teeth and three instances of enamel hypoplasia were encountered. Persistent deciduous teeth or teeth with an aberrant number of roots were not encountered in any of the specimens. Approximately one-third of the teeth examined (4,543, 37.8%) displayed attrition/abrasion, affecting nearly all of the specimens (n = 338, 97.1%). Incisor and molar teeth accounted for 52.5% and 34.3% of the affected teeth, respectively, with significantly more adults affected than young adults. Dental fractures were noted in 63 bears, affecting 18.1% of specimens and 1.0% of the total number of present teeth. The canine teeth were most often fractured, with adults having significantly more complicated crown fractures of these teeth than young adults. There were 11 specimens (3.2%) that displayed periapical lesions, affecting 12 (0.1%) dental alveoli. There were 179 specimens (51.4%) displaying bony changes indicative of periodontitis, affecting 816 (6.8%) dental alveoli. The proportion of adult bears affected by periodontitis (57.9%) was significantly greater than that of young adults (22.2%). Exactly half of the specimens (n = 174) possessed lesions consistent with mild temporomandibular joint osteoarthritis. The occurrence and severity of the dental pathology encountered in this study may play an important role in the morbidity and mortality of the American black bear.

Validation of a prognostic nomogram in patients undergoing resection for pancreatic ductal adenocarcinoma in a UK tertiary referral centre.

INTRODUCTION: Survival following resection for pancreatic ductal adenocarcinoma (PDAC) remains poor. The aim of this study was to validate a survival nomogram designed at the Memorial Sloan-Kettering Cancer Centre (MSKCC) in a UK tertiary referral centre. METHODS: Patients who underwent resection for PDAC between 1995 and 2005 were analysed retrospectively. Standard prognostic factors and nomogram-specific data were collected. Continuous data are presented as median (inter-quartile range). RESULTS: Sixty-three patients were analysed. The median survival was 326 (209-680) days. On univariate analysis lymph node status (node +ve 297 (194-471) days versus node -ve 367 (308-1060) days, p=0.005) and posterior margin involvement (margin +ve 210 (146-443) days versus margin -ve 355 (265-835) days, p=0.024) were predictors of a poor survival. Only lymph node positivity was significant on multivariate analysis (p=0.006). The median nomogram score was 217 (198-236). A nomogram score of 113-217 predicted a median survival of 367 (295-847) days compared to 265 (157-443) days for a score of 218-269, p=0.012. CONCLUSION: Increasing nomogram score was associated with poorer survival. However the accuracy demonstrated by MSKCC could not be replicated in the current cohort of patients and may reflect differences in patient demographics, accuracy of pathological staging and differences in treatment regimens between the two centres.

An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis.

OBJECTIVE: To elucidate the role of methionine aminopeptidase type-2 (MetAP-2) in the clinical pathology of rheumatoid arthritis, arthritis was induced in rats by administration of peptidoglycan-polysaccharide (PG-PS). DESIGN: The inhibitor of MetAP-2, PPI-2458, was administered orally at 5 mg/kg every other day during 3 distinct phases of the disease. In vitro studies were performed to clarify in vivo findings. RESULTS: Ankle swelling was completely alleviated by MetAP-2 inhibition. Inhibition of MetAP-2 in blood and tissues correlated with protection against PG-PS-induced arthritis. Histopathology of the tarsal joints improved following PPI-2458 administration, including a significant improvement of bone structure. In in vitro studies, osteoclast formation and activity were inhibited by PPI-2458, a mechanism not previously attributed to MetAP-2 inhibition. CONCLUSIONS: The important role that MetAP-2 has in the pathophysiological disease processes of PG-PS arthritis provides a strong rationale for evaluating PPI-2458 as a disease modifying antirheumatic treatment for rheumatoid arthritis.

Preoperative lymphocyte count as a prognostic factor in resected pancreatic ductal adenocarcinoma.

BACKGROUND AND AIMS: Recognized prognostic factors for resected pancreatic ductal adenocarcinoma (PDAC) include tumour size, differentiation, resection margin involvement and lymph node metastases. A further prognostic factor of less certain significance is lymphocyte count. The aim of this study was to investigate whether preoperative lymphocyte count is a prognostic indicator in patients with PDAC. MATERIAL AND METHODS: Patients who had undergone a potentially curative pancreaticoduodenectomy (PD) for PDAC between 1998 and 2005 were analysed. Standard prognostic factors, preoperative lymphocyte count, preoperative neutrophil count and survival data were collected. RESULTS: Of the 44 patients studied, univariate analysis identified predictors of a poor survival as lymph node status (node positive (+ve) 10.3 [5.4-20.9] months versus node negative (-ve) 14.2 [10.9-31.4] months; p=0.038), posterior resection margin invasion (margin +ve 7.0 [5.1-15.0] months versus margin -ve 13.1 [10.0-28.3] months; p=0.025) and lymphocyte count below the reference range (<1.5 x 10(9)/litre 8.8 [7.0-13.1] months versus > or = 1.5 x 10(9)/litre 14.3 [7.0-28.3] months; p=0.029). Low preoperative lymphocyte count (p=0.027) and posterior margin invasion (p=0.023) retained significance on multivariate analysis. Preoperative neutrophil to lymphocyte ratio was not a significant prognostic factor. CONCLUSION: Preoperative lymphocyte count is a significant prognostic factor in patients with PDAC.

The distribution of positive and negative species interactions across environmental gradients on a dual-lattice model.

There has been considerable recent interest in understanding the role of positive inter-specific interactions within ecology, and significant progress has been made both empirically and theoretically. Similarly, considerable progress has been made in improving our understanding of the mechanisms that limit species' ranges. In this contribution, we seek to understand the setting of species' borders when some species within the assemblage exhibit positive inter-specific interactions. We use a spatially explicit dual-lattice simulation model to explore the distribution of different interactions across environmental gradients. We first simulate community dynamics when there is either a gradient in reproductive rate or in mortality. We then consider what happens when gradients in reproduction and mortality run in parallel or perpendicular to one another. If the stress gradient impacts on reproductive potential, positive interactions are found where there is high abiotic stress. In this instance, the mutualists are able to tolerate an environment that the cheaters cannot. However, when the stress gradient influences mortality, we find that the mutualists occur as a stripe surrounded by cheaters both towards the better and the harsher ends of the gradient. Previous theory and most empirical evidence tend to indicate that net positive interactions are likely to occur in environments characterized by high abiotic stress. However, evidence from some stress gradients suggests that the distribution of positive and negative interactions can be more complex, with the most stressful environments being occupied by individuals engaging in negative rather than positive interactions. Our results provide a potential theoretical explanation for these recent field observation, and highlight the need for further theoretical and empirical work to better our understanding of how positive and negative interactions act to determine the limits to species' ranges.

Management strategies for community acquired pneumonia.

The past decade has witnessed dramatic changes in the etiology, diagnosis, and management of community acquired pneumonia (CAP). Due to the wide variation in practice patterns, physicians and professional societies have taken the lead in developing practice guidelines. To better understand the range of these multiple protocols, various stages of the disease and treatment are described and compared. Experts agree that CAP management should include: defining a correct diagnosis, identifying high risk populations in order to determine the severity of the disease, recommending appropriate treatment therapies, and obtaining positive and cost beneficial outcomes.

Interactions of gonadal steroids and pesticides (DDT, DDE) on gonaduct growth in larval tiger salamanders, Ambystoma tigrinum.

In view of the current worldwide decline in amphibian populations, exploratory studies are needed to assess the potential for environmental contaminants to act as endocrine disrupters of the amphibian reproductive system. The present study investigated the effects of DDT dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) on the development of amphibian gonaducts. Larval male and female tiger salamanders (Ambystoma tigrinum), with immature gonads, were immersed in a sublethal solution of p,p'-DDE or technical-grade DDT (80% p,p'-DDT and 20% o,p'-DDT). Additionally, larvae were injected with the steroid hormones estradiol or dihydrotestosterone (DHT). Morphometrics were used to analyze the effects and interactions of steroid and pesticide treatments on larval gonaducts. Estradiol and DHT stimulated cell proliferation and hypertrophy of the müllerian duct epithelium in both sexes. Wolffian duct epithelium, however, was stimulated only by DHT treatment. The pesticide DDT antagonized the estrogenic actions of the steroid treatments, and p,p'-DDE acted as an estrogen on the müllerian ducts of females only. The müllerian ducts of males, and the wolffian ducts of both sexes, were unaffected by DDT or DDE alone. While confirming the previously reported estrogenic actions of estradiol and DHT on urodelean gonaducts, the results contradict the expected estrogenic actions of DDT and antiandrogenic actions of p,p'-DDE. Instead, in A. tigrinum, technical-grade DDT had an antiestrogenic action and p,p'-DDE an estrogenic action.

Advocacy: the cornerstone of cancer survivorship.

PURPOSE: This article describes a cancer-related advocacy skill set that can be acquired through a learning process. OVERVIEW: Cancer survivorship is a process rather than a stage or time point, and it involves a continuum of events from diagnosis onward. There exists little consensus about what underlying processes explain different levels of long term functioning, but skills necessary for positive adaptation to cancer have been identified from both the professional literature and from the rich experiences of cancer survivors. CLINICAL IMPLICATIONS: Healthcare practitioners need to be more creative and assertive in fostering consumer empowerment and should incorporate advocacy training into care plans. Strategies that emphasize personal competency and increase self-advocacy capabilities enable patients to make the best possible decisions for themselves regarding their cancer care. In addition, oncology practitioners must become informed advocacy partners with their patients in the public debate about healthcare and cancer care delivery.

Perceptions of quality of life and quality of care for patients with cancer receiving biological therapy.

This retrospective, descriptive study was undertaken to identify patient and family perceptions about quality of life (QOL) and quality of care (QOC) after experimental biological therapy. A mail survey that included instruments designed to measure QOL (the Profile of Mood States [POMS] and the Linear Analogue Self-Assessment [Lasa]) and QOC was sent to patients (response rate, 60%) and to relatives of deceased patients (response rate, 70%). Bivariate and multivariate statistics were used to analyze the data. Patients reported a relatively good quality of life, as measured by POMS and LASA scores. The majority of living patients and of family members of deceased patients were positive about the QOC received; relatives were significantly less positive than patients. Four components were significant in respondents' assessment of QOC: adequate symptom control, availability of support services, communication with the medical team, and receiving information about response to treatment. The findings suggest that there is a need to supplement survival data and biomedical outcomes with information about patient and family perceptions about care and treatment.

Phorbol diesters regulate expression of the membrane neutral metalloendopeptidase (EC 3.4.24.11) in rabbit synovial fibroblasts and mammary epithelial cells.

The neutral zinc metalloendopeptidase (NEP, EC 3.4.24.11) is an integral membrane protein found in brain tissue, polymorphonuclear leukocytes, and many epithelia. We show here that NEP is expressed on rabbit synovial fibroblasts and on simian virus 40 (SV40) DNA- and H-ras-transformed rabbit mammary epithelial cells. Treatment of these cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 24 h decreased expression of NEP mRNA transcripts and decreased the biosynthetically labeled immunoprecipitable NEP antigen. In contrast to its effects on NEP, TPA treatment induced expression of the secreted metalloproteinase collagenase and the tissue inhibitor of metalloproteinases. TPA induced stromelysin, another secreted metalloproteinase, only in the fibroblasts. These data provide evidence that the expression of the membrane-bound NEP is regulated in several cell types.

Interaction of mouse macrophage elastase with native and oxidized human alpha 1-proteinase inhibitor.

Native and oxidized alpha 1-proteinase inhibitor (alpha 1-PI) were compared as substrates for the metalloproteinase macrophage elastase. At substrate concentrations at which native alpha 1-PI was readily degraded by macrophage elastase, oxidized alpha 1-PI was hardly degraded at all. Incubation of macrophage elastase with oxidized alpha 1-PI before the addition of native alpha 1-PI showed that oxidized alpha 1-PI was not an inhibitor of macrophage elastase. Competition experiments with up to twofold excess oxidized alpha 1-PI did not interfere with the degradation of native alpha 1-PI by macrophage elastase. Sequence analysis of amino acids in degraded native alpha 1-PI showed that macrophage elastase attacked a single peptide bond between Pro-357 and Met-358, the latter representing the P1 reactive-site residue of alpha 1-PI. In oxidized alpha 1-PI, Met-358 was converted to methionine sulfoxide and macrophage elastase hydrolyzed the bond between Phe-352 and Leu-353. These data suggest that methionine may be the primary cleavage site for macrophage elastase and not leucine, as previously thought.

Coordinate regulation of stromelysin and collagenase genes determined with cDNA probes.

Secreted proteinases are required for tumor metastasis, angiogenesis, and tissue remodeling during wound healing and embryonic growth. Thus, the regulation of the genes of secreted proteinases may serve as an interesting model for growth-controlled genes in general. We studied the genes of the secreted proteinases stromelysin and collagenase by using molecularly cloned cDNAs from each proteinase. Stromelysin cDNA was cloned by differential screening of a total cDNA library from rabbit synovial cells treated with phorbol 12-myristate 13-acetate, which yielded a clone of 1.2 kilobase pairs; collagenase cDNA was obtained by cloning reverse transcripts of anti-collagenase-immunoadsorbed polysomal mRNA, which yielded a clone of 0.8 kilobase pairs. Stromelysin and collagenase mRNA species of 2.2 and 2.4 kilobases, respectively, were detected on hybridization blots of RNA from phorbol 12-myristate 13-acetate-treated but not untreated rabbit synovial cells. Expression of stromelysin mRNA was also induced in rabbit alveolar macrophages and rabbit brain capillary endothelial cells treated with phorbol 12-myristate 13-acetate. Stromelysin and collagenase mRNA were both induced by phorbol 12-myristate 13-acetate and cytochalasin B at a constant ratio of the two gene products; this suggests coordinate regulation. The fact that induction was blocked after inhibition of protein synthesis by cycloheximide implicates an indirect signal transduction pathway that requires new protein synthesis.

Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors.

Rabbit brain capillary endothelial cells treated with 12-O-tetradecanoylphorbol-13-acetate produce the metalloproteinases, procollagenase and prostromelysin, as up to 20% of their total secreted protein. However, little or no catalytic activity of these enzymes can be found after treatment with either trypsin or an organomercurial agent, which are able to activate the proenzymes in the medium from stimulated rabbit fibroblasts. We now have shown that enzyme activities of procollagenase and prostromelysin are revealed after conditioned medium is analyzed by gel filtration chromatography or by electrophoresis on sodium dodecyl sulfate-substrate gels. In both systems, the metalloproteinases were separated from metalloproteinase inhibitors. The major inhibitor of Mr = 30,000 from capillary endothelial cells was immunologically identical with the rabbit tissue inhibitor of metalloproteinases. Two additional inhibitors of metalloproteinases at Mr = 22,000 and 19,000 were also observed. Inhibitors were present in the conditioned medium from rabbit fibroblasts in much lower quantities and were also qualitatively different. When gel filtration chromatography was used to remove the tissue inhibitor of metalloproteinases from medium conditioned by stimulated capillary endothelial cells, both activatable procollagenase and prostromelysin were readily demonstrable. These data suggest that endogenous inhibitors regulate the expression of metalloproteinases secreted by endothelial cells.

Gender differences in relationships and stress of medical and law students.

A small-scale, comparative study of medical and law students was undertaken at a large, southern state university to examine the sources and consequences of stress during professional training. Specifically, the impact of stress on personal relationships was explored. The authors of the study reported here found gender differences in the source and degree of stress perceived by students. Women reported significantly more stress than men. Unlike the men, women found sexism and difficulties with partners to be particular sources of stress. Although both men and women reported that the stress of their professional training had resulted in strained personal relationships, proportionately more women than men stated that their personal relationships had ended.

Regulation of alpha 1 proteinase inhibitor function by rabbit alveolar macrophages. Evidence for proteolytic rather than oxidative inactivation.

Rabbit alveolar macrophages were cultured in an environment conducive to the secretion of both reactive oxygen and proteinases, so that the relative importance of proteolytic and oxidative inactivation of alpha 1-proteinase inhibitor by alveolar macrophages could be evaluated. The inactivation of alpha 1-proteinase inhibitor was proportional to its proteolysis, and there was no detectable inactivation in the absence of proteolysis. Although the live macrophages were capable of secreting reactive oxygen, they did not inactivate alpha 1-proteinase inhibitor by oxidation. The inactivation of alpha 1-proteinase inhibitor by proteolysis was proportional to the secretion of elastinolytic activity by the alveolar macrophages. The inability of the alveolar macrophages to oxidize alpha 1-proteinase inhibitor was attributed to the methionine in the macrophages, in secreted proteins, and in the culture medium competing for oxidants. The data suggest that proteolytic inactivation of alpha 1-proteinase inhibitor may be important in vivo and that the methionine concentration in vivo may protect alpha 1-proteinase inhibitor from significant oxidative inactivation.

Selective proteolysis of immunoglobulins by mouse macrophage elastase.

Mouse macrophage elastase, a metalloproteinase secreted by inflammatory macrophages, catalyzed the limited proteolysis of selected subclasses of mouse immunoglobulins, including monomeric IgG2a, IgG3, and some forms of IgG2b. Mouse IgG1 was resistant to elastase degradation; however, human IgG1 was degraded. IgG3 in immune complexes was cleaved in a manner similar to that of monomeric IgG3. Degradation by macrophage elastase was limited to the heavy chain, resulting in products that did not compete for binding to the macrophage Fc receptor. Macrophage elastase usually produced a pepsin-like rather than a papain-like pattern of proteolysis, resulting in the release of F(ab')2 and Fc' subfragments. This degradation of IgG differed from the papain-like cleavage of IgG by granulocyte elastase. Macrophage elastase degraded papain-generated Fc fragments of IgG2a into multiple fragments. Therefore, macrophage elastase at concentrations found in culture medium has the potential to regulate some aspects of cellular events associated with immunoglobulins.