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Summary: We describe therapeutic monoclonal antibodies isolated from human volunteers vaccinated with recombinant adenovirus expressing Ebola virus glycoprotein (EBOV GP) and boosted with modified vaccinia virus Ankara. Among 82 antibodies isolated from peripheral blood B cells, almost half neutralized GP pseudotyped influenza virus. The antibody response was diverse in gene usage and epitope recognition. Although close to germline in sequence, neutralizing antibodies with binding affinities in the nano- to pico-molar range, similar to “affinity matured” antibodies from convalescent donors, were found. They recognized the mucin-like domain, glycan cap, receptor binding region, and the base of the glycoprotein. A cross-reactive cocktail of four antibodies, targeting the latter three non-overlapping epitopes, given on day 3 of EBOV infection, completely protected guinea pigs. This study highlights the value of experimental vaccine trials as a rich source of therapeutic human monoclonal antibodies. : Most antibodies used for Ebola virus treatment originate from convalescent donors or highly immunized animals. Rijal et al. find that monoclonal antibodies isolated early after vaccination from humans can be powerfully therapeutic, despite the relative immaturity of their sequences. Vaccine trials therefore can provide a valuable source of therapeutic antibodies. Keywords: Ebola virus, human monoclonal antibodies, immunotherapy, therapeutic antibodies, guinea pig model, Ebola virus glycoprotein epitopes, E-S-FLU virus, antibody binding kinetics, affinity maturation

In Alzheimer’s disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence suggest that Tau aggregates or “seeds” may propagate pathology by spreading from cell to cell in a “prion like” manner. Accordingly, blocking the spread of extracellular seeds with an antibody could be a viable therapeutic approach. However, as the structure of Tau seeds is unknown, it is only possible to rationally design therapeutic Tau antibodies by making a priori assumptions. To avoid this, we developed a robust and quantitative cell based assay and employed an unbiased screening approach to identify the antibody with the highest activity against human Tau seeds. The selected antibody (D), directed to the mid-region of Tau (amino acids 235–250), potently blocked the seeding of human AD Tau and was also fully efficacious against seeds from progressive supranuclear palsy. When we compared this antibody with previously described reference antibodies, we were surprised to find that none of these antibodies showed comparable efficacy against human pathological seeds. Our data highlight the difficulty of predicting antibody accessible epitopes on pathological Tau seeds and question the potential efficacy of some of the Tau antibodies that are currently in clinical development. Electronic supplementary material The online version of this article (10.1007/s00401-018-1911-2) contains supplementary material, which is available to authorized users.

The number of adults diagnosed with brain tumors is increasing, as are the survival rates. Neurological impairments from brain tumors can impact activity and participation. Adults with brain tumors benefit from post-acute rehabilitation. However, there is limited evidence from the acute care setting. The purpose of this study was to examine how acute care occupational therapy services were utilized and whether patients made functional gains after receiving occupational therapy services. A retrospective chart review of 153 electronic medical records was completed for patients who received occupational therapy services at a large teaching hospital. Data collected included number of occupational therapy visits, the types of interventions, and patient performance using the Boston University Activity Measure for Post-Acute Care "6 Clicks for Daily Activity" short form (AM-PAC). More than half the patients received one occupational therapy visit (54.2%) with a median length of stay of three days. Most interventions focused on activities of daily living (ADLs). Of those patients who received more than one visit, 67% showed improvements in their AM-PAC scores. Occupational therapy practitioners provided interventions that addressed ADLs, and patients demonstrated gains in functional performance. These findings suggest that patients benefit from occupational therapy services provided in the acute care setting.

Background Oculomotor dysfunction affects a significant number of adults with neurological conditions and binocular diplopia is a common symptom which impacts an individual's ability to participate in meaningful daily activities. Occupational therapists use partial and complete occlusion to minimize binocular diplopia, however a review of the literature reflected a lack of standardized protocol for each intervention technique. The purpose of this study was to examine occupational therapists' perspectives on the use of partial and complete occlusion and the clinical reasoning process used. Methods An electronic survey was distributed to occupational therapists working in a variety of practice settings. The survey contained questions relating to demographics, the selected occlusion technique, and clinical reasoning for that selection. Results More than half of the 106 respondents used partial occlusion more frequently than complete occlusion. There was no correlation between respondent experience and self-report of competence in managing binocular diplopia. Respondents based their clinical reasoning on available evidence, client factors, and clinical expertise. Conclusion Respondents offered conflicting perspectives on each occlusion technique. Future studies are required to examine which occlusion technique benefits clients.

Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met.

Research examining the impact of physical activity on body image dissatisfaction and physical self-perceptions has been both limited and equivocal. The current research investigated the effects of 6-week aerobic dance on these variables with 50 British schoolgirls aged 13-14 years. A cross-over design was used with two equivalent groups taught normal physical education and aerobic dance in a different order. The Body Attitude Questionnaire (BAQ) and Children and Youth Physical Self-Perception Profile (CY-PSPP) were administered as pre, mid and post-test to each participant in each group before the first intervention, at the change over and after 12 weeks. The results of this study revealed that participation in 6 weeks of aerobic dance significantly reduced body image dissatisfaction (Attractiveness, Feeling Fat, Salience and Strength and Fitness) and enhanced physical self-perceptions (Body Attractiveness and Physical Self-Worth), although these improvements were not sustained. The implications and future research directions are discussed.

Fertilization is well correlated with sperm concentration, rate of forward motility, and percentage of live, uncapacitated ejaculated spermatozoa, which is regulated in part by cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to their corresponding monophosphates, thereby counterbalancing the activities of cAMP and cGMP, and PDE11 is highly expressed in the testis, prostate, and developing spermatozoa. However, a physiological role of PDE11 is not known. We generated PDE11 knockout (PDE11-/-) mice to investigate the role of PDE11 in spermatozoa physiology. Ejaculated sperm from PDE11-/- mice displayed reduced sperm concentration, rate of forward progression, and percentage of live spermatozoa. Pre-ejaculated sperm from PDE11-/- mice displayed increased premature/spontaneous capacitance. These data are consistent with human data and suggest a role for PDE11 in spermatogenesis and fertilization potential. This is the first phenotype described for the PDE11-/- mouse and the first report of a physiological role for PDE11.

Objectives: Sildenafil is a widely-prescribed effective on-demand treatment of erectile dysfunction (ED). Chronic treatment with sildenafil could help patients with ED. Methods: The effects of an 8-week long treatment with sildenafil (60mg/kg/d sc ) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection of sildenafil (0.3mg/kg iv ). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36hours after the last injection of sildenafil. Results: Endothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment with sildenafil while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acute sildenafil were greater in chronically-treated rats with sildenafil. Conclusions: This is the first report providing experimental support for chronic dosing with sildenafil which could be of use for patients that are poor responders to on-demand treatment. Chronic sildenafil may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis.

The capsaicin-, heat-, and proton-activated ion channel TRPV1, a member of the transient receptor potential cation channel family is a polymodal nociceptor. For almost a decade, TRPV1 has been explored by the pharmaceutical industry as a potential target for example for pain conditions. Antagonists which block TRPV1 activation by capsaicin, heat, and protons were developed by a number of pharmaceutical companies. The unexpected finding of hyperthermia as an on-target side effect in clinical studies using polymodal TRPV1 antagonists has prompted companies to search for ways to circumvent hyperthermia, for example by the development of modality-selective antagonists. The significant lack of consistency of the pharmacology of many TRPV1 antagonists across different species has been a further obstacle. JYL-1421 for example was shown to block capsaicin and heat responses in human and monkey TRPV1 while it was largely ineffective in blocking heat responses in rat TRPV1. These findings suggested structural dissimilarities between different TRPV1 species relevant for small compound antagonism for example of heat activation. Using a chimeric approach (human and rat TRPV1) in combination with a novel FLIPR-based heat activation assay and patch-clamp electrophysiology we have identified the pore region as being strongly linked to the observed species differences. We demonstrate that by exchanging the pore domains JYL-1421, which is modality-selective in rat can be made modality-selective in human TRPV1 and vice-versa.

We describe the properties of a novel nonpeptide kinin B1 receptor antagonist, NVP-SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B1 receptor. NVP-SAA164 showed high affinity for the human B1 receptor expressed in HEK293 cells (K(i) 8 nM), and inhibited increases in intracellular calcium induced by desArg10kallidin (desArg10KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (K(i) 7.7 nM), NVP-SAA164 showed no affinity for the rat B1 receptor expressed in Cos-7 cells. In transgenic mice in which the native B1 receptor was deleted and the gene encoding the human B1 receptor was inserted (hB1 knockin, hB1-KI), hB1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B1 receptor was detected in mouse B1 receptor knockout (mB1-KO) mice following LPS treatment. Freund's complete adjuvant-induced mechanical hyperalgesia was similar in wild-type and hB(1)-KI mice, but was significantly reduced in mB1-KO animals. Mechanical hyperalgesia induced by injection of the B1 agonist desArg10KD into the contralateral paw 24 h following FCA injection was similar in wild-type and hB1-KI mice, but was absent in mB1-KO animals. Oral administration of NVP-SAA164 produced a dose-related reversal of FCA-induced mechanical hyperalgesia and desArg10KD-induced hyperalgesia in hB1-KI mice, but was inactive against inflammatory pain in wild-type mice. These data demonstrate the use of transgenic technology to investigate the in vivo efficacy of species selective agents and show that NVP-SAA164 is a novel orally active B1 receptor antagonist, providing further support for the utility of B1 receptor antagonists in inflammatory pain conditions in man.

We derive a theoretical model of how jumbo and conforming mortgage rates are determined and how the jumbo–conforming spread might arise. We show that mortgage rates reflect the cost of funding mortgages and that this cost of funding can drive a wedge between jumbo and conforming rates. Further, we show how the jumbo–conforming spread widens when mortgage demand is high or core deposits are not sufficient to fund mortgage demand, and tightens as the mortgage market becomes more liquid and realizes economies of scale. Using Mortgage Interest Rate Survey data for April 1997 through May 2003, we estimate that the government-sponsored enterprise funding advantage accounts for about 7 basis points of the 15–18 basis point jumbo–conforming spread.

Parents of 116 first‐year pupils at an urban comprehensive school were studied by questionnaire and interview. They were asked about their educational and occupational aspirations for their children, their views on sexual equality and their children's out‐of‐school activities. Educational aspirations were found to be high, with little differentiation between the sexes. Parents were enthusiastic about their daughters studying physical science and neutral about craft subjects. Occupational aspirations were also high and although they tended to be sex‐stereotyped, parents were found to be generally supportive of non‐traditional choices. Class differences were few. Most parents were in favour of working mothers, equal pay and men helping with housework. However these egalitarian attitudes coexisted with more traditional assumptions about male breadwinners and a woman's main responsibility being to her children. Parents’ own domestic labour and that which they required of their children was strongly s...