Loss to follow-up after arthroplasty: a new use for registry data.

We assessed the outcome of patients who were lost to follow-up after arthroplasty by a single surgeon. The aim was to validate the surgeon's data set with the Australian Orthopaedic Association National Joint Replacement Registry and determine the outcome of those patients lost to follow-up. Prospective data on patient demographics, operative details and outcomes of the surgeon's 1192 primary unicompartmental knee arthroplasty (UKA) procedures were analysed. There were 69 knees in patients who were lost to follow-up, among whom the Registry identified 31 deaths and eight revisions. The cumulative percentage revision (CPR) at seven years using the additional Registry data was 8.8% (95% confidence interval (CI) 7 to 11). Using the surgeon's data, the CPR at seven years was 8% (95% CI 6.3 to 10.1) for the best-case scenario where loss to follow-up was excluded, and 16% (95% CI 13.8 to 19.4) for the worst-case scenario, where all patients lost to follow-up were deemed to have been revised. There was a significantly higher mortality rate in those patients lost to follow-up. This study demonstrates that a national joint registry can be used by individual surgeons to establish more accurate revision rates in their arthroplasty patients. This is expected to facilitate a more rigorous audit of surgical outcomes by surgeons and lead to more accurate and uniform reporting of the results of arthroplasty in general.

Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films.

A sublingual soluble-film formulation of buprenorphine/naloxone (B/N) has been approved by the US Food and Drug Administration for the treatment of opioid dependency. This preparation provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid-dependent volunteers. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Subjects were randomized to receive either B (16 mg, n = 18) or B/N (16/4 mg, n = 16) soluble films for 5 days. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score. Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between the groups. The results support the use of B and B/N soluble films as safe and effective delivery methods for opioid induction.

Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders.

Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a beta-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.

Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats.

Spinal cord microglial toll-like receptor 4 (TLR4) has been implicated in enhancing neuropathic pain and opposing morphine analgesia. The present study was initiated to explore TLR4-mediated pain modulation by intrathecal lipopolysaccharide, a classic TLR4 agonist. However, our initial study revealed that intrathecal lipopolysaccharide failed to induce low-threshold mechanical allodynia in naive rats, suggestive that TLR4 agonism may be insufficient to enhance pain. These studies explore the possibility that a second signal is required; namely, heat shock protein-90 (HSP90). This candidate was chosen for study given its known importance as a regulator of TLR4 signaling. A combination of in vitro TLR4 cell signaling and in vivo behavioral studies of pain modulation suggest that TLR4-enhancement of neuropathic pain and TLR4-suppression of morphine analgesia each likely require HSP90 as a cofactor for the effects observed. In vitro studies revealed that dimethyl sulfoxide (DMSO) enhances HSP90 release, suggestive that this may be a means by which DMSO enhances TLR4 signaling. While 2 and 100 microg lipopolysaccharide intrathecally did not induce mechanical allodynia across the time course tested, co-administration of 1 microg lipopolysaccharide with a drug that enhances HSP90-mediated TLR4 signaling now induced robust allodynia. In support of this allodynia being mediated via a TLR4/HSP90 pathway, it was prevented or reversed by intrathecal co-administration of a HSP90 inhibitor, a TLR4 inhibitor, a microglia/monocyte activation inhibitor (as monocyte-derived cells are the predominant cell type expressing TLR4), and interleukin-1 receptor antagonist (as this proinflammatory cytokine is a downstream consequence of TLR4 activation). Together, these results suggest for the first time that TLR4 activation is necessary but not sufficient to induce spinally mediated pain enhancement. Rather, the data suggest that TLR4-dependent pain phenomena may require contributions by multiple components of the TLR4 receptor complex.

Long-distance soliton transmission through ultralong fiber lasers.

We present the first experimental demonstration (to our knowledge) of long-distance unperturbed fundamental optical soliton transmission in conventional single-mode optical fiber. The virtual transparency in the fiber required for soliton transmission, over 15 complete periods, was achieved by using an ultralong Raman fiber laser amplification scheme. Optical soliton pulse duration, pulse bandwidth, and peak intensity are shown to remain constant along the transmission length. Frequency-resolved optical gating spectrograms and numerical simulations confirm the observed optical soliton dynamics.

Computer-assisted learning and simulation lab with 40 DentSim units.

There are an increasing number of studies about the computer-assisted dental patient simulator DentSim (DenX, Israel), by which dental students can acquire cognitive motor skills in a multimedia environment. However, only a very few studies have been published dealing with efficient ways to use and to manage a computer-assisted dental simulation lab with 40 DentSim units. The current approach and optimization steps of the College of Dentistry at the University of Tennessee Health Science Center were evaluated based on theoretical and practical tests and by questionnaires (partial 5-point Likert scale). Half of the D1 (first-year) students (2004/05) already had experience with computer-assisted learning at their undergraduate college and most of the students even expected to be taught via computer-assisted learning systems (83.5%) at the dental school. 87.3% of the students working with DentSim found the experience to be very interesting or interesting. Before the students carried out the preparation exercises, they were trained in the skills they needed to work with the sophisticated technology, eg, system-specific operation skills (66.6% attained maximal reachable points) and information searching skills (79.5% attained maximal reachable points). The indirect knowledge retention rate / incidental learning rate of the preparation exercises in the sense of computer-assisted problem-oriented learning regarding anatomy, preparation procedures, and cavity design was promising. The wide- ranging number of prepared teeth needed to acquire the necessary skills shows the varied individual learning curves of the students. The acceptance of, and response to, additional elective training time in the computer-assisted simulation lab were very high. Integrating the DentSim technology into the existing curriculum is a way to improve dental education, but it is also a challenge for both teachers and the students. It requires a shift in both curriculum and instructional goals that have to be reevaluated and optimized continuously.

Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A.

BACKGROUND: BAY 79-4980 is a sucrose-formulated recombinant factor VIII (rFVIII-FS) combined with pegylated liposomes to prolong activity. OBJECTIVES: To investigate the safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics of a single administration of BAY 79-4980 compared with standard rFVIII-FS in patients with severe hemophilia A. METHODS: This randomized, double-blind study consisted of two crossover substudies comparing two doses of liposomal rFVIII-FS with standard rFVIII-FS. Males (12-60 years) with severe hemophilia A received a single infusion of standard rFVIII-FS (35 IU kg(-1)) followed by a single infusion of BAY 79-4980 (13 or 22 mg kg(-1) pegylated liposomes) or vice versa, with 12 observation days and a 2-day washout period between treatments. RESULTS: Twenty-six subjects were enrolled at two centers. No serious adverse events were reported. Transient increases in complement C3a, but not CH50, were seen in subjects receiving both the low- and high-liposome-dose BAY 79-4980. Mild transient elevations of total and low-density lipoprotein cholesterol were observed. There were no clinically significant differences in clotting or laboratory parameters or in pharmacokinetic behavior between BAY 79-4980 and standard rFVIII-FS. The number of subjects with spontaneous bleeds on days 1-14 postinfusion was low, and group comparisons were inconclusive. CONCLUSIONS: Single-dose administration of BAY 79-4980 is well tolerated in patients with severe hemophilia A. Plasma pharmacokinetics of FVIII cannot explain the extended protection from bleeding observed previously with BAY 79-4980. Further studies of efficacy and long-term safety of chronic administration are planned.

Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas.

Primary human brain tumours account for approximately 2% of all cancers. High levels of expression of vascular endothelial growth factor-A (VEGF-A), a potent angiogenic factor, are linked to poor prognosis. In contrast, the potential role in human brain tumour biology of newer VEGF family members, VEGF-C and VEGF-D, both of which are lymphangiogenic factors, is poorly understood. In the present study, the expression of all VEGFs (VEGF-A, -B, -C, and -D) and their receptors (VEGFR-1, -2, and -3) has been assessed in 39 primary human brain tumours. The well-established findings were confirmed with VEGF-A. Surprisingly, however, VEGF-C and VEGF-D, as well as VEGFR-3, were expressed in some tumour types such as haemangioblastomas and glioblastomas, despite their lack of lymphatic vessels. VEGF-C and VEGFR-3 transcripts were localized to the tumour palisade around necrotic areas in glioblastomas and were evenly distributed throughout haemangioblastomas. VEGF-C protein was localized by immunohistochemistry to the palisade layer in glioblastomas. More than 50% of VEGF-C-positive cells also expressed the intermediate-stage inflammatory macrophage marker CD163; however, a significant proportion of VEGF-C-positive cells were CD163-negative. These data demonstrate the presence of molecules, primarily described as regulators of lymphangiogenesis, in normal human brain and brain tumours that are devoid of lymphatics. Their localization in macrophages points to a role in tumour-associated inflammation.

Lymphatic vessel density in the neoplastic progression of Barrett's oesophagus to adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma is an aggressive neoplasm with poor prognosis as a result of early lymph node metastasis. AIMS: To measure lymphatic vessel density (LVD) in the neoplastic progression from Barrett's metaplasia to adenocarcinoma and determine whether LVD can predict the risk of cancer. In addition, to correlate LVD with lymph node metastasis and assess whether LVD could be used as a prognostic indicator for outcome or survival. METHODS: LVD and microvascular density (MVD) were assessed after immunohistochemical staining of vessels in Barrett's metaplasia, dysplasia, and adenocarcinoma tissues and were correlated with clinicopathological features. RESULTS: LVD was significantly reduced in adenocarcinoma, being half that seen in normal stomach/oesophagus or metaplasia/dysplasia. LVD did not correlate with tumour grade, stage, or clinical outcome; however, patients who had either lymph node metastasis or invasion of tumour cells into peritumorous lymphatic vessels had a significantly worse overall survival. MVD was also assessed as a prognostic marker; its increase appeared to be linked more with the development of Barrett's metaplasia than adenocarcinoma. CONCLUSIONS: The reduction in lymphatic vessel numbers was not useful for determining disease outcome in the patient group studied. It is the entry of tumour cells into pre-existing peritumorous lymphatic vessels that confers a significantly worse overall survival.

Denitrification across landscapes and waterscapes: a synthesis.

Denitrification is a critical process regulating the removal of bioavailable nitrogen (N) from natural and human-altered systems. While it has been extensively studied in terrestrial, freshwater, and marine systems, there has been limited communication among denitrification scientists working in these individual systems. Here, we compare rates of denitrification and controlling factors across a range of ecosystem types. We suggest that terrestrial, freshwater, and marine systems in which denitrification occurs can be organized along a continuum ranging from (1) those in which nitrification and denitrification are tightly coupled in space and time to (2) those in which nitrate production and denitrification are relatively decoupled. In aquatic ecosystems, N inputs influence denitrification rates whereas hydrology and geomorphology influence the proportion of N inputs that are denitrified. Relationships between denitrification and water residence time and N load are remarkably similar across lakes, river reaches, estuaries, and continental shelves. Spatially distributed global models of denitrification suggest that continental shelf sediments account for the largest portion (44%) of total global denitrification, followed by terrestrial soils (22%) and oceanic oxygen minimum zones (OMZs; 14%). Freshwater systems (groundwater, lakes, rivers) account for about 20% and estuaries 1% of total global denitrification. Denitrification of land-based N sources is distributed somewhat differently. Within watersheds, the amount of land-based N denitrified is generally highest in terrestrial soils, with progressively smaller amounts denitrified in groundwater, rivers, lakes and reservoirs, and estuaries. A number of regional exceptions to this general trend of decreasing denitrification in a downstream direction exist, including significant denitrification in continental shelves of N from terrestrial sources. Though terrestrial soils and groundwater are responsible for much denitrification at the watershed scale, per-area denitrification rates in soils and groundwater (kg N x km(-2) x yr(-1)) are, on average, approximately one-tenth the per-area rates of denitrification in lakes, rivers, estuaries, continental shelves, or OMZs. A number of potential approaches to increase denitrification on the landscape, and thus decrease N export to sensitive coastal systems exist. However, these have not generally been widely tested for their effectiveness at scales required to significantly reduce N export at the whole watershed scale.

Review of the role of alcohol in drowning associated with recreational aquatic activity.

OBJECTIVE AND DESIGN: To assess the role of alcohol in drowning associated with recreational aquatic activity by reviewing the English language literature published up to October 2003. RESULTS: Alcohol is widely used in association with recreational aquatic activity in the United States, but there is minimal information regarding the extent of use elsewhere. A priori and anecdotal evidence suggests that alcohol is an important risk factor for drowning associated with recreational aquatic activity. Specific studies provide good evidence supporting this, but the extent of increased risk associated with alcohol use, and the attributable risk due to alcohol use, is not well characterised. Drowning appears to be the overwhelming cause of death associated with recreational aquatic activity with alcohol detected in the blood in 30%-70% of persons who drown while involved in this activity. The few relevant studies on degree of increased risk suggest persons with a blood alcohol level of 0.10 g/100 ml have about 10 times the risk of death associated with recreational boating compared with persons who have not been drinking, but that even small amounts of alcohol can increase this risk. The population attributable risk seems to be in the range of about 10%-30%. CONCLUSIONS: Alcohol consumption significantly increases the likelihood of immersions resulting in drowning during aquatic activities. However, more information is required if appropriate prevention activities are to be planned, initiated, and evaluated. This includes better information on alcohol use, and attitudes to alcohol use, in association with recreational aquatic activity, and the nature and extent of increased risk associated with alcohol use. Evaluation of interventions is also needed.

Use of hand-held laser scanning in the assessment of facial swelling: a preliminary study.

A new generation lightweight, hand-held, laser surface scanner (FastSCAN) was validated and clinically evaluated for the assessment of postoperative facial swelling. The potential sources of error-scanner error, registration error, and repositioning and movement error were established for laser scans of a mannequin head and seven volunteers. For the mannequin head the mean (S.D.) volume of the simulated swelling was 12.5 (0.5) cm3. The measurement error was therefore about 4%, and reflected the error in scanned data and in surface registration. Among the volunteers, repositioning of the head introduced additional errors of up to 7.6 cm3 (mean 1.8 cm3), illustrating the additional influence of variable positions. We then scanned 20 patients (9 women and 11 men, age range 18-26) before and 2 days after, third molar removal. The external, facial soft tissue volume changes were calculated for both left and right sides (range 0.2-64.3 cm3). The main source of inaccuracy was again variability of position. Despite this, the FastSCAN proved to be a simple, accurate, and non-invasive method of measuring postoperative changes in volume in the external, soft tissues of the face. Minimising variability in position by using more precise positioning techniques will increase the accuracy of this technique and is a focus for future work.

Crystallization and X-ray diffraction measurements on recombinant molbindin, MopII, from Clostridium pasteurianum.

Clostridium pasteurianum carries three genes termed mopI, II and III encoding three molbindin isoforms, one of which has been cloned, the gene product expressed in high yield and crystallized using the hanging-drop vapour-diffusion method. Well ordered monoclinic crystals in two different crystal forms, both with space group C2, were obtained in the presence and absence of Na(2)MoO(4) and Na(2)WO(4). Ligand-bound MopII crystallized with polyethylene glycol (PEG) 400 as a precipitant, whereas apo MopII required PEG 6000. High-resolution diffraction data were collected for ligand-bound MopII structures using synchrotron radiation to 1.8 and 1.6 A resolution for the molybdate and tungstate complexes, respectively. Data were collected on apoMopII crystals to a resolution of 1.8 A in-house.

Home-style beef jerky: effect of four preparation methods on consumer acceptability and pathogen inactivation.

The safety of homemade jerky continues to be questioned. Producing a safe product that retains acceptable quality attributes is important. Lethality of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes as well as consumer acceptability and sensory attributes of jerky prepared by four methods were examined. Preparation methods were drying marinated strips at 60 degrees C (representing a traditional method), boiling strips in marinade or heating in an oven to 71 degrees C prior to drying, and heating strips in an oven after drying to 71 degrees C. A 60-member consumer panel rated overall acceptability. A 10-member descriptive panel evaluated quality attributes. Samples heated after drying and samples boiled in marinade prior to drying had slightly higher acceptability scores but were not statistically different from traditional samples. Although the four treatments were significantly different in color (P = 0.0001), saltiness (P = 0.0001), and texture (P = 0.0324), only texture appeared to influence overall consumer acceptability. Microbial challenge studies subjecting the pathogens to the four treatments showed a 5.8-, 3.9-, and 4.6-log reduction of E. coli O157:H7, L. monocytogenes, and Salmonella, respectively, even with traditional drying. Oven treatment of strips after drying was shown to have the potential to reduce pathogen populations further by approximately 2 logs. In conclusion, a safer, yet acceptable home-dried beef jerky product can be produced by oven-heating jerky strips after drying.

The involvement, understanding and attitudes of dietitians towards research and audit.

AIM: To investigate the involvement of dietitians in research and audit and to assess their understanding of and attitudes towards these activities. METHODS: A postal questionnaire was used to investigate the knowledge, attitude towards and involvement in research and audit of State Registered Dietitians practising in the National Health Service (NHS) in the UK. RESULTS: A response rate of 64% was achieved. Few respondents (15%) were currently involved in research, although more (65%) were currently involved in audit. Involvement in audit rose significantly with increasing grade and managerial responsibility. Dietitians qualifying more recently were more likely to believe that their college training prepared them to undertake research, but felt less confident about undertaking audit. Experience of audit made respondents more confident about auditing their work and improved their belief that they understood audit terminology. Higher grade dietitians were more likely to see audit as an important part of their role than were their more junior colleagues. Understanding of the terms 'research' and 'audit' was poor, although 48% of respondents identified the link between the two activities. Perceived constraints to involvement in research and audit were identified. CONCLUSION: The present level of involvement of dietitians in research and audit activities falls below that recommended in the BDA's (1997a) National Professional Standards for Dietitians Practising in Healthcare. This study identifies factors that influence dietitians' involvement in, understanding of and attitudes towards research and audit and recommends ways of increasing their involvement in these activities.

Hydrolase and sialyltransferase activities of trypanosoma cruzi trans-sialidase towards NeuAc-alpha-2,3-gal-Gal-beta-O-PNP.

NeuAc-alpha-2,3-Gal-beta-O-PNP has been synthesised and its ability to act as a substrate for the hydrolase and transferase activities of Trypanosoma cruzi trans-sialidase have been investigated. The turn-over of this compound shows marked differences from the behaviour of NeuAc-MU. In addition, distinct differences in the action of T. cruzi trans-sialidase and Clostridium perfringens neuraminidase on NeuAc-alpha-2,3-Gal-beta-O-PNP were apparent.

A novel suture anchor of high-density collagen compared with a metallic anchor. Results of a 12-week study in sheep.

We report the early mechanical properties and histologic findings of a high-density, type I collagen bone anchor. This new anchor was compared with a traditional metallic anchor in a sheep patellar tendon model. No difference in strength of the repair was noted between the two devices at any time point. The insertions on the repaired side approached the strength of the nonoperated side by 12 weeks. Histologic analysis showed that the collagen anchor integrated with the surrounding bone by 6 weeks, and there was little degradation at 12 weeks. The high-density collagen anchor supported tendon healing to bone comparable with that seen with a traditional metallic device, but it has the potential advantage of the anchor being incorporated into bone.