Pilot Data: Are Vertical and Lateral Hop Tests Appropriate for Patients Post-Ankle Fracture?

Ankle fractures effect 5 out of 10,000 individuals (van Staa, 2001). A recent study shows rapid functional gains over the first 6 months after an ankle fracture, but there are little or no gains 18-24 months into the recovery cycle (Beckenkamp, 2014). Similarly, other studies have shown that ankle fracture patients are categorized as having good recovery outcomes on popular measures such as the modified Olerud Molander scale (Egol, 2006), yet are unable to return to previous level of sport (Hong, 2013), indicating there may be persisting higher level performance deficits. This brings up the issue of whether there are performance based tests that would be appropriate for ankle fracture patients to determine return to sport or higher level activity without risk of injury. The purpose of this project is to determine the biomechanical load and side to side comparisons of vertical and lateral hopping tests that may be used in ankle fracture patients

Identification and in vivo characterization of a brain-penetrating nanobody

BACKGROUND: Preclinical models to determine blood to brain transport ability of therapeutics are often ambiguous. In this study a method is developed that relies on CNS target-engagement and is able to rank brain-penetrating capacities. This method led to the discovery of an anti-transferrin receptor nanobody that is able to deliver a biologically active peptide to the brain via receptor-mediated transcytosis. METHODS: Various nanobodies against the mouse transferrin receptor were fused to neurotensin and injected peripherally in mice. Neurotensin is a neuropeptide that causes hypothermia when present in the brain but is unable to reach the brain from the periphery. Continuous body temperature measurements were used as a readout for brain penetration of nanobody-neurotensin fusions after its peripheral administration. Full temperature curves were analyzed using two-way ANOVA with Dunnett multiple comparisons tests. RESULTS: One anti-transferrin receptor nanobody coupled to neurotensin elicited a drop in body temperature following intravenous injection. Epitope binning indicated that this nanobody bound a distinct transferrin receptor epitope compared to the non-crossing nanobodies. This brain-penetrating nanobody was used to characterize the in vivo hypothermia model. The hypothermic effect caused by neurotensin is dose-dependent and could be used to directly compare peripheral administration routes and various nanobodies in terms of brain exposure. CONCLUSION: This method led to the discovery of an anti-transferrin receptor nanobody that can reach the brain via receptor-mediated transcytosis after peripheral administration. This method could be used to assess novel proteins for brain-penetrating capabilities using a target-engaging readout

Effect of bilayer coupling on tunneling conductance of double-layer high T_c cuprates

Physical effects of bilayer coupling on the tunneling spectroscopy of high T$_{c}$ cuprates are investigated. The bilayer coupling separates the bonding and antibonding bands and leads to a splitting of the coherence peaks in the tunneling differential conductance. However, the coherence peak of the bonding band is strongly suppressed and broadened by the particle-hole asymmetry in the density of states and finite quasiparticle life-time, and is difficult to resolve by experiments. This gives a qualitative account why the bilayer splitting of the coherence peaks was not clearly observed in tunneling measurements of double-layer high-T$_c$ oxides.Comment: 4 pages, 3 figures, to be published in PR

Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics

The blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases. Unfortunately, most of the biologicals do not reach their brain targets in sufficient quantities. The antibody targeting of receptor-mediated transcytosis (RMT) receptors is an exploited mechanism that increases brain permeability. We previously discovered an anti-human transferrin receptor (TfR) nanobody that could efficiently deliver a therapeutic moiety across the BBB. Despite the high homology between human and cynomolgus TfR, the nanobody was unable to bind the non-human primate receptor. Here we report the discovery of two nanobodies that were able to bind human and cynomolgus TfR, making these nanobodies more clinically relevant. Whereas nanobody BBB00515 bound cynomolgus TfR with 18 times more affinity than it did human TfR, nanobody BBB00533 bound human and cynomolgus TfR with similar affinities. When fused with an anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) antibody (1A11AM), each of the nanobodies was able to increase its brain permeability after peripheral injection. A 40% reduction of brain Aβ1–40 levels could be observed in mice injected with anti-TfR/BACE1 bispecific antibodies when compared to vehicle-injected mice. In summary, we found two nanobodies that could bind both human and cynomolgus TfR with the potential to be used clinically to increase the brain permeability of therapeutic biologicals

Do good health and material circumstances protect older people from the increased risk of death after bereavement?

This is an open access Article. Copyright @ 2012 The AuthorsAn increased risk of death in persons who have suffered spousal bereavement has been described in many populations. The impact of modifying factors, such as chronic disease and material circumstances, is less well understood. The authors followed 171,120 couples 60 years of age or older in a United Kingdom primary care database between 2005 and 2010 for an average of 4 years. A total of 26,646 (15.5%) couples experienced bereavement, with mean follow up after bereavement of 2 years. In a model adjusted for age, sex, comorbid conditions at baseline, material deprivation based on area of residence, season, and smoking status, the hazard ratio for mortality in the first year after bereavement was 1.25 (95% confidence interval: 1.18, 1.33). Further adjustment for changes in comorbid conditions throughout follow up did not alter the hazard ratio for bereavement (hazard ratio = 1.27, 95% confidence interval: 1.19, 1.35). The association was strongest in individuals with no significant chronic comorbid conditions throughout follow up (hazard ratio = 1.50, 95% confidence interval: 1.28, 1.77) and in more affluent couples (P = 0.035). In the first year after bereavement, the association between bereavement and death is not primarily mediated through worsening or new onset of chronic disease. Good health and material circumstances do not protect individuals from increased mortality rates after bereavement.This study was funded by a grant from the Dunhill Medical Trust

Implications of the problem orientated medical record (POMR) for research using electronic GP databases: a comparison of the Doctors Independent Network Database (DIN) and the General Practice Research Database (GPRD).

Background The General Practice Research Database (GPRD) and Doctor's Independent Network Database (DIN), are large electronic primary care databases compiled in the UK during the 1990s. They provide a valuable resource for epidemiological and health services research. GPRD (based on VAMP) presents notes as a series of discrete episodes, whereas DIN is based on a system (MEDITEL) that used a Problem Orientated Medical Record (POMR) which links prescriptions to diagnostic problems. We have examined the implications for research of these different underlying philosophies. Methods Records of 40,183 children from 141 practices in DIN and 76,310 from 464 practices in GRPD who were followed to age 5 were used to compare the volume of recording of prescribing and diagnostic codes in the two databases. To assess the importance and additional value of the POMR within DIN, the appropriateness of diagnostic linking to skin emollient prescriptions was investigated. Results Variation between practices for both the number of days on which prescriptions were issued and diagnoses were recorded was marked in both databases. Mean number of "prescription days" during the first 5 years of life was similar in DIN (19.5) and in GPRD (19.8), but the average number of "diagnostic days" was lower in DIN (15.8) than in GPRD (22.9). Adjustment for linkage increased the average "diagnostic days" to 23.1 in DIN. 32.7% of emollient prescriptions in GPRD appeared with an eczema diagnosis on the same day compared to only 19.4% in DIN; however, 86.4% of prescriptions in DIN were linked to an earlier eczema diagnosis. More specifically 83% of emollient prescriptions appeared under a problem heading of eczema in the 121 practices that were using problem headings satisfactorily. Conclusion Prescribing records in DIN and GPRD are very similar, but the usage of diagnostic codes is more parsimonious in DIN because of its POMR structure. Period prevalence rates will be underestimated in DIN unless this structure is taken into account. The advantage of the POMR is that in 121 of 141 practices using problem headings as intended, most prescriptions can be linked to a problem heading providing a specific reason for their issue

Predominantly Superconducting Origin of Large Energy Gaps in Underdoped Bi2Sr2CaCu2O8-d from Tunneling Spectroscopy

New tunneling data are reported in underdoped Bi2Sr2CaCu2O8-d using superconductor-insulator-superconductor break junctions. Energy gaps, Delta, of 51+2, 54+2 and 57+3 meV are observed for three crystals with Tc=77, 74, and 70 K respectively. These energy gaps are nearly three times larger than for overdoped crystals with similar Tc. Detailed examination of tunneling spectra over a wide doping range from underdoped to overdoped, including the Josephson IcRn product, indicate that these energy gaps are predominantly of superconducting origin.Comment: 10 pages, 4 figures, 1 tabl

Coupling of disulfide bond and distal histidine dissociation in human ferrous cytoglobin regulates ligand binding

Earlier kinetics studies on cytoglobin did not assign functional properties to specific structural forms. Here, we used defined monomeric and dimeric forms and cysteine mutants to show that an intramolecular disulfide bond (C38-C83) alters the dissociation rate constant of the intrinsic histidine (H81) (∼1000 fold), thus controlling binding of extrinsic ligands. Through time-resolved spectra we have unequivocally assigned CO binding to hexa- and penta-coordinate forms and have made direct measurement of histidine rebinding following photolysis. We present a model that describes how the cysteine redox state of the monomer controls histidine dissociation rate constants and hence extrinsic ligand binding