Trends in health care utilization and costs attributable to hepatocellular carcinoma, 2002-2009: a population-based cohort study.

BACKGROUND: The incidence of hepatocellular carcinoma (hcc) and the complexity of its diagnosis and treatment are increasing. We estimated trends in net health care utilization, costs of care attributable to hcc in Ontario, and rate ratios of resource use at various stages of care. METHODS: This population-based retrospective cohort study identified hcc patients and non-cancer control subjects, and health care resource utilization between 2002 and 2009. Generalized estimating equations were then used to estimate net health care utilization (hcc patients vs. the matched control subjects) and net costs of care attributable to hcc. Generalized linear models were used to analyze rate ratios of resource use. RESULTS: We identified 2832 hcc patients and 2808 matched control subjects. In comparison with the control subjects, hcc patients generally used a greater number of health care services. Overall, the mean net cost of care per 30 patient-days (2013 Canadian dollars) attributable to outpatient visits and hospitalizations was highest in the pre-diagnosis (1 year before diagnosis), initial (1st year after diagnosis), and end-of-life (last 6 months before death, short-term survivors) phases. Mean net homecare costs were highest in the end-of-life phase (long-term survivors). In the end-of-life phase (short-term survivors), mean net costs attributable to outpatient visits and total services significantly increased to $14,220 from $1,547 and to $33,121 from $14,450 (2008-2009 and 2002-2003 respectively). CONCLUSIONS: In hcc, our study found increasing resource use and net costs of care, particularly in the end-of-life phase among short-term survivors. Our findings offer a basis for resource allocation decisions in the area of cancer prevention and control.

Spiteful interactions between sympatric natural isolates of Xenorhabdus bovienii benefit kin and reduce virulence.

Spite occurs when an individual harms itself in the act of harming others. Spiteful behaviour may be more pervasive in nature than commonly thought. One of the clearest examples of spite is the costly production and release of bacteriocins, antimicrobial toxins noted for their ability to kill conspecifics. A key question is to what extent these toxins provide a fitness advantage to kin of the producer cell, especially in natural communities. Additionally, when bacteria are involved in parasitic relationships, spiteful interactions are predicted to lower bacterial densities within a host, causing a reduction in parasite-induced virulence. Using five sympatric, field-collected genotypes of the insect pathogen Xenorhabdus bovienii, we experimentally demonstrate that bacteriocin production benefits kin within the host, and that it slows the mortality rate of the host. These results confirm that spite among naturally coexisting bacterial clones can be a successful kin-selected strategy that has emergent effects on virulence.

Biophysical properties and microfilament assembly in neutrophils: modulation by cyclic AMP.

The microfilament lattice, composed primarily of filamentous (F)-actin, determines in large part the mechanical (deformability) properties of neutrophils, and thus may regulate the ability of neutrophils to transit a microvascular bed. Circulating factors may stimulate the neutrophil to become rigid and therefore be retained in the capillaries. We hypothesized that cell stiffening might be attenuated by an increase in intracellular cAMP. A combination of cell filtration and cell poking (mechanical indentation) was used to measure cell deformability. Neutrophils pretreated with dibutyryl cAMP (db-cAMP) or the combination of prostaglandin E2 (PGE2, a stimulator of adenylate cyclase) and isobutylmethylxanthine (IBMX, an inhibitor of phosphodiesterase) demonstrated significant inhibition of the n-formyl-methionyl-leucyl-phenylalanine (fMLP)-inducing stiffening. The inhibition of cell stiffening was associated with an increase in intracellular cAMP as measured by enzyme-linked immunoassay (EIA) and an increase in the activity of the cAMP-dependent kinase (A-kinase). Treatment with PGE2 and IBMX also resulted in a decrease in the F-actin content of stimulated neutrophils as assayed by NBD-phallacidin staining and flow cytometry or by changes in right angle light scattering. Direct addition of cAMP to electropermeabilized neutrophils resulted in attenuation of fMLP-induced actin assembly. Neutrophils stimulated with fMLP demonstrated a rapid redistribution of F-actin from a diffuse cortical location to a peripheral ring as assessed by conventional and scanning confocal fluorescence microscopy. Pretreatment of neutrophils with the combination of IBMX and PGE2 resulted in incomplete development and fragmentation of the cortical ring. We conclude that assembly and redistribution of F-actin may be responsible for cell stiffening after exposure to stimulants and that this response was attenuated by agents that increase intracellular cAMP, by altering the amount and spatial organization of the microfilament component of the cytoskeleton.

The clinical relevance of sound changes produced during cementless hip arthroplasty: a correctly sized femoral broach creates a distinctive pattern of audio frequencies directly related to bone geometry.

AIMS: Cementless femoral stems must be correctly sized and well-seated to obtain satisfactory biological fixation. The change in sound that occurs during impaction of the femoral broach is said to indicate good fit, but this has not been widely studied. We set out to find whether the presence or absence of these sound changes could predict correct sizing. PATIENTS AND METHODS: We recorded the sound generated during femoral broaching for 105 cementless total hip arthroplasties using the Corail stem. Four cases were excluded, leaving 101 recordings for analysis. There were 36 male patients and 65 female patients, with a mean age of 69.9 years (sd 12.3) and median body mass index (BMI) of 29 kg/m 2 (interquartile range (IQR) 26 to 32). The recordings were analyzed to identify the frequencies of the sounds produced during impaction of the femoral broach. RESULTS: The emergence of a low-frequency band of sound in the 1 kHz range, during the final femoral broaching, was a strong predictor of a well-sized implant stem. The frequency was related to femoral length, supporting our hypothesis that the sound arose from the bone itself. CONCLUSION: The low-frequency sound generated during femoral broaching can be monitored spectrographically, its frequency can be predicted from femoral length, and it is a good predictor of appropriate stem sizing.

Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.

Stimulation of human neutrophils with chemoattractants FMLP or platelet activating factor (PAF) results in different but overlapping functional responses. We questioned whether these differences might reflect patterns of intracellular signal transduction. Stimulation with either PAF or FMLP resulted in equivalent phosphorylation and activation of the mitogen-activated protein kinase (MAPk) homologue 38-kD murine MAP kinase homologous to HOG-1 (p38) MAPk. Neither FMLP nor PAF activated c-jun NH2-terminal MAPk (JNKs). Under identical conditions, FMLP but not PAF, resulted in significant p42/44 (ERK) MAPk activation. Both FMLP and PAF activated MAP kinase kinase-3 (MKK3), a known activator of p38 MAPk. Both MAP ERK kinase kinase-1 (MEKK1) and Raf are activated strongly by FMLP, but minimally by PAF. Pertussis toxin blocked FMLP-induced activation of the p42/44 (ERK) MAPk cascade, but not that of p38 MAPk. A specific p38 MAPk inhibitor (SK&F 86002) blocked superoxide anion production in response to FMLP and reduced adhesion and chemotaxis in response to PAF or FMLP. These results demonstrate distinct patterns of intracellular signaling for two chemoattractants and suggest that selective activation of intracellular signaling cascades may underlie different patterns of functional responses.

Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils.

Activation of leukocytes by proinflammatory stimuli selectively initiates intracellular signal transduction via sequential phosphorylation of kinases. Lipopolysaccharide (LPS) stimulation of human neutrophils is known to result in activation of p38 mitogen-activated protein kinase (MAPk); however, the upstream activator(s) of p38 MAPk is unknown, and consequences of p38 MAPk activation remain largely undefined. We investigated the MAPk kinase (MKK) that activates p38 MAPk in response to LPS, the p38 MAPk isoforms that are activated as part of this pathway, and the functional responses affected by p38 MAPk activation. Although MKK3, MKK4, and MKK6 all activated p38 MAPk in experimental models, only MKK3 was found to activate recombinant p38 MAPk in LPS-treated neutrophils. Of p38 MAPk isoforms studied, only p38alpha and p38delta were detected in neutrophils. LPS stimulation selectively activated p38alpha. Specific inhibitors of p38alpha MAPk blocked LPS-induced adhesion, nuclear factor-kappa B (NF-kappaB) activation, and synthesis of tumor necrosis factor-alpha (TNF-alpha). Inhibition of p38alpha MAPk resulted in a transient decrease in TNF-alpha mRNA accumulation but persistent loss of TNF-alpha synthesis. These findings support a pathway by which LPS stimulation of neutrophils results in activation of MKK3, which in turn activates p38alpha MAPk, ultimately regulating adhesion, NF-kappaB activation, enhanced gene expression of TNF-alpha, and regulation of TNF-alpha synthesis.

In vivo delivery of recombinant human growth hormone from genetically engineered human fibroblasts implanted within Baxter immunoisolation devices.

Continuous delivery of therapeutic peptide to the systemic circulation would be the optimal treatment for a variety of diseases. The Baxter TheraCyte system is a membrane encapsulation system developed for implantation of tissues, cells such as endocrine cells or cell lines genetically engineered for therapeutic peptide delivery in vivo. To demonstrate the utility of this system, cell lines were developed which expressed human growth hormone (hGH) at levels exceeding 1 microgram per million cells per day. These were loaded into devices which were then implanted into juvenile nude rats. Significant levels of hGH of up to 2.5 ng/ml were detected in plasma throughout the six month duration of the study. In contrast, animals implanted with free cells showed peak plasma levels of 0.5 to 1.2 ng four days after implantation with no detectable hGH beyond 10 days. Histological examination of explanted devices showed they were vascularized and contained cells that were viable and morphologically healthy. After removal of the implants, no hGH could be detected which confirmed that the source of hGH was from cells contained within the device. The long term expression of human growth hormone as a model peptide has implications for the peptide therapies for a variety of human diseases using membrane encapsulated cells.

Competitive effects of long-chain-triglyceride emulsion on the metabolism of medium-chain-triglyceride emulsions.

This study was conducted to assess the potential metabolic competitive interactions of intravenous medium-chain-triglyceride (MCT) and long-chain-triglyceride (LCT) lipid emulsions. To assess this competition increasing concentrations of LCT emulsion were added to an intravenous dose of MCT emulsion of 3.0 g/kg body wt up to a maximum dose of 3.0 g LCTs/kg body wt. Blood samples were assessed for competitive interactions by analyzing the following metabolites: glucose, insulin, lactate, pyruvate, ketones (acetoacetate, beta-hydroxybutyrate), elimination of triglycerides, and free fatty acids. Evaluation of the data showed a strong competitive interaction between the MCT and LCT emulsions. This competition was evident as soon as LCTs were added to the MCT infusions and appeared to favor LCTs for removal and metabolism over MCTs. This appears to indicate that there is a peripheral, strong affinity site for LCT removal and metabolism and a shared peripheral site and specific visceral site for MCT removal and metabolism.

Medium-chain-triglyceride lipid emulsion: metabolism and tissue distribution.

The utilization and distribution of radioactively labeled lipid emulsions were evaluated in Sprague-Dawley rats. Animals received one of three lipid emulsions. Group 1 received [14C]medium-chain-triglyceride (MCT) lipid emulsion, group 2 received a 75%:25% (vol:vol) admixture of [14C]MCT: unlabeled long-chain-triglyceride (LCT) lipid emulsion, and group 3 received only [14C]LCT. The radioactive dose appearing in expired carbon dioxide and various body tissues was monitored over a 24-h period. Results indicate that MCT is oxidized more rapidly and completely than in LCT; approximately 90% of the MCT is converted to carbon dioxide with in 24 h compared with 45% for LCT. When MCT and LCT are administered together, the metabolism of MCT is slowed but remains more rapid than that of LCT. Removal of MCT from the blood was more rapid than was removal of LCT, and tissue radioactivity was lower.

Local inflammatory response around diffusion chambers containing xenografts. Nonspecific destruction of tissues and decreased local vascularization.

Immunoisolation of xenogeneic pancreatic islets within membrane-bound devices has been proposed as an approach to cure diabetes. We examined the local response to implanted xenografts and allografts in comparison with isografts in diffusion chambers with 0.4-microm pore membranes when implanted into epididymal fat pads of rats. These membranes prevented host cell entry into the device but did not prevent passage of large molecules such as IgG and IgM. Well-differentiated allogeneic tissues (Sprague-Dawley rat embryonic lung implanted into Lewis rats) survived for 1 year when implanted in intact devices, but similar tissues were destroyed within 3 weeks when implanted within devices with holes poked in the membrane to allow host cell contact. In contrast, xenografts (CF1 mouse embryonic lung implanted into Lewis rats) were destroyed within 3 weeks even when implanted in devices with intact membranes. The death of the xenogeneic tissues was accompanied by a severe local accumulation of inflammatory cells and a decrease in local vascularization. When isogeneic tissues (Lewis rat embryonic lung implanted in Lewis rats) were mixed with xenogeneic tissues, a local inflammatory response occurred and both iso- and xenogeneic tissues were destroyed within 5 weeks. These results suggest the possibility that xenografts are killed by local accumulation of inflammatory cells, perhaps mediated by the release of antigens from the tissues within the device and presentation by an indirect pathway. The observation that the local response to xenografts is sufficient to kill isografts complicates issues of immunoprotection, suggesting that successful immunoisolation will require membranes that not only provide protection of the encapsulated tissues from the host immune system but also have properties that diminish the release of xenogeneic antigens.

Dissociation between emotional and endocrine responses preceding an academic examination in male medical students.

A study was made in 2 consecutive years of the emotional states and morning and afternoon serum levels of prolactin, cortisol and testosterone of male medical students during a 4- to 5-week period preceding a major university examination. 'Distress', 'anxiety' and, to a lesser degree, 'depression' increased during the 2 weeks immediately preceding the examination and were positively correlated with personality anxiety or neuroticism traits. Group means for hormones showed no consistent change over the same period. Neither was there evidence for a correlation between endocrine and emotional changes within individual students during the pre-examination period. A restricted study showed that there were significant increments in cortisol in samples taken during the examination itself. Changes in emotional state before an examination occurred in the absence of equally dramatic changes in levels of the three hormones studied, though this relationship may have altered during the examination itself. This suggests that the factors controlling the two categories of response may relate differently, in some way, to the imminence of this stressful event.

Plasma and submandibular saliva lysosomal enzymes in cystic fibrosis.

This study determined in a blind fashion the activity levels and thermostability properties of two lysosomal hydrolytic enzymes, acid phosphatase and alpha-mannosidase, in plasma samples from 25 cystic fibrosis (CF) patients and 25 age- and sex-matched normal controls. Mean alpha-mannosidase activity (3.2 +/- 1.0 mU/ml) and acid phosphatase activities (6.5 +/- 2.9 mU/ml) in CF patients were not significantly different from those found in normal individuals (2.8 +/- 0.7 and 7.6 +/- 3.4 mU/ml, respectively). Using stringent conditions no differences in thermostability properties of these enzymes were found between plasma from CF patients as compared to that of normal controls. When activity levels of these enzymes and of four additional hydrolytic enzymes, alpha-L-fucosidase, alpha-galactosidase, alpha-glucosidase and beta-galactosidase, were determined in submandibular saliva, no significant differences in enzyme levels between CF and age- and sex-matched controls were noted nor were thermostability differences found. Our data do not support the concept that altered properties of these enzymes are useful as markers for detection of CF homozygotes and heterozygotes, nor the hypothesis that the defect underlying this disease is a deficiency of post-translational modification of glycoproteins leading to their mis-compartmentalization and qualitative alteration.

The relations between temperament and empathy in 2-year-olds.

The role of infant and toddler temperament in the prediction of empathy in 2-year-old children was examined. Assessments of temperament included reactivity and affect observed at 4 months of age, as well as inhibition at Age 2. Empathy was measured in 2-year-old children's responses to simulations of distress performed by their mothers and by an unfamiliar person. Children showed relatively more concern for the mother's distress, but they were also responsive to unfamiliar victims. Infants who were unreactive and showed little affect also showed less empathy toward the unfamiliar adult almost 2 years later. Inhibition toward an unfamiliar adult (but not toward the mother) at 2 years of age was negatively related to empathy. Inhibited temperament may thus have a major impact on young children's empathy in unfamiliar contexts. Findings also highlight the need to consider early underarousal as another dimension of temperament that may dampen expressions of empathic concern.

Control of bleeding in cemented arthroplasty.

Bleeding from cancellous bone causes lamination within bone cement and at its prosthetic interfaces, and weakens the fixation of joint replacements. We examined the effects of anaesthesia and blood pressure on bleeding in human cancellous bone, and investigated the local response to freezing saline, 1:200,000 adrenaline and hydrogen peroxide. Spinal anaesthesia reduced cancellous bleeding by an average of 44%, local freezing saline by 24%. Saline at room temperature, adrenaline solution and hydrogen peroxide each reduced it by 14%. The effects of spinal anaesthesia and of freezing saline were additive: used together they reduced bleeding by 56%. The reduction of blood contamination of cement and its interfaces should contribute to better prosthetic fixation.

Desmoplastic fibroma of the mandible in a child: report of a case.

A 6-year-old girl was seen with a history of progressive trismus and expansion of the right mandible over a 9-month period. Desmoplastic fibroma was diagnosed on biopsy. This report reviews the diagnostic criteria and surgical management of this uncommon primary bone tumor of the maxillofacial region.

Oral mucosal melanomas: the WESTOP Banff workshop proceedings. Western Society of Teachers of Oral Pathology.

A workshop to discuss primary oral melanomas was convened at the annual Western Society of Teachers of Oral Pathology meeting in Bannf, Alberta, Canada. Fifty oral melanomas, identified from the files of the participants, were reviewed in order to better understand the clinical features, histologic spectrum, and natural history of these perplexing lesions. Results confirmed that oral melanomas occur in adults almost three times more frequently in men than women and have a decided predilection for the palate and gingiva. Some lesions exhibit a clinically detectable and prolonged in situ growth phase, whereas others seem to lack this property and exhibit only or predominantly invasive characteristics. Recurrences, metastases, and death from tumor were characteristic of the follow-up of a limited number of patients. Until definitive prospective data are collected that elucidate natural history, oral mucosal melanomas should be tracked separately from cutaneous lesions. All oral pigmented lesions that are not clinically diagnostic should be biopsied. Lesions with equivocal histopathologic features might be referred to as "atypical melanocytic proliferation" and should be excised. Recognition of lesions in an early in situ phase and aggressive treatment should have a favorable effect on prognosis. To enhance future or prospective study of these rare neoplasms, guidelines for reporting oral melanomas are suggested.

Pseudobattering of Vietnamese children (cao gio).

The case of a Vietnamese child who was subjected to the folk medicine practice of cao gio by his father after a routine dental extraction is described. The practice and the clinical appearance are discussed to distinguish it from child abuse.

Prevalence of herpes simplex virus disease in a professional population.

By virtue of occupation, dentists are frequently exposed to the herpes simplex virus. The risk of infection by the virus was evaluated by assessing disease experience as shown by history compared with the results of complement fixing or antibody titration tests, or both.

Engineering design of vascular prostheses.

The replacement and bypass of arteries of diameter greater than 6 mm with textile vascular prostheses has proved very successful since they were first introduced forty years ago. Although manufacturers continue to improve their products and make them of consistent quality for increased safety and performance and to facilitate their use by surgeons, most of the research work in this area is concerned with the development of small-diameter prostheses. Current expanded PTFE and textile prostheses do not perform satisfactorily when their diameters are reduced to less than 6 mm. For the small-diameter prostheses it will be necessary to develop less thrombogenic materials and to design the structure of the prostheses more closely to match the mechanical properties of the natural arteries. The purpose of this paper is to discuss the design requirements and to review the development of large- and small-diameter vascular prostheses.

Issues in the assessment of expert nurses: purposes, standards and methods.

It is generally agreed that experts seek and use different information, and that the solutions they propose and implement are also different in kind and quality from those of non-experts. This makes assessment of experts a challenging problem. The difficulty of establishing standards and criteria by which the expert can be assessed should not necessarily prevent such assessment from being undertaken. However, the purpose of assessing experts should be clearly articulated before engaging in such practices, since different purposes may legislate different assessment methods. This paper canvasses concerns relating to the assessment of expert nurses, including: the definition of expertise; establishing standards of expert nursing performance; the training of appropriate assessors; and the choice of assessment method. Care needs to be exercised at all times to avoid obscuring the issues by concentration on assessing isolated expert behaviours to the exclusion of consideration of the underlying political purposes and the economic consequences of assessing expertise.