OBJECTIVE

The objective was to evaluate the effect of combined oral contraceptives (OCs) on sexual function, either alone or together with dehydroepiandrosterone (DHEA).

METHODS

An exploratory randomized, double-blind, placebo-controlled, comparative, crossover study was conducted in 81 OC users. Subjects discontinued their OC for one cycle before being randomized for 10cycles to a 30-mcg ethinyl estradiol (EE)/levonorgestrel (LNG) OC or a 30-mcg EE/drospirenone (DRSP) OC, along with daily use of 50mg dehydroepiandrosterone (DHEA) or placebo during five OC cycles before crossing over from DHEA to placebo or the reverse for another fivecycles. First, the effect on sexual function of five OC cycles + placebo was compared to baseline. Then, the effect of five OC cycles + DHEA was compared to the OC+placebo. Results regarding endocrine changes have been published separately. Primary efficacy outcomes of the current study were genital response (measured by vaginal pulse amplitude [VPA]) and sexual feelings (measured by the subjective self-assessment questionnaire [SSAQ]) to self-induced erotic fantasy and visual sexual stimuli in a laboratory setting and measures of desire and arousability using a sexual function diary (SFD). Secondary efficacy outcomes were the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale Revised.

RESULTS

Eighty-one women were enrolled, and 74 women completed the study. Five cycles of OC+placebo resulted in a significant decline compared to baseline of four out of six SFD self-ratings of sexual desire and arousability with both OCs. The LNG OC also resulted in significant declines in the FSFI scores (baseline vs. LNG OC+placebo: total score, 28.7±3.7 vs. 25.6±7.4; arousal, 5.0±0.7 vs. 4.5±1.4; lubrication, 5.2±0.9 vs. 4.6±1.7; pain, 4.9±0.9 vs. 4.5±1.4), but no changes were observed using the DRSP OC. In the laboratory setting, five cycles of OC+DHEA showed no significant differences with placebo except for a significant increase in genital sensations (SSAQ) during erotic fantasy (OC+placebo vs. OC+DHEA: 3.3±1.4 vs. 3.6±1.5; p<.05). No significant changes were observed for genital response (VPA) and the other two variables of the SSAQ assessed after visual erotic stimulus exposure. Using the SFD, 5 out of 10 variables showed a significant improvement with DHEA. Partner's initiative was rejected less often with OC+DHEA compared to placebo (OC+placebo vs. OC+DHEA: 1.1±1.5 vs. 0.8±1.0; p<.05). Women with free testosterone levels in the upper quartile during DHEA co-administration showed significantly better effects on sexual arousal and desire compared to the three lower quartiles (lower vs. upper quartiles: sexual arousability: 25.0±19.8 vs. 41.2±29.0; sexual desire: 5.6±3.7 vs. 9.6±8.0; desire for sex with partner: 4.9±3.1 vs. 8.6±7.4; number of sex fantasies: 3.0±3.2 vs. 5.5±4.4; all p<.05).

CONCLUSIONS

In this exploratory study, OC use was associated with decreases in some measures of sexual functioning, whereas others remained unchanged. Maintaining or restoring physiological testosterone concentrations by the co-administration of DHEA to the OC may prevent these effects on sexuality, particularly in women with relatively high but physiologic levels of free testosterone during DHEA co-administration.

CONCLUSIONS

The results of this exploratory study warrant further testing of the hypothesis that restoration and/or preservation of physiologic testosterone levels during OC use by co-administration of DHEA has favorable effects on those aspects of sexual function compromised by OCs.

Sorsby Fundus Dystrophy (SFD) is a rare inherited autosomal dominant macular degeneration caused by specific mutations in TIMP3. Patients with SFD present with pathophysiology similar to the more common Age-related Macular Degeneration (AMD) and loss of vision due to both choroidal neovascularization and geographic atrophy. Previously, it has been shown that RPE degeneration in AMD is due in part to oxidative stress. We hypothesized that similar mechanisms may be at play in SFD. The objective of this study was to evaluate whether mice carrying the S179C-Timp3 mutation, a variant commonly observed in SFD, showed increased sensitivity to oxidative stress. Antioxidant genes are increased at baseline in the RPE in SFD mouse models, but not in the retina. This suggests the presence of a pro-oxidant environment in the RPE in the presence of Timp3 mutations. To determine if the RPE of Timp3 mutant mice is more susceptible to degeneration when exposed to low levels of oxidative stress, mice were injected with low doses of sodium iodate. The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice. These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant-antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD.

Keywords: Age-related macular degeneration; Antioxidants; Oxidative stress; Retinal pigment epithelium; Sodium iodate; Sorsby Fundus Dystrophy.

Purpose. The study was aimed at comparing the long-term effects of different antiglaucoma eye drops on conjunctival structures using laser scanning confocal microscopy. Methods. Eighty patients diagnosed with primary open-angle glaucoma and twenty healthy volunteers were included in this study. The participants were divided into 5 groups according to the different medications. The lachrymal film break-up time, Schirmer's I test, and Ocular Surface Disease Index Questionnaire were performed in all subjects. The confocal microscopy was used to observe the basal epithelial cell density (ECD), goblet cell density (GCD), dendritic cell density (DCD), and subepithelial collagen fiber diameter (SFD). Results. Statistically significant differences were found among the control group and the antiglaucoma therapy groups in the values of three clinical data (P < 0.05). The GCD, DCD, and SFD showed significant differences in all glaucoma groups when compared to the control (P < 0.001). Moreover, the prostaglandin group differed from the other antiglaucoma therapy groups in the GCD and SFD (P < 0.05). Conclusions. Our study confirmed the significant differences in the conjunctival structures based on the effects of antiglaucoma medications. Less pronounced changes were found in the patients treated with prostaglandin analogue than in the other kinds of antiglaucoma therapies.

A rapid, simple and sensitive spectrophotometric method for the determination of some sulfa drugs is described. The method is based on the formation of orange yellow colored azo product by the diazotization of sulfonamides, viz., dapsone (DAP), sulfathiazole (SFT), sulfadiazine (SFD), sulfacetamide (SFA), sulfamethoxazole (SFMx), sulfamerazine (SFMr), sulfaguanidine (SFG) and sulfadimidine (SFDd) followed by a coupling reaction with 3-aminophenol in aqueous medium. Absorbance of the resulting orange yellow product is measured at 460 nm and is stable for 6 days at 27 degrees C. Beer's law is obeyed in the concentration range of 0.05-8.0 microg/ml at the wavelength of maximum absorption. The method is successfully employed for the determination of sulfonamides in various pharmaceutical preparations and common excipients used as additives in pharmaceuticals do not interfere in the proposed method. Plausible reaction mechanism is proposed for the formation of the azo product.

Objective: Because higher parental psychosocial stress is associated with worsened asthma outcomes in children, we sought to determine if a parent-focused stress management intervention would improve outcomes among their at-risk African American children. Methods: We enrolled self-identified African American parent-child dyads (children aged 4-12 years old with persistent asthma, no co-morbidities, on Medicaid) in a prospective, single-blind, randomized clinical trial with follow-up at 3, 6, and 12 months. All children received care based on the guidelines of the National Institutes of Health. Developed with extensive local stakeholder engagement, the intervention consisted of four individual sessions with a community wellness coach (delivered over 3 months) supplemented with weekly text messaging and twice monthly group sessions (both delivered for 6 months). The main outcome was asthma symptom-free days in the prior 14 days by repeated measures at 3 and 6 months follow-up. Results: We randomized 217 parent-child dyads and followed 196 (90.3%) for 12 months. Coaches completed 338/428 (79%) of all individual sessions. Symptom-free days increased significantly from baseline in both groups at 3, 6, and 12 months, but there were no significant differences between groups over the first 6 months. At 12 months, the intervention group sustained a significantly greater increase in symptom-free days from baseline [adjusted difference = 0.92 days, 95% confidence interval (0.04, 1.8)]. Conclusion: The intervention did not achieve its primary outcome. The efficacy of providing psychosocial stress management training to parents of at-risk African American children with persistent asthma in order to improve the children's outcomes may be limited. ClinicalTrials.gov: NCT02374138 Abbreviations NIH National Institutes of Health AA African American ED emergency department SFD symptom free days RA research assistant GEE generalized estimating equations SD standard deviation CI confidence interval.

Chronic severe somatoform disorder (SFD) is resistant to treatment. In a prospective observational study, we evaluated an intensive multidisciplinary treatment focusing on body-related mentalization and acceptance. Patients included in the study were 183 (146 women, 37 men) of 311 eligible patients with chronic severe SFD, referred consecutively to a specialized tertiary care center between 2002 and 2009. Primary outcome measures were somatic symptoms (SCL-90) and health-related quality of life (EuroQol 5-Dimensional [EQ-5D]). These measures were assessed four times before treatment (on intake, twice during an observation period, at start of treatment) and four times after treatment (during follow-up for 2 years). Multilevel analysis was used to separate effects of time (maturation) and treatment. Results revealed significant improvements in SCL-90 somatic symptoms (d = 0.51), EQ-5D index (d = 0.27), and EQ visual analogue scale (d = 0.56). Significant reductions were also observed in SCL-90 anxiety, depression, and overall psychopathology as well as in medical consumption associated with psychiatric illness (Trimbos/iMTA Questionnaire for Costs Associated With Psychiatric Illness). Large interindividual differences were found in treatment outcome. The long-term improvement seen in many patients suggests that intensive multidisciplinary tertiary care treatment is a useful approach to chronic severe SFD.

Diabetic nephropathy (DN) is a micro-vascular complication of chronic diabetes. Sterol regulatory element binding protein1 (SREBP1) participation in the development of DN is reported. Oryzanol concentrate (OC) at 0.1% and 0.3% is tested for its antioxidant and hypolipidemic effects. The aim of the work is to study the involvement of OC in the amelioration of DN in STZ-induced diabetic animal model.

Animals were grouped into starch, high-fat, and OC-treated control/diabetic groups (SFC/SFD, HFC/HFD, OFC/OFD). The markers of DN, increased glomerular filtration rate and kidney weight, were evident in HFD and reduced in OFD group by ≈1.09 and ≈1.3 fold, respectively. The amelioration of defensive antioxidant enzyme activities and lipid peroxidation, expressions of lipid-associated biomolecules (SREBP1 and FAS) were also observed. HFD showed increased ECM accumulation of glycoproteins, particularly Type IV collagen, fibronectin. SREBP1-associated gene transforming growth factor-β (TGF-β) was reduced on treatment (OFD ≈ 1.3 fold) as to HFD (≈2.7 fold).

Oryzanol concentrate, having hypolipidemic and antioxidant properties, also downregulated the lipid biosynthesis through reduced SREBP1-TGF-β interactions (EMSA) and could effectively ameliorate DN. Gene (ACC2, Cpt1, and ACOX) expression studies showed that β-oxidation was not involved in reducing DN.

Dome-shaped macula (DSM) was first described by Gaucher et al. as a convex protrusion of macula within a staphyloma in highly myopic eyes that cause visual impairment associated with serous foveal detachment (SFD). We describe a patient with persistent SFD in DSM documented by serial spectral domain optical coherence tomography for 7 years with stable vision.

This study employed the ultrasonic spray-freeze-drying technique to prepare porous mannitol carriers that incorporated hydrophobic cyclosporine A (CsA) nanoparticles (NPs) for pulmonary delivery. Two nanosuspension stabilization systems, (1) a combination of lecithin and lactose system and (2) a D-α-tocopheryl polyethylene glycol succinate (TPGS) system, were investigated. The ability of the lecithin and TPGS in anchoring the hydrophobic CsA NPs to the porous hydrophilic mannitol structure was first reported. Formulations stabilized by TPGS provided a much better dose uniformity, suggesting that TPGS is a better anchoring agent compared with lecithin. The effects of mannitol carrier density and CsA loading (4.9-27%) on aerosol performance and dissolution profiles were assessed. The fine particle fraction (FPF) increased from 44 to 63% as the mannitol concentration decreased from 1 to 5%. All formulations achieved full dissolution within an hour without significant influence from the mannitol content and CsA loading. The initial dissolution rates of the present formulations were almost double than that of the spray-dried counterpart, with 90% of the drug dissolved in 10 min. Overall, the CsA NPs were successfully incorporated into the porous mannitol which demonstrated good aerosol performance and enhanced dissolution profiles. These spray-freeze-drying (SFD) powders were stable after 2-year storage under desiccation at 20 ± 3°C.

A rapid, selective and simple spectrophotometric method for the determination of sulfa-drugs is described. The method is based on the formation of violet colored azo product by the diazotization of sulfonamides, viz. sulfathiazole (SFT), sulfadiazine (SFD), sulfacetamide (SFA), sulfamethoxazole (SFMx), sulfamerazine (SFMr), sulfaguanidine (SFG) and sulfadimidine (SFDd) followed by a coupling reaction with iminodibenzyl in alcohol medium. Absorbance of the resulting violet azo product is measured at 570-580 nm and is stable for 24 h at 27 degrees C. Beer's law is obeyed in the concentration range of 0.05-6.0 microg ml(-1) at the wavelength of maximum absorption. The method is successfully employed for the determination of sulfonamides in various pharmaceutical preparations and common excipients used as additives in pharmaceuticals do not interfere in the proposed method. The method offers the advantages of simplicity, rapidity and sensitivity without the need for extraction or heating. A reaction mechanism is proposed for the formation of the violet azo product.

Once lifestyle measures implemented, if hyperglycemia persists, above individual HbA1c targets, a medication should be started in type 2 diabetic patients (T2DM). First, unless exception, an oral antidiabetic drug. Except in case of intolerance, the initial monotherapy, metformin remains the strengthening treatment. Latter, combination of two oral drugs, now offers several options, mainly the choice to associate a "conventional insulin-secretor", sulfonylureas, glinide, or a "new one" belonging the class of "incretin", more readily a gliptine (DPP-4 inhibitors) rather than injectable GLP-1 analogue which can also be sometimes chosen at this stage. These options are mostly new and have the advantage a neutral or favourable (for GLP-1) effect on body weight in obese type 2 DM patient and the absence of any hypoglycaemic risk in both classes of incretins. But this risk varies depending on the patient profile, much higher if the target HbA1c is low (6 to 6.5 or 7%), or in the elderly, fragile and/or in case of renal insufficiency. These two different situations with a high risk of hypoglycaemia, define best indications of this new class. If dual oral therapy does not achieve the goals we are faced with three options: triple oral therapy: metformin-sulfonylurea-gliptine or one of two approaches with injections, insulin or GLP-1 analogues. The use of GLP-1 analogues is often delayed today and put wrongly in balance with the transition to insulin, a use already delayed in France and insufficient. The use of incretins is new and needs to be validated by studies of sustainability on glycemic control, prevention of microvascular and macrovascular complications and after years on the market security of use, primarily on the exocrine pancreas. In short, individualization of strategies and HbA1c targets are required, the new molecules can help us in this process. This individualization can easily be done through the handy guide proposed by the experts ADA EASD statement, endorsed by the SFD, abandoning the complex algorithm recently again proposed by HAS and ANSM in 2013. A recommendation that prioritizes the costs of the strategies. An absolutely critical issue, while admitting not to have the tools to measure them in all their dimensions. Finally, we must reconsider every treatment after a maximum of 6 months of use, if the results are deemed inadequate substitute rather than adding drugs.

Review on the problem of sanitary-epidemiological welfare of the population in the Siberian Federal District (SFD) was conducted based on literature data and authors own research in the period of 2002−2014. Authors provided broad information on the health and demographic and epidemiological characteristics of SFD population. SFD in comparison with other regions of the Russian Federation overcomes one of the most adverse situations including mortality rates from external causes. SFD population’s infectious and somatic morbidity rates were analyzed. Analysis demonstrated that the situation relating to priority epidemiologically and socially important infections (HIV-infection, parenteral viral hepatitis, tuberculosis etc.) on the territory of the SFD remains tense. Authors provided information on the increase in the level of the actual for Siberian regions natural-foci tick-borne infections. Detailed analysis for the environment anthropogenic pollution impact for the epidemic, infectious and vaccine induced processes. Authors suggest that anthropogenic (biological) environmental pollution is one of the most important factors influencing the epidemiological welfare of the Siberian population. A new strategic direction in epidemiological research associated with the problem of comorbid diseases is planned.

Interleukin (IL)‑1β serves a crucial role in the progression of rheumatoid arthritis. Previous studies have indicated that the ERK/STAT1 signaling pathway may be involved in the inflammatory response in synovial fluid‑derived fibroblast‑like synoviocytes (sfd‑FLSs). However, the molecular mechanisms underlying the pathological effects of the inflammatory factors induced by IL‑1β in sfd‑FLSs remain unclear. The aim of the present study was to investigate the IL‑1β‑mediated signaling pathways involved in the expression of inflammatory factors in sfd‑FLSs and in a rat model of rheumatoid arthritis. Reverse transcription‑quantitative PCR, western blotting, and immunohistochemistry were used to analyze the role of IL‑1β in the rat model of rheumatoid arthritis. The results suggested that IL‑1β administration exacerbated rheumatoid arthritis, bone injury and increased the expression levels of inflammatory factors, such as IL‑17 and tumor necrosis factor α (TNF‑α), whereas treatment with anti‑IL‑1β exhibited opposite effects. In vitro experiments in sfd‑FLSs further suggested that treatment with IL‑1β influenced the expression levels of various inflammatory factors. In specific, IL‑1β increased the expression of IL‑17 and TNF‑α, and decreased the expression of IL‑6 and IL‑10 in sfd‑FLSs. Additionally, treatment with IL‑1β increased the mRNA expression and protein phosphorylation of NF‑κB, ERK and STAT1 in sfd‑FLSs. Treatment with anti‑IL‑1β exhibited opposite effects on the expression levels of inflammatory factors and suppressed the NF‑κB‑mediated ERK‑STAT1 signaling pathway activation in sfd‑FLSs. Finally, treatment with a NF‑κB inhibitor suppressed the effects of IL‑1β, and NF‑κB overexpression reversed the effects of anti‑IL‑1β on the expression levels of IL‑17, TNF‑α, NF‑κB, ERK and STAT1. In conclusion, the present results demonstrated that treatment with IL‑1β increased the expression levels of inflammatory factors in sfd‑FLSs via the regulation of the NF‑κB‑mediated ERK/STAT1 signaling pathway in a rat model of rheumatoid arthritis. Therefore, the NF‑κB/ERK/STAT1 signaling pathway may represent a potential target for the development of novel treatments for rheumatoid arthritis.

The dose measurements of the small field sizes, such as conical collimators used in stereotactic radiosurgery (SRS), are a significant challenge due to many factors including source occlusion, detector size limitation, and lack of lateral electronic equilibrium. One useful tool in dealing with the small field effect is Monte Carlo (MC) simulation. In this study, we report a comparison of Monte Carlo simulations and measurements of output factors for the Varian SRS system with conical collimators for energies of 6 MV flattening filter-free (6 MV) and 10 MV flattening filter-free (10 MV) on the TrueBeam accelerator. Monte Carlo simulations of Varian's SRS system for 6 MV and 10 MV photon energies with cones sizes of 17.5 mm, 15.0 mm, 12.5 mm, 10.0 mm, 7.5 mm, 5.0 mm, and 4.0 mm were performed using EGSnrc (release V4 2.4.0) codes. Varian's version-2 phase-space files for 6 MV and 10 MV of TrueBeam accelerator were utilized in the Monte Carlo simulations. Two small diode detectors Edge (Sun Nuclear) and Small Field Detector (SFD) (IBA Dosimetry) were applied to measure the output factors. Significant errors may result if detector correction factors are not applied to small field dosimetric measurements. Although it lacked the machine-specific kfclin,fmsrQclin,Qmsr correction factors for diode detectors in this study, correction factors were applied utilizing published studies conducted under similar conditions. For cone diameters greater than or equal to 12.5 mm, the differences between output factors for the Edge detector, SFD detector, and MC simulations are within 3.0% for both energies. For cone diameters below 12.5 mm, output factors differences exhibit greater variations.

In the present study, a novel dry small interfering RNA (siRNA) powder for inhalation, containing polyethyleneimine (PEI) as a delivery vector, was produced by spray freeze drying (SFD). The powder had spherical and highly porous structure of approximately 10 μm in diameter with high aerosol performance for emission and lung delivery. The reconstituted siRNA/PEI complex after dissolution of the powder had almost the same physicochemical properties and in vitro gene silencing activity as the original one constituted in the sample solution before SFD, showing that the integrity of the siRNA was maintained. In in vivo studies of intratracheal administration into lung metastasis mice and healthy mice, powder with a low dose of 3 μg siRNA exhibited strong and specific gene silencing activity against tumors metastasized to the lungs, whereas it caused no significant histological changes, lactate dehydrogenase leakage, or inflammatory cytokine induction in the lungs. These results strongly indicated that inhalable dry siRNA/PEI powders can provide effective pulmonary gene silencing without severe lung injury and that SFD can be applied to the production of such powders.

Monoclonal antibodies requiring higher doses for exerting therapeutic effect but having lower stability, are administered as dilute infusions, or as two (low concentration) injections both resulting in reduced patient compliance. Present research summarizes impact of manufacturing conditions on ultra-high concentration (≥150mg/mL) IgG1 formulation, which can be administered as one subcutaneous injection. IgG1 was concentrated to ∼200mg/mL using tangential flow filtration (TFF). Alternatively, spray dried (SPD) and spray freeze dried (SFD) IgG1, was reconstituted in 30%v/v propylene glycol to form ultra-high concentration (∼200 mg/mL) injectable formulation. Reconstituted, SPD and SFD IgG1 formulations, increased viscosity beyond an acceptable range for subcutaneous injections (<20 cP). Formulations developed by reconstitution of SPD IgG1, demonstrated increase in high and low molecular weight impurities, at accelerated and stressed conditions. Whereas, the stability data suggested reconstituted SFD IgG1 was comparable to control IgG1 formulation concentrated by TFF. Also, formulation of IgG1 diafiltered with proline using TFF, reduce viscosity from ∼21.9 cP to ∼11 cP at 25°C and had better stability. Thus, conventional TFF technique stands to be one of the preferred methods for manufacturing of ultra-high concentration IgG1 formulations. Additionally, SFD could be an alternative method for long term storage of IgG1 in a dry powder state.

Keywords: High concentration; IgG antibody(s); Injectable(s); Monoclonal antibody(s); Protein formulation(s); Spray drying; Spray freeze-drying; Tangential flow filtration; Viscosity modifiers.

OBJECTIVE

To study the relationship between the static foot disorders (SFDs) and chronic venous disease (CVD).

METHODS

A retrospective study of 824 feet in unselected 412 patients seen by one phlebologist using a standardized record form. A complete clinical, aetiological, anatomical and pathological elements (CEAP) classification was determined. Alleged venous symptoms were recorded using a 10-point visual analogue scale and scored using a customized questionnaire. A standardized measurement of the Djian-Annonier angle was used to quantify and identify the presence of any static disorder of the foot.

RESULTS

There were 156 men (37.8%) and 256 women (62.2%) who were included in this study. A majority of patients (59.3%) had a CEAP classification of C3 or greater. Static disorders of the feet were found to be very common in the study population: 137 feet were hollow feet (16.6%) and 120 flat feet (14.5%). Thus, 31% of all of the feet had some form of SFD. A significant correlation was found between the incidence of SFD and body mass index (P < 0.01), the presence of symptoms (P<0.001) and prolonged standing during the day (>5 hours, P < 0.05). The severity of the CVD, represented by the CEAP clinical classes, was also found to be very significantly related to the SFD (P < 0.001). This correlation was found to be independent of age.

CONCLUSIONS

Static disorders of the foot can be considered as an important risk factor that negatively affects CVD. In daily practice, it is often underestimated. This emphasizes the crucial importance of the detection of SFD during the clinical exam of all CVD patients. Correction of static disorders of the feet will improve symptoms due to the SFD, as well as those related to venous stasis. These results can easily be explained by improvement of foot pump efficacy during walking.

Purpose: To describe and quantify Bruch's membrane (BM) and retinal pigment epithelium (RPE) separation using spectral-domain (SD) optical coherence tomography (OCT) in patients affected by inherited macular degenerations associated with BM thickening.

Methods: Patients with molecularly confirmed Sorsby fundus dystrophy (SFD), dominant drusen (DD), and late-onset retinal degeneration (L-ORD) were included in this retrospective study. Each disease was classed as early stage if subjects were asymptomatic, intermediate stage if they had nyctalopia alone, and late stage if they described loss of central vision. The main outcome was measurement of BM-RPE separation on SD-OCT. The BM-RPE separation measurements were compared against those in normal age-matched controls.

Results: Seventeen patients with SFD, 22 with DD, and eight with L-ORD were included. BM-RPE separation on SD-OCT demonstrated a high test-retest and interobserver reproducibility (intraclass correlation coefficients >0.9). BM-RPE separation was not identified in normal subjects. In SFD, there was greater BM-RPE separation in late-stage disease compared with intermediate-stage patients both at subfoveal (P < 0.05) and juxtafoveal (P < 0.01) locations. In DD, there was increased BM-RPE separation in late-stage disease compared with early stage at subfoveal (P < 0.001) and juxtafoveal (P < 0.05) topographies. There was no significant difference in BM-RPE separation between disease stages in L-ORD.

Conclusions: BM-RPE separation is a novel, quantifiable phenotype in the three monogenic macular dystrophies studied, and may be an optical correlate of the histopathological thickening in BM that is known to occur. BM-RPE separation, as measured by OCT, varies with stage of disease in SFD and DD, but not in L-ORD.

Translational relevance: SFD, DD, and L-ORD are associated with BM thickening. In this group of patients, OCT assessment of macular structure identifies a separation of the usually single, hyperreflective line thought to represent BM and the overlying RPE. This separation is a novel and quantifiable feature of disease staging in SFD and DD.

Keywords: inherited macular degeneration; macular degeneration; optical coherence tomography; retinal dystrophy.

Sorsby's fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD.

In this study, in order to evaluate influences of different drying methods on the structural characteristics, physicochemical properties and antioxidant activities of exopolysaccharides (EPS) from Lactobacillus helveticus MB2-1, three drying methods, including spray-drying (SD), freeze-drying (FD) and spray freeze-drying (SFD), were applied to dry EPS. Results showed that different drying procedures had no significant influence on the primary structure and constituent monosaccharides of EPSs. However, the surface morphology of the three dried EPSs varied greatly in size and shape due to different drying processes. Among three dried EPSs, the particle size distribution of spray freeze-dried EPS (SF-EPS) was relatively narrower and uniform. Additionally, SF-EPS behaved better apparent viscosity and emulsifying property than spray-dried EPS (S-EPS) and freeze-dried EPS (F-EPS). SF-EPS exhibited stronger antioxidant activities when compared with S-EPS and F-EPS, according to the results of scavenging activities on different radicals and chelating activity on ferrous ion. Overall, SFD was the appropriate method for industrial production of EPS from Lactobacillus helveticus MB2-1 with better physicochemical properties and antioxidant activities.

To evaluate short-term efficacy of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) in serous foveal detachment (SFD) in dome-shaped macula (DSM).

A retrospective, noncomparative case series. Three monthly aflibercept injections were administered. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA), optical coherence tomography central subfield thickness (CST), and subretinal fluid (SRF) at baseline and at 2 months and 4 months after the last injection were considered for statistical analysis.

The authors reviewed nine eyes affected by SFD in DSM. Mean BCVA improved from 0.42 LogMAR at baseline to 0.33 LogMAR at final follow-up (P = .06), and mean CST and SRF reduced from 347 μm to 295 μm (P = .09) and from 146 μm to 99 μm (P < .01), respectively. None of the considered eyes had resolution of the SRF.

Three monthly aflibercept injections may improve BCVA and reduce CST and SRF in SFD of DSM. Further prospective studies are necessary to state the real efficacy of this approach. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:822-828.].

Spray freeze drying (SFD) produces suitable particles for the pharmaceutical formulation of dry powders used in dry powder inhalers (DPIs). However, SFD particles have large specific surface area and are partially made up of amorphous solids; this state is hygroscopic and would lead to changes in physicochemical properties by humidity when the particles are stored over the long-term or under high humidity conditions such as in the lungs. This study focused on the application of SFD with a cocrystal technique which can add humidity resistance to the active pharmaceutical ingredients (APIs), and the investigation of the physicochemical properties under high humidity conditions. Cocrystal samples containing theophylline anhydrate (THA) and oxalic acid (OXA) in a molar ratio of 2:1 were prepared by SFD. The crystalline structure, thermal behavior, solid-state, hygroscopicity, stability, and aerodynamic properties were evaluated. Simultaneous in situ measurement by near-infrared and Raman (NIR-Raman) spectroscopy was performed to analyze the humidification process. The SFD sample had a porous particle and an optimal aerodynamic particle size (3.03 μm) although the geometric particle diameter was 7.20 μm. In addition, the sample formed the THAOXA cocrystal with partial coamorphous. The hydration capacity and pseudopolymorphic transformation rate of the SFD sample were much lower than those of THA under conditions of 96.4% relative humidity and 40.0 °C temperature because of the cocrystal formation. The reasons were discussed based on the crystalline structure and energy. The SFD technology for cocrystallization would enable the pharmaceutical preparation of DPI products under environmentally friendly conditions.

Growing rates of tuberculosis (TB) superbugs are alarming, which has hampered the progress made to-date to control this infectious disease, and new drug candidates are few. Epigallocatechin gallate (EGCG), a major polyphenolic compound from green tea extract, shows powerful efficacy against TB bacteria in in vitro studies. However, the therapeutic efficacy of the molecule is limited due to poor pharmacokinetics and low bioavailability following oral administration. Aiming to improve the treatment outcomes of EGCG therapy, we investigated whether encapsulation and pulmonary delivery of the molecule would allow the direct targeting of the site of infection without compromising the activity. Microencapsulation of EGCG was realized by scalable spray-freeze-drying (SFD) technology, forming free-flowing micrometer-sized microspheres (epigallocatechin-3-gallate-loaded trehalose microspheres, EGCG-t-MS) of trehalose sugar. These porous microspheres exhibited appropriate aerodynamic parameters and high encapsulation efficiencies. In vitro studies demonstrated that EGCG-t-MS exhibited dose- and time-dependent killing of TB bacteria inside mouse macrophages by cellular mechanisms of lysosome acidification and autophagy induction. In a preclinical study on TB-infected Balb/c mice model (4 weeks of infection), we demonstrate that the microencapsulated EGCG, administered 5 days/week for 6 weeks by pulmonary delivery, showed exceptional efficacy compared to oral treatment of free drug. This treatment approach exhibited therapeutic outcomes by resolution of inflammation in the infected lungs and significant reduction (P < 0.05) in bacterial burden (up to ∼2.54 Log₁₀ CFU) compared to untreated control and orally treated mice groups. No pathological granulomas, lesions, and inflammation were observed in the histopathological investigation, compared to untreated controls. The encouraging results of the study may pave the avenues for future use of EGCG in TB therapeutics by targeted pulmonary delivery and lead to its translational success.

Keywords: autophagy; epigallocatechin gallate; pulmonary drug delivery; trehalose microspheres; tuberculosis.