Orodispersible films based on blends of trehalose and pullulan for protein delivery.

During the last decades the number of therapeutic proteins increased tremendously on the pharmaceutical market. However, due to their often poor stability and limitations of the administration route, the application of therapeutic proteins is a major challenge. The oral mucosa has been suggested as a possible route for protein delivery. In this study, we prepared protein loaded orodispersible films (ODFs), based on blends of trehalose/pullulan by air- and freeze-drying. These two carbohydrates were selected based on the excellent protein stabilizing capacity of trehalose and film-forming ability of pullulan. ODFs were loaded with three model proteins. Ovalbumin was used to study the effect of protein incorporation on the mechanical properties, disintegration time, uniformity of weight and thickness of the ODFs. Lysozyme and ß-galactosidase were used to evaluate protein stability. Ovalbumin loading did not significantly influence the mechanical properties of freeze-dried ODFs, while incorporation of ovalbumin in air-dried ODFs led to a substantial reduction in tensile strength. The trehalose/pullulan ratio had no impact on the stability of lysozyme, while the stability of ß-galactosidase increased with increasing trehalose/pullulan ratios. Furthermore, freeze-drying appeared to be favorable over air-drying for process stability while the reverse was found for storage stability. In conclusion, trehalose/pullulan-based ODFs are from a technical point promising for possible protein delivery via the oral cavity.

[Home and recreational injuries in children under 1year: 10years of experience]. / Accidents de la vie courante chez les enfants âgés de moins d'un an : expérience sur 10 ans.

BACKGROUND: There is little research on the prevalence and characteristics of home and recreational injuries in infants under 12months of age. However, domestic accidents result in an average of 50 infant deaths in France every year. METHODS: A descriptive and retrospective study was conducted, based on data from the permanent investigation on home and recreational injuries in infants under 12months of age (EPAC) published by the Institute for Public Health. Data were collected from 2004 to 2013 in the pediatric emergency department of Le Havre hospital. A global quantitative analysis was carried out, as well as age-group-based analyses (groups of infants of similar age within a specific range of 3months of age). RESULTS: A total of 3708 infants under 1year of age were victims of home and recreational injuries. The incidence of domestic accidents was found to be an average of one case per day (gender ratio, 1.12). Up to 85% of reported injuries were found to occur in the home. Falls were the leading cause of home accidents or injuries (73% of the total number of reported accidents), 7% of which resulted from a fall from stairs. Children frequently suffered from concussion or contusions (65%). The neck and head were affected in 73% of cases. A higher proportion of foreign body injuries occurred after 6months of age (RR=2.9, p<0.001). The number of hospitalizations decreased with age: 21% of accidents occurred before 3 months of age; 7% occurred between 9 and 11 months of age (RR=0.32, p<0.001). Falling from a changing table accounted for 9% of fall-related hospitalizations. CONCLUSIONS: This survey characterized for the first time the occurrence of home and recreational injuries in infants under 12months of age in France.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.

BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.

A pilot iron substitution programme in female blood donors with iron deficiency without anaemia.

BACKGROUND AND OBJECTIVES: Blood donation can contribute to iron deficiency. The possibly resulting anaemia importantly affects donor return rate. The determination of serum ferritin levels revealed iron deficiency in many non-anaemic premenopausal female blood donors at our Institution. We started an iron substitution programme targeting this donor group to prevent anaemia and enhance donor retain. MATERIALS AND METHODS: Women aged≤50 with haemoglobin levels adequate for donation and serum ferritin≤10 ng/ml were offered iron supplementation. Substitution lasted 16 weeks and the donation interval was extended. History collection including iron deficiency-related symptoms, whole blood count and serum ferritin determination was performed at baseline and after 2 and 6 months. Data were recorded prospectively and compared with those of 108 female controls with iron deficiency not receiving iron substitution (retrospective data). RESULTS: Of the 116 participating subjects, 60% completed the programme. Significant results were serum ferritin increase (from a mean value of 7.12 to 25.2 ng/ml), resolution of prostration, fatigue, sleep disturbances, tension in the neck, hair loss and nail breakage. No case of anaemia occurred. Sixty per cent of the women completed the programme and donated blood again. CONCLUSIONS: Targeted iron substitution prevents the development of anaemia and enhances donation return in premenopausal female blood donors with iron deficiency.

Discrete breathers in one-dimensional diatomic granular crystals.

We report the experimental observation of modulational instability and discrete breathers in a one-dimensional diatomic granular crystal composed of compressed elastic beads that interact via Hertzian contact. We first characterize their effective linear spectrum both theoretically and experimentally. We then illustrate theoretically and numerically the modulational instability of the lower edge of the optical band. This leads to the dynamical formation of long-lived breather structures, whose families of solutions we compute throughout the linear spectral gap. Finally, we experimentally observe the manifestation of the modulational instability and the resulting generation of localized breathing modes with quantitative characteristics that agree with our numerical results.

Intrinsic energy localization through discrete gap breathers in one-dimensional diatomic granular crystals.

We present a systematic study of the existence and stability of discrete breathers that are spatially localized in the bulk of a one-dimensional chain of compressed elastic beads that interact via Hertzian contact. The chain is diatomic, consisting of a periodic arrangement of heavy and light spherical particles. We examine two families of discrete gap breathers: (1) an unstable discrete gap breather that is centered on a heavy particle and characterized by a symmetric spatial energy profile and (2) a potentially stable discrete gap breather that is centered on a light particle and is characterized by an asymmetric spatial energy profile. We investigate their existence, structure, and stability throughout the band gap of the linear spectrum and classify them into four regimes: a regime near the lower optical band edge of the linear spectrum, a moderately discrete regime, a strongly discrete regime that lies deep within the band gap of the linearized version of the system, and a regime near the upper acoustic band edge. We contrast discrete breathers in anharmonic Fermi-Pasta-Ulam (FPU)-type diatomic chains with those in diatomic granular crystals, which have a tensionless interaction potential between adjacent particles, and note that the asymmetric nature of the tensionless interaction potential can lead to hybrid bulk-surface localized solutions.

OPTN gene: profile of patients with glaucoma from India.

PURPOSE: Optineurin gene (OPTN) mutations are reported in primary open angle glaucoma patients (POAG) from different populations. The coding and noncoding regions of OPTN were screened for mutations in 100 Indian high tension glaucoma patients (HTG). The frequency of the OPTN M98K mutation in an additional 120 patients (70 HTG and 50 normal tension glaucoma [NTG]) was analyzed by restriction enzyme digestion. METHODS: The HTG patients (about 40 years of age) were characterized by open angles on gonioscopy, with raised intraocular pressure (IOP) more than 21 mmHg (<21 mmHg on office diurnal phasing for NTG), and typical glaucomatous disc changes with corresponding visual field defects in the absence of any secondary cause. One hundred HTG patients and controls were screened for OPTN mutations by direct sequencing using an ABI prism 310/3100 Avant genetic analyzer. The M98K status was analyzed by restriction enzyme digestion with StuI. A genotype/phenotype correlation was also attempted for OPTN sequence alterations with clinical parameters such as age at diagnosis, intraocular pressure, cup:disc ratio, etc. The putative change in the transcription factor binding site for the IVS7 +24G>A polymorphism was attempted with AliBaba software (version 2.1). RESULTS: Six sequence alterations were observed in the 100 POAG patients by direct sequencing. The M98K substitution was observed in a total of 10 patients (7/170 HTG and 3/50 NTG) contributing to 4.1% in HTG and 6% in the NTG group and not in the controls. The IVS7+24G>A nucleotide change showed a significant difference in the HTG group (7/100) when compared to the control group (0/100) and found to be associated with increased IOP at diagnosis (p=0.03). The IVS7+24G>A polymorphism resulted in the creation of binding sites for transcription factors NF-1 and CPE that were not present in the wild type. CONCLUSIONS: The current study suggests a possible role of SNPs rather than mutations in OPTN in POAG pathology in the Indian population.

Usefulness of the Rowland Universal Dementia Assessment scale in South India.

BACKGROUND: The number of older people with cognitive impairment being seen in out patient settings is increasing. A brief screening test, which is culturally and educationally fair, would be very useful for clinicians for identifying dementia in these settings. OBJECTIVES: To examine the new cognitive screening test, the Rowland Universal Dementia Assessment Scale (RUDAS), and to compare it with the Mini-Mental State Examination (MMSE). METHOD: We administered MMSE and RUDAS to 116 subjects, consisting of 58 patients with mild to moderate dementia and 58 age and sex matched controls. The two screening tests were compared with regard to sensitivity and specificity. We looked at the correlation of both tests with years of formal education among the controls. RESULT: RUDAS had a similar sensitivity but better specificity than MMSE, but did have an educational bias. CONCLUSIONS: RUDAS is a useful brief screening test in clinical settings.

Acoustic streaming in annular thermoacoustic prime-movers

The theory of acoustic streaming in an annular thermoacoustic prime-mover is developed. It is predicted that above the threshold for traveling wave excitation the device considered (which does not contain any moving parts or externally imposed pressure gradients) produces circulation of fluid. The heat flux carried by this directional mass flow inside the thermoacoustic stack exceeds (or is comparable with) the heat flux associated with the acoustically induced increase of thermal diffusivity of the gas. The effects investigated are important for optimization of the performance of thermoacoustic devices.