Purpose: The goal of this study was to improve the solubility and dissolution behavior of Raloxifene Hydrochloride (RH) using Spray Freeze Drying (SFD) technique. Methods: For achieving this goal, series of samples containing RH with polyvinylpyrrolidone (PVP) or hydroxypropyl beta cyclodextrin (HPβCD) used as solubility enhancers were prepared and microparticles were formed via SFD. The resultant microparticles were physicochemically characterized. Morphology of the microparticles were observed using Scanning Electron Microscopy (SEM). High Performance Liquid Chromatography (HPLC) was used for analyzing the solubility and dissolution profile of the samples. Results: Fourier Transmission Infrared (FTIR) spectra showed that SFD processed compositions did not affect chemical structure of RH. SEM and Thermal Gravimetric Analysis (TGA) revealed that the fabricated spherical and highly porous microparticles were in amorphous state. SFD processed powders showed superior solubility and dissolution behavior; where, 80% of the drug was dissolved within 5 minutes. Conclusion: SFD method can be a promising alternative for enhancing the solubility of poorly water soluble compounds.

With recent proliferation in compact and/or low-cost clinical multispectral imaging approaches and commercially available components, questions remain whether they adequately capture the requisite spectral content of their applications. We present a method to emulate the spectral range and resolution of a variety of multispectral imagers, based on in-vivo data acquired from spatial frequency domain spectroscopy (SFDS). This approach simulates spectral responses over 400 to 1100 nm. Comparing emulated data with full SFDS spectra of in-vivo tissue affords the opportunity to evaluate whether the sparse spectral content of these imagers can (1) account for all sources of optical contrast present (completeness) and (2) robustly separate and quantify sources of optical contrast (crosstalk). We validate the approach over a range of tissue-simulating phantoms, comparing the SFDS-based emulated spectra against measurements from an independently characterized multispectral imager. Emulated results match the imager across all phantoms (<3 % absorption, <1 % reduced scattering). In-vivo test cases (burn wounds and photoaging) illustrate how SFDS can be used to evaluate different multispectral imagers. This approach provides an in-vivo measurement method to evaluate the performance of multispectral imagers specific to their targeted clinical applications and can assist in the design and optimization of new spectral imaging devices.

In spray freeze drying (SFD) solutions are frozen by spraying into a very cold environment and subsequently dried by sublimation. In contrast to conventional freeze drying, spray freeze drying has the possibility to produce flowable lyophilizates which offers a variety of new pharmaceutical applications. Here, a drop jet nozzle is proposed as liquid dispenser that is able to produce droplets with a very narrow size distribution compared to standard methods. The drop jet nozzle is mounted in a spray tower designed to prevent direct contact of the product with the freezing medium. Various formulations have been tested containing lysozyme as model protein and stabilizers such as bovine serum albumin, polyvinylpyrrolidone or dextran in various concentrations and mannitol. Excellent free flowing and nearly monodispersed, porous particles are produced where particle properties can be controlled by formulation and process conditions. The particle diameter varied between 231 ± 3 μm and 310 ± 10 μm depending on the formulation composition. The lysozyme activity was >94 ± 5% for all formulations exhibiting a full preservation of enzyme activity. This new method is very promising for the production of nearly monodisperse particulate lyophilizates in various therapeutic applications.

Radiation leakage through electron applicators by 6-, 9-, 12-, 16-, and 20-MeV electron beams from Varian Clinac-1800 has been measured with films. High levels of leakage were found under the corners of applicators and the touch-plate mounting port holes. The radiation leakage, relative to the central-axis dose at dmax, was found to be up to 13% on the patient plane [100-cm source-to-film distance (SFD)] and up to 35% beneath the corners of applicators (96-cm SFD). Up to 18% radiation leakage was measured beneath the touch plate near the mounting port holes (96-cm SFD). The extent of radiation leakage in all electron beams was investigated and some simple shielding solutions to reduce the leakage are suggested.

BACKGROUND

There is increasing emphasis on the sagittal spino-pelvic alignment and its interpretation is of critical importance in the management of spinal disorders. A cross-sectional study of several spino-pelvic radiographic parameters was conducted to determine the physiological values of these parameters, to calculate the variations of these parameters according to epidemiological data, and to study the relationships among these parameters.

METHODS

Fifty normal healthy volunteers (29 males and 21 females) with no history of back pain were selected and were subjected to standing sagittal spino-pelvic radiographs. All the measurements of various radiographic parameters were performed with use of a software program. A statistical analysis was done to study the relationships among them.

RESULTS

The mean values of pelvic incidence (PI) and lumbar Lordosis Angle (LLA) were 48.52 ± 8.99 and 58.78 ± 9.51, respectively. There was statistical difference between male and female parameters in LLA, lumbo-sacral angle (LSA), sacral horizontal angle (SHA), sacral inclination angle (SIA), sacropelvic angle (PRS1), pelvisacral angle (PSA), and PI. A majority of parameters had higher values for female subjects when compared to male subjects. PI was positively correlated with LLA, pelvic angle (PA), pelvic overhang (PO), pelvic tilt (PT), sacrofemoral distance (SFD), SHA, and sacropelvic translation (SPT), which were highly significant, whereas LLA was positively correlated with SHA and SIA only. PI and LLA were both negatively correlated with PSA, pelvic thickness (PTH), and PRS1.

CONCLUSIONS

This study presents the various spino-pelvic radiographic parameter values of a sample of the normal asymptomatic Indian population. There was significant difference in radiographic parameters between males and females in about half of the parameters studied in the sample. The values obtained are comparable with the values presented as normal in the literature. A comparison of the study results with data published about other populations revealed no differences in any of the pelvic parameters between the Indian, Brazilian, and Korean populations.

Spray-freeze-drying (SFD) is a process in which a solution is dispersed into a freezing medium and dried by sublimation, resulting in lyophilized powders with spherical particles. This study aims at screening and evaluating the impact of the excipient choice and spray solution characteristics in SFD on the physico-chemical characteristics of lyospheres and rate their suitability for producing pulmonary applicable powders using a novel SFD method. A monodisperse droplet-stream was injected into a vortex of cold gas for the production of inhalable, uniform spherical lyophilisates with a narrow particle size distribution. Model solutions containing graded contents (0.3%, 1.0%, and 3.0% w/v) of common bulk-forming excipients like mannitol, lactose, poylvinylpyrrolidone (PVP), maltodextrin or hydroyxpropyl methylcellulose (HPMC) and their blends were dispersed using a single 20 μm pinhole diaphragm. Powders were analyzed regarding their geometric particle size, apparent density, mechanical stability and aerodynamic performance. The diameter of the frozen droplets partially correlated with the Ohnesorge number of the spray solutions. The lyosphere powders had median geometric particle diameters ranging from 20 µm to 81 µm. Some powders showed signs of particle shrinkage during the drying step and diameters were reduced down to 30% of their initial size. The apparent particle densities ranged from 0.009 g/cm³ to 0.087 g/cm³. The mechanical stability of the lyospheres depended on the constituents and concentration of the initial spray solution. Mannitol/maltodextrin formulations yielded large porous particles with promising performance in the Next-Generation-Impactor, emitted fractions between 92 and 98% (w/w) and fine-particle-fractions of over 55% (w/w). According to our first steps towards formulations for free-flowing inhalable spray freeze-dried powders the impact of excipient choice on the SFD process is significant and based on the current findings we consider mannitol or mannitol/maltodextrin as best performing formulations.

Keywords: Droplet collision; Droplet-stream generator; Lyophilization; Lyosphere; Porous particles; Protein formulations; Pulmonary drug delivery; Spray freeze drying.

This study aims to determine the impacts of drying method and excipient on changes in protein structure and physical stability of model protein solids. Protein solids containing one of two model proteins (lysozyme or myoglobin) were produced with or without excipients (sucrose or mannitol) using freeze drying or spray freeze drying (SFD). The protein powders were then characterized using solid-state Fourier transform infrared spectroscopy (ssFTIR), differential scanning calorimetry (DSC), circular dichroism spectrometry (CD), size exclusion chromatography (SEC), BET surface area measurements and solid-state hydrogen deuterium exchange with mass spectrometry (ssHDX-MS). ssFTIR and CD could identify little to no difference in structure of the proteins in the formulation. ssHDX-MS was able to identify the population heterogeneity, which was undetectable by conventional characterization techniques of ssFTIR and CD. ssHDX-MS metrics such as D_max and peak area showed a good correlation with the protein physical instability (loss of the monomeric peak area by size exclusion chromatography) in 90-day stability studies conducted at 40°C for lysozyme. Higher specific surface area was associated with greater loss in monomer content for myoglobin-mannitol formulations as compared to myoglobin-only formulations. Spray freeze drying seems a viable manufacturing technique for protein solids with appropriate optimization of formulations. The differences observed within the formulations and between the processes using ssHDX-MS, BET surface area measurements and SEC in this study provide an insight into the influence of drying methods and excipients on protein physical stability.

Keywords: Freeze drying; biopharmaceutical processing; protein structure; solid formulation; solid-state hydrogen/deuterium exchange with mass spectrometric analysis (ssHDX-MS); spray freeze drying.

BACKGROUND

Experience with the endovascular treatment of unruptured small intracranial aneurysms by flow diverter devices is still limited.

OBJECTIVE

To assess the safety and efficacy of the SILK flow diverter (SFD) in the treatment of small unruptured cerebral aneurysms (<10 mm).

METHODS

We performed a retrospective review of a prospectively maintained database of patients treated with a SFD between July 2008 and December 2013 at 4 institutions in Spain to identify all patients with small unruptured aneurysms (<10 mm). Data for patient demographics, aneurysm characteristics, and technical procedures were analyzed. Angiographic and clinical findings were recorded during the procedure and at 6- and 12-month follow-ups.

RESULTS

A total of 109 small aneurysms were treated with a SFD in 104 patients (78 women; 26 men; mean, median, and range of age: 55.2, 57.1, and 19-80 years, respectively). A total of 60 patients were asymptomatic (57.7%). All except 7 aneurysms (6.4%) arose from the anterior circulation. The mean size of the aneurysms was 4.7±1.9 mm. At 6 months, the neuromorbidity and neuromortality rates were 2.9% and 0.9%, respectively. Imaging at the 12-month follow-up showed complete occlusion, neck remnants, and residual aneurysm in 88.5% (69/78), 7.7% (6/78), and 3.3% (3/78) of cases, respectively. No delayed hemorrhage occurred.

CONCLUSIONS

The findings suggest that the indications for SFD can be safely extended to small intracranial aneurysms.

In patients with aortic coarctation it would be desirable to assess pressure gradients as well as information about blood flow profiles at rest and during exercise. We aimed to assess the hemodynamic responses to physical exercise by combining MRI-ergometry with computational fluid dynamics (CFD). MRI was performed on 20 patients with aortic coarctation (13 men, 7 women, mean age 21.5 ± 13.7 years) at rest and during ergometry. Peak systolic pressure gradients, wall shear stress (WSS), secondary flow degree (SFD) and normalized flow displacement (NFD) were calculated using CFD. Stroke volume was determined based on MRI. On average, the pressure gradient was 18.0 ± 16.6 mmHg at rest and increased to 28.5 ± 22.6 mmHg (p < 0.001) during exercise. A significant increase in cardiac index was observed (p < 0.001), which was mainly driven by an increase in heart rate (p < 0.001). WSS significantly increased during exercise (p = 0.006), whereas SFD and NFD remained unchanged. The combination of MRI-ergometry with CFD allows assessing pressure gradients as well as flow profiles during physical exercise. This concept has the potential to serve as an alternative to cardiac catheterization with pharmacological stress testing and provides hemodynamic information valuable for studying the pathophysiology of aortic coarctation.

Aims: To evaluate proposals considering HbA1c and fasting plasma glucose (FPG) measurement as a substitute for oral glucose tolerance test (OGTT) to diagnose hyperglycaemia in pregnancy (HIP) during COVID-19 pandemic.

Methods: Of the 7,334 women who underwent the OGTT between 22-30 weeks gestation, 966 had HIP (WHO diagnostic criteria, reference standard). The 467 women who had an available HbA1c were used for analysis. French-speaking Society of Diabetes (SFD) proposal to diagnose HIP during COVID-19 pandemic was retrospectively applied: HbA1c ≥5.7% (39mmol/mol) and/or FPG level ≥5.1mmol/l. SFD proposal sensitivity for HIP diagnosis and the occurrence of HIP-related events (preeclampsia, large for gestational age infant, shoulder dystocia or neonatal hypoglycaemia) in women with false negative (FN) and true positive (TP) HIP-diagnoses were evaluated.

Results: The sensitivity was 57% [95% confidence interval 52-62]. FN women had globally lower plasma glucose levels during OGTT, lower HbA1c and body mass index than those TP. The percentage of HIP-related events was similar in FN (who were cared) and TP cases, respectively 19.5 and 16.9 % (p=0.48). We observed similar results when women at high risk for HIP only were considered.

Conclusion: The SFD proposal has a poor sensitivity to detect HIP. Furthermore, it fails to have any advantages in predicting adverse outcomes.

Keywords: COVID-19; Collège National des Gynécologues Obstétriciens Français (CNGOF); HbA1c; Société Francophone du Diabète (SFD); oral glucose tolerance test.

A 45-year-old man had developed a choroidal neovascular membrane (CNVM) in his left eye at the age of 38 years and had received six intravitreal ranibizumab injections with resulting visual acuities of 6/60 in the affected eye and 6/4 in the unaffected right eye (Snellen charts). Family history and genetic testing revealed tissue inhibitor of metalloproteinase-3 (TIMP3) gene positive Sorsby fundus dystrophy (SFD). The patient has been under regular follow-up since. At the age of 45 years, he presented with subretinal fluid accumulation in his right eye suggestive of CNVM and received six intravitreal ranibizumab injections, which maintained visual acuity of 6/7.5 in his right eye. Although SFD is a rare condition, it should be suspected and ruled out in young patients presenting with suspicious fundoscopic findings and subretinal fluid on optical coherence tomography. Early intervention can possibly delay macular fibrosis and loss of vision secondary to SFD associated with CNVM.

Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy with an estimated prevalence of 1 in 220,000 and an onset of disease around the 4th to 6th decade of life. Similar to age-related macular degeneration (AMD), ophthalmoscopy reveals accumulation of protein/lipid deposits under the retinal pigment epithelium (RPE), referred to as drusen, in the eyes of patients with SFD. SFD is caused by variants in the gene for tissue inhibitor of metalloproteinases-3 (TIMP3), which has been found in drusen-like deposits of SFD patients. TIMP3 is constitutively expressed by RPE cells and, in healthy eyes, resides in Bruch's membrane. Most SFD-associated TIMP3 variants involve the gain or loss of a cysteine residue. This suggests the protein aberrantly forms intermolecular disulphide bonds, resulting in the formation of TIMP3 dimers. It has been demonstrated that SFD-associated TIMP3 variants are more resistant to turnover, which is thought to be a result of dimerisation and thought to explain the accumulation of TIMP3 in drusen-like deposits at the level of Bruch's membrane. An important function of TIMP3 within the outer retina is to regulate the thickness of Bruch's membrane. TIMP3 performs this function by inhibiting the activity of matrix metalloproteinases (MMPs), which have the function of catalysing breakdown of the extracellular matrix. TIMP3 has an additional function to inhibit vascular endothelial growth factor (VEGF) signalling and thereby to inhibit angiogenesis. However, it is unclear whether SFD-associated TIMP3 variant proteins retain these functions. In this review, we discuss the current understanding of the potential mechanisms underlying development of SFD and summarise all known SFD-associated TIMP3 variants. Cell culture models provide an invaluable way to study disease and identify potential treatments. These allow a greater understanding of RPE physiology and pathophysiology, including the ability to study the blood-retinal barrier as well as other RPE functions such as phagocytosis of photoreceptor outer segments. This review describes some examples of such recent in vitro studies and how they might provide new insights into degenerative diseases like SFD. Thus far, most studies on SFD have been performed using ARPE-19 cells or other, less suitable, cell-types. Now, induced pluripotent stem cell (iPSC) technologies allow the possibility to non-invasively collect somatic cells, such as dermal fibroblast cells and reprogram those to produce iPSCs. Subsequent differentiation of iPSCs can generate patient-derived RPE cells that carry the same disease-associated variant as RPE cells in the eyes of the patient. Use of these patient-derived RPE cells in novel cell culture systems should increase our understanding of how SFD and similar macular dystrophies develop.

METHODS

The case is presented of a 32-year-old man referring to metamorphopsia and blurred vision in both eyes for 3 days. Best corrected visual acuity of 20/32 in the right eye and 20/25 in the left eye. Fundus examination revealed the presence of drusen-like deposits, suggestive of Sorsby's fundus dystrophy (SFD) and choroidal neovascularization (CNV) bilaterally. The patient received intravitreal ranibizumab. Visual acuity improved to 20/20 in both eyes at 6-months follow-up, and results of fundus examination showed complete regression of neovascularization. No mutations were found in the TIMP-3 gene.

CONCLUSIONS

The known mutations in TIMP-3 may not be extended to all patients with SFD. The use of intravitreal ranibizumab may be considered as a therapeutic option in CNV secondary to SFD.

SHetA2 is a novel anticancer drug with poor aqueous solubility. In formal toxicological studies, Kolliphor HS 15 was used as a solubilizing agent to increase the oral bioavailability of SHetA2. The purpose of this study was to formulate SHetA2 and Kolliphor HS 15 as solid powders to facilitate their filling in hard gelatin capsules for clinical trials. Two manufacturing processes, ultra-rapid freeze-drying (URFD) and spray freeze drying (SFD), were employed to fabricate solid powders of SHetA2-Kolliphor HS 15 and trehalose. The morphology, size, flowability, and compressibility of URFD-SHetA2 and SFD-SHetA2 powders were characterized. The crystallinity and apparent maximum solubility of SHetA2 in both powders were also determined. SFD-SHetA2 powders were spherical in shape, small, and with a wide size distribution while the URFD-SHetA2 powders were irregularly shaped and big but with a narrower distribution. DSC and XRD analyses indicated that SHetA2 was mostly amorphous in both powders. The flow of both powders was categorized as "good" (angle of repose < 35°). The uniformity of drug content in URFD-SHetA2 powders was more variable than that in SFD-SHetA2 powders. The solubility profile of SHetA2 in both powders SGF exhibited a transient supersaturation "spring effect" due to the drug's amorphousness followed by extended supersaturation "parachute effect" at approximately 6 μg/ml for both powders compared to 0.02 ± 0.01 μg/ml for unprocessed drug. In conclusion, both URFD and SFD formed solid SHetA2 Kolliphor powders that are possible formulation candidates to be filled in hard gelatin capsules for clinical trials.

OBJECTIVE

To report the prevalence of severe functional difficulties and disability (SFD) in a nationally representative sample of children ages 5 to 17 in Mexico, to identify factors associated with SFD, and population profiles predictive of SFD.

METHODS

Using data from the National Survey on Children and Women we estimated prevalence and 95% confidence intervals of SFD and risk factors. We fitted bivariate and multivariate logistic regression models. We then examined which combinations of the sociodemographic factors best predicted SFD.

RESULTS

The prevalence of SFD was 11.2%. The most prevalent SFD were on the socioemotional dimension (8.3%). The associated risk factors in the three dimensions were: living in a poor household, being a boy, having a mother with basic education or less, and non-indigenous background or living in an urban area.

CONCLUSIONS

Identifying groups of the population at higher risk for SFD provides useful information for targeted intervention implementation.

The effects of five different drying processes, air drying (AD), sulphur fumigation drying (SFD), hot air drying (HAD), freeze drying (FD) and microwave drying (MWD) for yams in terms of starch-related properties and antioxidant activity were studied. From the results of scanning electron microscopy (SEM), polarized optical microscopy (POM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR), the MWD sample was found to contain gelatinized starch granules. The FD yam had more slow digestible (SDS) and resistant starches (RS) compared with those processed with other modern drying methods. The bioactive components and the reducing power of the dried yams, were lower than those of fresh yam. When five dried samples were compared by principal component analysis, the HAD and SFD samples were observed to have the highest comprehensive principal component values. Based on our results, HAD would be a better method for yam drying than the more traditional SFD.

Spray-freeze-drying (SFD) is a unique powderization technique to produce highly porous dry powders with a low density. The characteristic morphology can markedly contribute to the superior inhalation performances of SFD powders. Due to the increased specific surface area of the powders, however, moisture adsorption may readily occur, subsequently leading to losses of their inhalation potentials. In this study, hydrophobic amino acids were newly applied as pharmaceutical excipients to obtain SFD powders with both a favorable inhalation performance and antihygroscopic property. SFD powders composed of several hydrophobic amino acids were prepared. The morphology, particle size distribution, and crystallinity of the prepared powders were evaluated by scanning electron micrography, laser diffraction, and X-ray powder diffraction, respectively. The inhalation characteristics of the SFD powders were examined using a twin-stage liquid impinger equipped with an inspiratory pattern simulator and devices. To investigate their antihygroscopicity, moreover, the SFD powders were stored under a humidified condition to assess the morphology, crystallinity, and inhalation performance as described above. It was demonstrated that a SFD powder composed of L-leucine, L-isoleucine, or L-phenylalanine showed a superior inhalation performance, which was sufficiently maintained after storage under the humidified condition, strongly indicating their antihygroscopicity. These results indicated that the hygroscopicity of SFD powders can be effectively improved by the application of hydrophobic amino acids as excipients.

Molecular targeting of growth factors has shown great therapeutic potential in pharmaceutical research due to their roles in pathological conditions. In the present study, we developed a novel suramin fragment and deoxycholic acid conjugate (SFD) that exhibited the potential to bind to the heparin-binding site (HBD) of vascular endothelial growth factor (VEGF) and to inhibit its pathogenic action for the first time. Notably, SFD was optimally designed for binding to the HBD of VEGF using the naphthalenetrisulfonate group, allowing to observe its excellent binding efficacy in a surface plasmon resonance (SPR) study, showing remarkable binding affinity (K_D = 3.8 nM) as a small molecule inhibitor. In the tubular formation assay, it was observed that SFD could bind to HBD and exhibit antiangiogenic efficacy by inhibiting VEGF, such as heparins. The cellular treatment of SFD resulted in VEGF-inhibitory effects in human umbilical vein endothelial cells (HUVECs). Therefore, we propose that SFD can be employed as a novel drug candidate to inhibit the pathophysiological action of VEGF in diseases. Consequently, SFD, which has a molecular structure optimized for binding to HBD, is put forward as a new chemical VEGF inhibitor.

Keywords: VEGF; drug development; heparin; molecular targeting; suramin.

BACKGROUND

Erosive pustular dermatosis of the leg (EPDL) is a poorly understood entity first described by Lanigan and Cotteril in 1987. Its clinical diagnosis is based on exclusion since the physiopathology is unknown. The primary objective of this investigation was to specify the clinical aspects and outcomes in a prospective study. The secondary objectives were to describe associated diseases, the circumstances of occurrence, and the laboratory tests used.

METHODS

This was a prospective study that included 45 patients selected by members of the Angiology-Dermatology Group of the SFD (French Dermatology Society) at 13 centres between 01/09/2013 and 31/10/2014. There was a 180-day monitoring period. The records of 36 patients were analysed. Clinical and laboratory data were collected.

RESULTS

Mean patient age was 79.6±9.9 years with a M/F sex ratio of 0.2. Among the patients, 16.7% had skin cancer and 91.7% had venous insufficiency. The proportion of patients wearing venous compression hose was constant between inclusion and D180. Lesions were bilateral (53%), affected the middle third of the leg, and were on the anterior aspect. Complete healing was achieved in 77.8% of cases with time to healing of 2.4±1.2 months, and under topical corticosteroids in 97.3% of cases. During follow-up, relapse occurred in 38.9% of cases after a mean time of 2.4±1.2 months.

CONCLUSIONS

EPDL appears to be an idiopathic inflammatory dermatosis with a particular topographic expression. The physiopathology could be related to chronic inflammation associated with venous insufficiency and with certain trigger factors. Currently, there are few therapeutic alternatives to topical corticosteroids.

The stability of live-attenuated viruses is very challenging due to thermal sensitivity; therefore, solid form is usually required (often freeze-dried products). Micropellet technology is a lyophilization technology that has the potential to provide greater flexibility in the presentation of a given vaccine particularly in multi-dose format or in combination of different vaccines. As a novel vaccine alternative process, this spray freeze-dried (SFD) micropellet technology was evaluated using as a model a yellow fever virus produced in Vero cells (vYF). Screening of excipients was performed in order to optimize physico-chemical properties of the micropellets. Sugar/polymer-based formulations induced high glass transition temperature (Tg), adequate breaking force and attrition resistance of the SFD micropellets. These mechanical parameters and their stability are of considerable importance for the storage, the transport but also the filling process of the SFD micropellets. By adding excipients required to best preserve virus infectivity, an optimal sugar/polymer-based formulation was selected to build micropellets containing vYF. Monodisperse and dried micropellets with a diameter of about 530 µm were obtained, exhibiting similar potency to conventional freeze-dried product in terms of vYF infectious titer when both solid forms were kept under refrigerated conditions (2-8 °C). Comparable kinetics of degradation were observed for vYF formulated in micropellets or as conventional freeze-dried product during an accelerated stability study using incubations at 25 °C and 37 °C over several weeks. The results from this investigation demonstrate the ability to formulate live-attenuated viruses in micropellets. Pharmaceutical applications of this novel vaccine solid form are discussed.

BACKGROUND

BMI and ADAMTS13 levels are positively correlated in man. Development of obesity is associated with angiogenesis and inflammation, and increased ADAMTS13 synthesis in the liver.

METHODS

Male wild-type (WT) and ADAMTS13 deficient (Adamts13-/-) mice were kept on normal chow (SFD) or high fat diet (HFD) for 15 weeks.

RESULTS

HFD feeding of WT mice resulted in significantly enhanced levels of ADAMTS13 antigen and activity as compared to SFD feeding. ADAMTS13 deficiency had no significant effect on body weight gain, subcutaneous (SC) or gonadal (GN) adipose tissue mass, or on adipocyte size. In GN fat of obese (HFD) Adamts13-/- mice, adipocyte density was higher and blood vessel density lower as compared to obese WT mice. No marked effects of genotype were observed on mRNA expression of adipogenic, endothelial, inflammatory or oxidative stress markers in adipose tissue. Analysis of metabolic parameters and of glucose and insulin tolerance did not reveal significant differences between both obese genotypes, except for higher adiponectin and cholesterol levels in obese Adamts13-/- as compared to WT mice.

CONCLUSIONS

Our data do not support a functional role of ADAMTS13 in adiposity nor in associated angiogenesis or inflammation in mice.

CONCLUSIONS

ADAMTS13 deficiency may cause thrombotic thrombocytopenic purpura (TTP). Obesity, which is associated with enhanced ADAMTS13 levels is nevertheless considered to be an independent risk factor for TTP. To resolve this apparent contradiction, we show that ADAMTS13 does not directly promote development of adipose tissue in a mouse model.

OBJECTIVE

To investigate the accuracy of the dosimetry of radiation fields produced by small ELEKTA cone collimators used for stereotactic radiosurgery treatments (SRS) using commercially available detectors EBT3 GafchromicTM film, IBA Stereotactic diode (SFD), and the recently developed detector DUO, which is a monolithic silicon orthogonal linear diode array detector.

METHODS

These three detectors were used for the measurement of beam profiles, output factors, and percentage depth dose for SRS cone collimators with cone sizes ranging from 5 to 50 mm diameter. The measurements were performed at 10 cm depth and 90 cm SSD.

RESULTS

The SRS cone beam profiles measured with DUO, EBT3 film, and IBA SFD agreed well, results being in agreement within ±0.5 mm in the FWHM, and ±0.7 mm in the penumbra region. The output factor measured by DUO with 0.5 mm air gap above agrees within ±1% with EBT3. The OF measured by IBA SFD (corrected for the over-response) agreed with both EBT3 and DUO within ±2%. All three detectors agree within ±2% for PDD measurements for all SRS cones.

CONCLUSIONS

The characteristics of the ELEKTA SRS cone collimator have been evaluated by using a monolithic silicon high spatial resolution detector DUO, EBT3, and IBA SFD diode. The DUO detector is suitable for fast real-time quality assurance dosimetry in small radiation fields typical for SRS/SRT. This has been demonstrated by its good agreement of measured doses with EBT 3 films.

A radioactive source is usually replaced and disposed after being used for a certain amount of time (usually a half-life). In this study, a simple method is proposed to prolong its service life. Instead of replacing the used source with a new source of full activity, a new source of less activity is added in the source holder in front of the used one, so that the total activity of two sources is equal to the initial activity of the used source or even higher. Similarly, more sources can be added to the previous ones. Attenuation of front source(s) to the back source(s) was evaluated with exponential attenuation equation, and variation of source-focus distance (SFD) with inverse square law for Leksell 4C Gamma Knife, which served as an example of external radiotherapy units. When the number of front sources increased from 1 to 3, the relative air kerma decreased from 36.5% to 5.0%. Both the attenuation effect and SFD variation contributed to the decrease in air kerma, with the former being the major factor. If the height of the source can be decreased in some way, such as increasing the specific activity of sources, the sources can be used more efficiently. The method prolongs the service life of sources by several factors, and reduces the expense of source exchange and reclamation.

Objective: Altered interoception may play a major role in the etiology of medically unexplained symptoms (MUS). It remains unclear, however, if these alterations concern noticing of signals or if they are limited to the interpretation of signals. We investigated whether individuals with MUS differ in interoceptive awareness as assessed with the Multidimensional Assessment of Interoceptive Awareness (MAIA) questionnaire. Methods: Study 1: A total of 486 individuals completed the Screening for Somatoform Disorders (SOMS-2). Thirty-two individuals each of the upper and lower decile of the SOMS distribution (low symptom reporters/LSR, high symptom reporters/HSR) completed the MAIA. Study 2: MAIA scores of individuals diagnosed with somatoform disorder (SFD; n = 26) were compared to individuals with major depressive disorder (MDD; n = 25) and healthy controls (HC; n = 26). Results: HSR had lower scores than LSR on the MAIA scales Not-Distracting and Not-Worrying. The SFD and MDD groups showed lower scores than HC on the MAIA scales Not-Distracting, Self-Regulation, and Trusting. The MDD group scored lower than the other two groups on the scales Body Listening and Attention Regulation. There were no group differences on the scale Noticing. Conclusion: HSR, SFD, and MDD patients do not differ from HC in the awareness of noticing of interoceptive signal processing, whereas cognitive facets of interoception, such as distraction or self-regulation are differentially affected. This highlights the necessity of including specifically targeted interventions, which improve interoceptive awareness, in the prevention and treatment of SFDs.

Keywords: interoception; interoceptive awareness; medically unexplained symptoms; somatoform disorder; symptom reporting.