Progression and stop organization reveals conservation of movement organization during dark exploration across rats and mice.

Spatial orientation is a ubiquitous feature of animal behavior. Environmental and self-movement cues are sources of information used to maintain spatial orientation. The literature has typically focused on differences between mice and rats using environmental cues to guide movement. The current study uses the organization of exploratory behavior under dark conditions to investigate species differences in self-movement cue processing. Mouse and rat exploratory behavior was recorded under dark conditions on a circular table without walls. The resulting movements were segmented in progressions (movement ≥ 3 cm/s) and stops (movement < 3 cm/s). Mice exhibited longer travel distances, faster progression peak speeds, and weaker tendency to scale progression peak speeds to Euclidean distances relative to rats. In contrast, similar levels of performance were observed on measures (progression path circuity, change in heading, stability of stopping behavior) sensitive to vestibular pathology. These results are consistent with species differences in a variety of performance variables; however, self-movement cue based spatial orientation did not differentiate between mice and rats. This work establishes a translational foundation for future work investigating the neurobiology of self-movement cue processing using species-unique neuroscience techniques.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients.

BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non-bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid-suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality.

A simulator study of adverse wear with metal and cement debris contamination in metal-on-metal hip bearings.

OBJECTIVES: Third-body wear is believed to be one trigger for adverse results with metal-on-metal (MOM) bearings. Impingement and subluxation may release metal particles from MOM replacements. We therefore challenged MOM bearings with relevant debris types of cobalt-chrome alloy (CoCr), titanium alloy (Ti6Al4V) and polymethylmethacrylate bone cement (PMMA). METHODS: Cement flakes (PMMA), CoCr and Ti6Al4V particles (size range 5 µm to 400 µm) were run in a MOM wear simulation. Debris allotments (5 mg) were inserted at ten intervals during the five million cycle (5 Mc) test. RESULTS: In a clean test phase (0 Mc to 0.8 Mc), lubricants retained their yellow colour. Addition of metal particles at 0.8 Mc turned lubricants black within the first hour of the test and remained so for the duration, while PMMA particles did not change the colour of the lubricant. Rates of wear with PMMA, CoCr and Ti6Al4V debris averaged 0.3 mm(3)/Mc, 4.1 mm(3)/Mc and 6.4 mm(3)/Mc, respectively. CONCLUSIONS: Metal particles turned simulator lubricants black with rates of wear of MOM bearings an order of magnitude higher than with control PMMA particles. This appeared to model the findings of black, periarticular joint tissues and high CoCr wear in failed MOM replacements. The amount of wear debris produced during a 500 000-cycle interval of gait was 30 to 50 times greater than the weight of triggering particle allotment, indicating that MOM bearings were extremely sensitive to third-body wear. Cite this article: Bone Joint Res 2015;4:29-37.

Targeting Plasmodium falciparum purine salvage enzymes: a look at structure-based drug development.

New antimalarials are needed due to the rapid development of resistance to currently deployed drugs. Because Plasmodium species are unable to synthesize purines, purine salvage pathways have been proposed as novel anti-malarial targets. The purine salvage pathway in Plasmodium is streamlined with adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and hypoxanthine-xanthine-guanine-phosphoribosyltransferase (HXGPRT) representing the major pathway for purine acquisition. Plasmodium falciparum enzymes PfADA and PfPNP have unique dual specificity that enable them to act upon methylthiopurines resulting from polyamine synthesis. Thus Plasmodium ADA and PNP function in both purine salvage and purine recycling. Genetic studies have confirmed the importance of Plasmodium PNP for viability of malaria parasites. Immucillins, powerful picomolar transition state inhibitors of PNP, are active against cultured Plasmodium falciparum and inhibit all Plasmodium PNPs tested. Several immucillins have undergone human clinical trials, and these compounds represent a new class of compounds with potential activity against human malarias.

What is a "normal" wear pattern for metal-on-metal hip bearings?

In addition to classical run-in and steady-state wear phases, metal-on-metal (MOM) hip bearings have encountered "runaway wear" (RAW) trends in simulator studies. This puzzling behavior has resulted in 2- to 19-fold wear increases compared with other apparently "identical" bearings. MOM bearings have shown five identifiable RAW wear patterns in joint simulators; therefore, additional descriptive terms were used here to indicate various observed patterns, for example, "breakaway wear" (BAW), which was defined as a higher wear trend that recovers to steady-state wear. As these trends commonly occur for MOM, this raises the question of what can be considered "normal" behavior or "abnormal"? In an effort to identify possible causes for this behavior, the current study investigated six Co-Cr bearings, which closely matched with respect to geometrical tolerances. Despite close control of design and test variables, BAW occurred in 30% of the MOM bearings, producing a threefold wear increase above otherwise identical MOM bearings within the same group. The majority of the BAW (85%) occurred on the cup side and was validated by growth of wear scars and concentrations of metal ions. One bearing that showed continuing BAW at 5 Mc revealed a cup that was 50% smoother than other cups whereas its mating head was 50% rougher, thus signifying that highly polished areas were sites of the highest MOM wear. The two BAW bearings with high wear showed the greatest conformity at 5 Mc, in apparent contradistinction to classical lubrication theory.

Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration.

BACKGROUND: Several studies indicate that age-related macular degeneration (AMD) and atherosclerosis may share common pathogenetic pathways. The aim of this study was to determine the role of systemic matrix metalloproteinases (MMPs) in AMD, given that MMPs are implicated in the pathogenesis of atherosclerosis. METHODS: This study determined the plasma matrix metalloproteinases (MMP-2 and MMP-9) levels in three groups of subjects: group 1 included subjects with age-related maculopathy (ARM), group 2 included subjects with choroidal neovascularization (CNV) owing to AMD and group 3 consisted of age-matched controls. RESULTS: The mean plasma levels of MMP-2 were not significantly different in the three groups. In contrast, the mean plasma MMP-9 levels were significantly higher in ARM and CNV groups compared to that of the control group. However, there was no significant difference in MMP-9 levels between ARM and CNV groups. CONCLUSION: This is the first study that reveals a link between raised plasma MMP-9 levels with AMD. Further studies are required to identify the factors that contribute to this association.

"Severe" wear challenge to 36 mm mechanically enhanced highly crosslinked polyethylene hip liners.

Our purpose was to compare the wear performance of mechanically enhanced 5Mrad highly crosslinked polyethylene (MEP, ArComXL) hip liners to (control) 3Mrad UHMWPE liners (ArCom) in 36 mm head size. As a more severe synergy of clinically relevant test models, we contrasted wear with custom roughened Co-Cr surfaces (Ra 500 nm) to the standard pristine Co-Cr heads (Ra < 20 nm) using a severe microseparation test mode in our hip simulator. We adopted a previously published model to estimate potential biological activity. On new Co-Cr heads, the MEP liners showed a 47% reduction in volumetric wear a 13% reduction in wear particle size and a 27% reduction in Functional Biological Activity (FBA) compared to our control. On rough Co-Cr heads, the MEP liners showed little advantage in terms of volumetric wear compared with the control. However, the MEP liners overall showed a 38% reduction in FBA compared to the control owing to a larger volume fraction of larger particles. Thus overall the MEP liners appeared to offer advantages in terms of reduced FBA indices.

Incidence and risk factors for newly acquired hepatitis C virus infection among Aboriginal versus non-Aboriginal Canadians in six regions, 1999-2004.

The purpose of this study was to compare hepatitis C virus (HCV) incidence and recent patterns of transmission within Aboriginal and non-Aboriginal Canadians. Cases of newly acquired HCV infection (in patients > or =15 years) reported to the Enhanced Hepatitis Strain Surveillance System from six jurisdictions in Canada were analyzed. Information on demographic and clinical characteristics as well as risk factors for HCV infection was collected using standardized questionnaires. Univariate analysis showed Aboriginal patients to be significantly more likely than non-Aboriginal patients to report injection drug use (77.1% vs. 64.0%; p < 0.05), to be female (54.6% vs. 37.6%; p < 0.05), to report high-risk sexual behaviors (48.6% vs. 34.1%, p < 0.05), and to report drug snorting (45.7% vs. 32.7%, p < 0.05). The median age of Aboriginal patients was significantly younger than that of non-Aboriginal patients (31 years [range, 15-71] vs. 34 years [range, 15-81]; p < 0.05). The overall incidence of HCV infection per 100,000 people aged 15 years and older was 18.9 (95% confidence interval [CI] 15.5-23.1) in Aboriginal people and 2.8 (95%CI 2.6-3.1) in non-Aboriginal people. Poisson regression analysis revealed that Aboriginal Canadians were more likely than non-Aboriginal Canadians to develop acute hepatitis C (adjusted rate ratio 5.8, 95%CI 4.7-7.3). An appropriate and effective public health strategy that includes planned and implemented prevention programs in partnership with the Aboriginal community is needed.

Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration.

BACKGROUND: Several studies indicate that age-related macular degeneration (AMD) and atherosclerosis may share common pathogenetic pathways. The aim of this study was to determine the role of systemic matrix metalloproteinases (MMPs) in AMD, given that MMPs are implicated in the pathogenesis of atherosclerosis. METHODS: This study determined the plasma matrix metalloproteinases (MMP-2 and MMP-9) levels in three groups of subjects: group 1 included subjects with age-related maculopathy (ARM), group 2 included subjects with choroidal neovascularization (CNV) owing to AMD and group 3 consisted of age-matched controls. RESULTS: The mean plasma levels of MMP-2 were not significantly different in the three groups. In contrast, the mean plasma MMP-9 levels were significantly higher in ARM and CNV groups compared to that of the control group. However, there was no significant difference in MMP-9 levels between ARM and CNV groups. CONCLUSION: This is the first study that reveals a link between raised plasma MMP-9 levels with AMD. Further studies are required to identify the factors that contribute to this association.

Precision and accuracy in ceramic-on-ceramic wear analyses: influence of simulator test duration.

In this, the first report of precision and accuracy in simulator studies, ceramic-ceramic implants with ultra-low wear trends represented a relevant wear model. The effect of test durations was examined in a standard simulator test mode on the quality of the linear regression trends, the average wear estimates, and the amount of noise in the data. Three sets of diametral tolerances were compared in 28 mm diameter alumina implants. The authors' hypothesis was that wear data would be significantly improved with increased test durations. The average wear rates varied little with test duration, the biggest change amounting to only 30 and 15 per cent decreases in the wear estimate by 10 and 14 million cycles respectively. The most satisfactory improvement in the study was the decrease in variance (noise) with increasing duration, +/- 200 per cent at 5 million cycles reduced to +/- 55 per cent at 14 million cycles. The quality of the linear regression coefficients improved 150 per cent by 10 million cycles and 250 per cent by 14 million cycles. Overall the ceramic implants with highest diametral tolerances showed the least wear (15 per cent less, but not statistically significant). However, given such low wear rates for alumina liners, it was unlikely that any differences owing to diametral tolerances would be clinically significant in the typical patient.

Morselized bone grafting of defects in revision total knee arthroplasty.

In a prospective, multicenter study evaluating one revision knee system, 33 of 409 patients underwent morselized bone grafting for tibial and femoral defects. Fifty-four percent of defects were bicondylar and the defect volumes averaged 36 cc3. There was no difference in preoperative or postoperative knee scores between patients undergoing morselized grafting and the entire group. Radiographic evaluation showed remodeling of the grafted areas consistent with viable incorporation of the graft. The incidence of radiolucent lines, at 2 years followup, was not different between the patients who received grafting and the patients who did not receive grafting. There have been no clinical failures or reoperations in the patients who received morselized bone grafting. Morselized bone grafting seems to offer a viable alternative in the reconstruction of osseous defects in patients undergoing revision total knee arthroplasty.

Left internal mammary artery graft retransplantation from the recipient to the donor heart: a case report.

A case of heart transplantation with concomitant coronary artery bypass graft is reported. The patient was an alternate transplant list candidate with a history of bilateral below-knee amputation and 2 previous myocardial revascularization procedures. The previously used and patent left internal mammary artery graft was successfully removed and retransplanted from the recipient to the donor heart.

Tissue-specific regulation of vein/EGF receptor signaling in Drosophila.

Signaling by the Drosophila EGF receptor (DER) is modulated by four known EGF-like proteins: the agonists Vein (Vn), Spitz (Spi), and Gurken (Grk) and the antagonist Argos (Aos). DER is broadly expressed and thus tissue-specific regulation of ligand expression and activity is an important mechanism for controlling signaling. Here we investigate the tissue-specific regulation of Vn signaling by examining vn transcriptional control and Vn target gene activation in the embryo and the wing. The results show a complex temporal and spatial regulation of vn transcription involving multiple signaling pathways and tissue-specific activation of Vn target genes. In the embryo, vn is a target of Spi/DER signaling mediated by the ETS transcription factor PointedP1 (PntP1). This establishes a positive feedback loop in addition to the negative feedback loop involving Aos. The simultaneous production of Vn provides a mechanism for dampening Aos inhibition and thus fine-tunes signaling. In the larval wing pouch, vn is not a target of Spi/DER signaling but is expressed along the anterior-posterior boundary in response to Hedgehog (Hh) signaling. Repression by Wingless (Wg) signaling further refines the vn expression pattern by causing a discontinuity at the dorsal-ventral boundary. The potential for vn to activate DER target genes correlates with its roles in development: vn has a minor role in embryogenesis and does not induce DER target genes such as aos and pntP1 in the embryo. Conversely, vn has a major role in wing development and Vn/DER signaling is a potent inducer of DER target genes in the wing disc. Spi also has the potential to induce DER target genes in the wing disc. However, the ligands appear to evoke specific responses that result in different patterns of target gene expression. Finally, we show that other factors modulate the potential of Vn so that induction of Vn/DER target genes in the wing pouch is cell specific.

Femoral neck fracture fixation: a biomechanical study of two cannulated screw placement techniques.

This biomechanical study evaluated two different methods of femoral neck fracture fixation. Ten pairs of embalmed femora were used. A standardized midcervical osteotomy was performed. One side from each pair was fixed with either conventional (central) or calcar (cortical adjacent) screw placement. The femora pairs then were subjected to cyclic and load to failure biomechanical testing. The results demonstrated significant improved stability, load, stiffness, and displacement in all tested parameters for the group with calcar screw fixation. Grossly, the conventional fixation group tended to fail in an excessively varus position, while the calcar fixation group failed with impaction of the head on the calcar, a potentially stable position.

EGF domain swap converts a drosophila EGF receptor activator into an inhibitor.

In Drosophila the function of the epidermal growth factor (EGF) receptor is modulated zygotically by three EGF-like proteins: Spitz (Spi), which is a potent activator; Vein (Vn), which is a moderate activator; and Argos (Aos), which is an inhibitor. Chimeric molecules were constructed in which the EGF domain of Vn was swapped with the EGF domain from each factor. The modified Vn proteins behaved both in vitro and in vivo with properties characteristic of the factor from which the EGF domain was derived. These results demonstrate that the EGF domain is the key determinant that gives DER inhibitors and activators their distinct properties.

Vein is a novel component in the Drosophila epidermal growth factor receptor pathway with similarity to the neuregulins.

The activation signal from tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), is relayed via a highly conserved intracellular pathway involving Ras, Raf, and MAPK. In Drosophila, the EGFR and components of the intracellular pathway are broadly expressed, yet receptor activation evokes tissue-specific cell responses. Extracellular events that lead to receptor activation are one mechanism by which signaling is modulated. Here we show molecular and genetic evidence that Drosophila vein (vn) encodes a candidate EGFR ligand and that vn expression is spatially restricted. Consequently, vn may promote tissue-specific receptor activation. Unlike two other ligands, Gurken (Grk) and Spitz (Spi), which are transforming growth factor alpha-like proteins, Vn has both an immunoglobulin-like and an EGF-like domain. This combination of domains mirrors those in the vertebrate neuregulins that bind EGFR relatives.