Limitations in odour simulation may originate from differential sensory embodiment

Across diverse lineages, animals communicate using chemosignals, but only humans communicate about chemical signals. Many studies have observed that compared with other sensory modalities, communication about smells is relatively rare and not always reliable. Recent cross-cultural studies, on the other hand, suggest some communities are more olfactorily oriented than previously supposed. Nevertheless, across the globe a general trend emerges where olfactory communication is relatively hard. We suggest here that this is in part because olfactory representations are different in kind: they have a low degree of embodiment, and are not easily expressed as primitives, thereby limiting the mental manipulations that can be performed with them. New exploratory data from Dutch children (9-12 year-olds) and adults support that mental imagery from olfaction is weak in comparison with vision and audition, and critically this is not affected by language development. Specifically, while visual and auditory imagery becomes more vivid with age, olfactory imagery shows no such development. This is consistent with the idea that olfactory representations are different in kind from representations from the other senses. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'

Enoximone echocardiography: a novel test to evaluate left ventricular contractile reserve in patients with heart failure on chronic beta-blocker therapy

BACKGROUND: It has been suggested that an extensive contractile reserve identified recognised by means of dobutamine stress echocardiography may predict a better prognosis in patients with severe left ventricular dysfunction at rest. However, the clinical use of dobutamine stress echocardiography may be limited in patients with chronic heart failure by the substantial proportion of such patients treated with beta-blockers, since the inotropic response to adrenergic stimulation is known to be attenuated in patients receiving beta-adrenoceptor blockers. Enoximone is a positive inotropic agent that inhibits cyclic adenosine monophosphate-specific phosphosdiesterase. We therefore tested the hypothesis that enoximone may be an alternative to dobutamine in evaluating left ventricular contractile reserve in patients with systolic dysfunction on chronic beta-blocker therapy. METHODS: We studied 26 patients (21 males and five females) with a mean age of 58 ± 10 years: 11 were not receiving beta-blockers (noBB group); 15 were receiving carvedilol at a mean dose of 34 mg/day (BB group). Dobutamine was infused at doses of 5 and 10 micrograms/kg/min, and enoximone at a dose of 1.5 mg/kg. RESULTS: The ejection fraction in the noBB group increased by 9% with dobutamine and 8.73% with enoximone (p = 0.86); in the BB group, it increased by 6% with dobutamine and 8.94% with enoximone (p = 0.03). Regional peak systolic velocities were evaluated by means of tissue Doppler imaging in four basal and four medium level segments. In the noBB group, they increased more with dobutamine than with enoximone in three of the eight segments; no significant differences were found in the BB group. Dobutamine induced non-sustained ventricular tachycardia in three patients and supraventricular tachycardia in one, whereas enoximone did not induce any repetitive arrhythmias. CONCLUSIONS: Enoximone might be preferable to low-dose dobutamine for evaluating left ventricular contractile reserve in chronically beta-blocked heart failure patients as it is slightly more potent and has a better safety profile

Synthesis of Bio-Compatible SPION–based Aqueous Ferrofluids and Evaluation of RadioFrequency Power Loss for Magnetic Hyperthermia

Bio-compatible magnetic fluids having high saturation magnetization find immense applications in various biomedical fields. Aqueous ferrofluids of superparamagnetic iron oxide nanoparticles with narrow size distribution, high shelf life and good stability is realized by controlled chemical co-precipitation process. The crystal structure is verified by X-ray diffraction technique. Particle sizes are evaluated by employing Transmission electron microscopy. Room temperature and low-temperature magnetic measurements were carried out with Superconducting Quantum Interference Device. The fluid exhibits good magnetic response even at very high dilution (6.28 mg/cc). This is an advantage for biomedical applications, since only a small amount of iron is to be metabolised by body organs. Magnetic field induced transmission measurements carried out at photon energy of diode laser (670 nm) exhibited excellent linear dichroism. Based on the structural and magnetic measurements, the power loss for the magnetic nanoparticles under study is evaluated over a range of radiofrequencies

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma

Adoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence.We conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 10(10)/m(2); the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m(2)/dayx5 days). This design permits intra-patient comparison of in vivo T cell persistence pre- and post-fludarabine. Nineteen CTL infusions were administered to ten patients. No serious toxicities were observed. Three of nine evaluable patients experienced minor response or stable disease for periods of 5.8-11.0 months with two additional patients demonstrating delayed disease stabilization. The median overall survival in this heavily pre-treated population was 9.7 months. Fludarabine led to a 2.9 fold improvement in the in vivo persistence of transferred CTL clones from a median of 4.5 days (range 0-38+) to 13.0 days (range 2-63+) (p<0.05). Fludarabine lymphodepletion increased plasma levels of the homeostatic cytokines IL-7 and IL-15. Surprisingly, fludarabine also increased the relative percentage of CD4+ T cells expressing the regulatory protein Foxp3.Lymphodepletion with fludarabine enhances transferred T cell persistence but suggest that additional improvements to optimize T cell survival and address regulatory T cells are critical in providing anti-tumor efficacy.ClinicalTrials.gov NCT00317759

Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t1/2 ∼1 h), or a slow, zero-order release rate (t1/2 ∼ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies

The impact of HIV/SRH service integration on workload: analysis from the Integra Initiative in two African settings.

BACKGROUND: There is growing interest in integration of HIV and sexual and reproductive health (SRH) services as a way to improve the efficiency of human resources (HR) for health in low- and middle-income countries. Although this is supported by a wealth of evidence on the acceptability and clinical effectiveness of service integration, there is little evidence on whether staff in general health services can easily absorb HIV services. METHODS: We conducted a descriptive analysis of HR integration through task shifting/sharing and staff workload in the context of the Integra Initiative - a large-scale five-year evaluation of HIV/SRH integration. We describe the level, characteristics and changes in HR integration in the context of wider efforts to integrate HIV/SRH, and explore the impact of HR integration on staff workload. RESULTS: Improvements in the range of services provided by staff (HR integration) were more likely to be achieved in facilities which also improved other elements of integration. While there was no overall relationship between integration and workload at the facility level, HIV/SRH integration may be most influential on staff workload for provider-initiated HIV testing and counselling (PITC) and postnatal care (PNC) services, particularly where HIV care and treatment services are being supported with extra SRH/HIV staffing. Our findings therefore suggest that there may be potential for further efficiency gains through integration, but overall the pace of improvement is slow. CONCLUSIONS: This descriptive analysis explores the effect of HIV/SRH integration on staff workload through economies of scale and scope in high- and medium-HIV prevalence settings. We find some evidence to suggest that there is potential to improve productivity through integration, but, at the same time, significant challenges are being faced, with the pace of productivity gain slow. We recommend that efforts to implement integration are assessed in the broader context of HR planning to ensure that neither staff nor patients are negatively impacted by integration policy

Management of breakthrough disease in patients with multiple sclerosis: when an increasing of Interferon beta dose should be effective?

<p>Abstract</p> <p>Background</p> <p>In daily clinical setting, some patients affected by relapsing-remitting Multiple Sclerosis (RRMS) are switched from the low-dose to the high-dose Interferon beta (IFNB) in order to achieve a better control of the disease.</p> <p>Purpose</p> <p>In this observational, post-marketing study we reported the 2-year clinical outcomes of patients switched to the high-dose IFNB; we also evaluated whether different criteria adopted to switch patients had an influence on the clinical outcomes.</p> <p>Methods</p> <p>Patients affected by RRMS and switched from the low-dose to the high-dose IFNB due to the occurrence of relapses, or contrast-enhancing lesions (CELs) as detected by yearly scheduled MRI scans, were followed for two years. Expanded Disability Status Scale (EDSS) scores, as well as clinical relapses, were evaluated during the follow-up period.</p> <p>Results</p> <p>We identified 121 patients switched to the high-dose IFNB. One hundred patients increased the IFNB dose because of the occurrence of one or more relapses, and 21 because of the presence of one or more CELs, even in absence of clinical relapses. At the end of the 2-year follow-up, 72 (59.5%) patients had a relapse, and 51 (42.1%) reached a sustained progression on EDSS score. Overall, 85 (70.3%) patients showed some clinical disease activity (i.e. relapses or disability progression) after the switch.</p> <p>Relapse risk after increasing the IFNB dose was greater in patients who switched because of relapses than those switched only for MRI activity (HR: 5.55, p = 0.001). A high EDSS score (HR: 1.77, p < 0.001) and the combination of clinical and MRI activity at switch raised the risk of sustained disability progression after increasing the IFNB dose (HR: 2.14, p = 0.01).</p> <p>Conclusion</p> <p>In the majority of MS patients, switching from the low-dose to the high-dose IFNB did not reduce the risk of further relapses or increased disability in the 2-year follow period.</p> <p>Although we observed that patients who switched only on the basis on MRI activity (even in absence of clinical attacks) had a lower risk of further relapses, larger studies are warranted before to recommend a switch algorithm based on MRI findings.</p

Immunospecific Responses to Bacterial Elongation Factor Tu during Burkholderia Infection and Immunization

Burkholderia pseudomallei is the etiological agent of melioidosis, a disease endemic in parts of Southeast Asia and Northern Australia. Currently there is no licensed vaccine against infection with this biological threat agent. In this study, we employed an immunoproteomic approach and identified bacterial Elongation factor-Tu (EF-Tu) as a potential vaccine antigen. EF-Tu is membrane-associated, secreted in outer membrane vesicles (OMVs), and immunogenic during Burkholderia infection in the murine model of melioidosis. Active immunization with EF-Tu induced antigen-specific antibody and cell-mediated immune responses in mice. Mucosal immunization with EF-Tu also reduced lung bacterial loads in mice challenged with aerosolized B. thailandensis. Our data support the utility of EF-Tu as a novel vaccine immunogen against bacterial infection