Managing Obesity in Primary Care: Breaking Down the Barriers

Several Australian obesity management guidelines have been developed for general practice but, to date, implementation of these guidelines has been shown to be inadequate. In this review, we explore the barriers to obesity treatment and propose a four-stage plan to manage individuals with obesity in general practice using a framework of a multidisciplinary team.Funding: Novo Nordisk.     

A Review of Microbiota and Irritable Bowel Syndrome: Future in Therapies

Irritable bowel syndrome (IBS), one of the most frequent digestive disorders, is characterized by chronic and recurrent abdominal pain and altered bowel habit. The origin seems to be multifactorial and is still not well defined for the different subtypes. Genetic, epigenetic and sex-related modifications of the functioning of the nervous and immune-endocrine supersystems and regulation of brain-gut physiology and bile acid production and absorption are certainly involved. Acquired predisposition may act in conjunction with infectious, toxic, dietary and life event-related factors to enhance epithelial permeability and elicit mucosal microinflammation, immune activation and dysbiosis. Notably, strong evidence supports the role of bacterial, viral and parasitic infections in triggering IBS, and targeting microbiota seems promising in view of the positive response to microbiota-related therapies in some patients. However, the lack of highly predictive diagnostic biomarkers and the complexity and heterogeneity of IBS patients make management difficult and unsatisfactory in many cases, reducing patient health-related quality of life and increasing the sanitary burden. This article reviews specific alterations and interventions targeting the gut microbiota in IBS, including prebiotics, probiotics, synbiotics, non-absorbable antibiotics, diets, fecal transplantation and other potential future approaches useful for the diagnosis, prevention and treatment of IBS.     

Femoroazetabuläres Impingement

Background

There is a high prevalence of femoroacetabular impingement (FAI) in the population and it is associated with an increased risk for the development of coxarthrosis, particularly in impact sports (2–8 times).

Material and methods

Methods for screening and prevention of FAI and their application are demonstrated. Cross-sectional and longitudinal cohort studies are presented in this article and expert recommendations and meta-analyses are discussed.

Results

The development of a cam FAI and also the formation of secondary hip arthritis can (and should) be prevented by avoidance of certain impact sports (training methods) during the skeletal growth phase. The internal rotation of the hips during flexion is a useful screening test to identify individuals with FAI. A recently developed specific examination chair has clearly improved the precision of this test compared to the classical clinical test.

Conclusion

The prevention of FAI and secondary hip arthritis may occur at two levels: during the sensitive (prepubertal) phase the development of FAI can (should) be prevented by avoiding activities that potentially injure the growth plate of the femoral head. Furthermore, screening tests could enable early detection of patients with FAI. These individuals could (should) be advised regarding appropriate behavioral modifications and treatment options depending on the symptoms.

     

Optical coherence tomography shows early loss of the inferior temporal quadrant retinal nerve fiber layer in autosomal dominant optic atrophy

Purpose

The aim of the study was to evaluate the relationship between visual function and retinal nerve fiber layer thickness (RNFLT) determined using Stratus optical coherence tomography (OCT) in patients with autosomal dominant optic atrophy (ADOA).

Methods

The study was a retrospective, institutional, and comparative case series. Thirty-six consecutive patients with ADOA and 72 age-matched normal controls were compared with regard to RNFLT, best-corrected visual acuity (BCVA), and visual field.

Results

The relative reduction of RNFLT of ADOA patients was most evident in the temporal quadrant (56.8 %), followed by the inferior (35.5 %), superior (27.2 %), and nasal quadrants (26.4 %). In ADOA patients, BCVA decreased with RNFL thinning (p?<?0.001), and was not related to age (p?=?0.210). Papillomacular bundle RNFLT decreased with age throughout the study period of 3.7?±?2.3 years (?3.83?±?9.96 μm, p?=?0.017). The presence of a superotemporal central scotoma (61.1 %) was related to decreased inferotemporal RNFLT (7 and 8 o’clock, p?=?0.016 and p?=?0.036, respectively).

Conclusions

The papillomacular bundle RNFL of ADOA is most vulnerable and progressively damaged with age, despite early temporal RNFL loss. Early loss of inferior temporal RNFL in ADOA is related to superotemporal central scotoma.

     

A novel <Emphasis Type="Italic">C</Emphasis>x<Emphasis Type="Italic">50</Emphasis> (<Emphasis Type="Italic">GJA8</Emphasis>) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing

Background

To unravel the molecular genetic background responsible for autosomal dominant congenital pulverulent nuclear cataracts in a four-generation Chinese family.

Methods

Family history data were collected, ophthalmological examinations were performed, and genomic DNA was extracted from peripheral blood of the family members. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. The structure modelling of the protein was displayed based on Swiss-Model Server, and its possible changes in the secondary structure were predicted using Antheprot 2000 software. The chemical dissimilarity and possible functional impact of an amino acid substitution were performed with Grantham score, PolyPhen-2, and SIFT predictions. Protein distributions were assessed by confocal microscopy.

Results

A novel heterozygous c.829C?>?T transition that led to the substitution of a highly conserved histidine by tyrosine at codon 277 (p.H277Y) in the coding region of connexin50 (Cx50, GJA8) was identified. Bioinformatics analysis showed that the mutation likely altered the secondary structure of the protein by replacing the helix of the COOH-terminal portion with a turn. The mutation was predicted to be moderately conservative by Grantham score and to be deleterious by both PolyPhen-2 and SIFT with consistent results. In addition, when expressed in COS1 cells, the mutation led to protein accumulation and caused changes in Cx?50 protein localization pattern.

Conclusions

This is a novel missense mutation [c.829C?>?T, (p.H277Y)] identified in exon 2 of Cx50. Our findings expand the spectrum of Cx50 mutations that are associated with autosomal dominant congenital pulverulent nuclear cataract.

     

Mesenchymal stem cells for treating ocular surface diseases

Mesenchymal stem cells (MSC) have become a promising tool for cell therapy in regenerative medicine. They are readily available, demonstrate powerful differentiation capabilities and present immunosuppressive properties that aid them in surviving from host immune rejection for its great potential use in allograft. Currently clinical trials are underway using MSC, both culture-expanded allogeneic and autologous, for the treatment of a range of diseases not treatable by conventional therapies. A vast array of studies has dedicated towards the use of MSC for treating corneal diseases with very promising outcomes. MSC have successfully differentiated into keratocytes both in vitro and in vivo, and corneal epithelial cells in vitro, but it is uncertain if MSC can assume corneal epithelial cells in vivo. However, to date few studies have unequivocally established the efficacy of MSC for treating corneal endothelial defects. Currently, the diversity in protocols of the isolation and expansion of MSC are hindering to the assessment of cell treatment ability and the further development of treatment regimens. Therefore, future studies should develop international standards for MSC isolation and characterization. In this review, we discuss recent advances in MSC for treating ocular surface diseases.     

Two-stage designs in bioequivalence trials

Purpose

The aim of this study is to assess the current status of non-fixed sample size designs in bioequivalence trials with a focus on two-stage adaptive approaches.

Methods

We searched PubMed and Google Scholar from inception to October 2014. Regulatory guidelines were obtained from the public domain. Different methods were compared by Monte Carlo simulations for their impact on the patient’s and producer’s risks.

Results

Add-on designs, group sequential designs and adaptive two-stage sequential designs are currently accepted to demonstrate bioequivalence in various regulations. All three approaches may inflate the patient’s risk if applied inconsiderately. Direct transfer of methods developed for superiority testing to bioequivalence is not warranted. Published two-stage frameworks maintain the type I error and generally the desired power. Adaptation based on the observed T/R ratio observed in the first stage should be applied with caution. Monte Carlo simulations are an efficient tool to explore the operating characteristics of methods.

Conclusions

Validated two-stage frameworks can be applied without requiring the sponsor to perform own simulations—which could further improve power based on additional assumptions. Two-stage designs are both ethical and economical alternatives to fixed sample designs.

     

Increased brain uptake of venlafaxine loaded solid lipid nanoparticles by overcoming the efflux function and expression of P-gp

Venlafaxine (VLX) could be pumped out of the brain by P-glycoprotein (P-gp). Moreover, the expression of P-gp distributed in blood–brain barrier could be significantly induced by VLX. Thus, P-gp could be considered as the nature barrier for delivering of VLX to the brain. The aim of this study was to investigate whether the efflux function and increased expression of P-gp could be reversed by utilizing solid lipid nanoparticles (SLN). VLX solid lipid nanoparticles (VLX ? SLN) were prepared and evaluated. Pharmacokinetics and brain distribution of VLX in different formulations were conducted after oral or intravenous administration. P-gp efflux function to VLX was evaluated by the brain uptake amount of VLX, while P-gp expression was investigated by Western blotting. Results indicated that the entrapment, mean size and zata potential of VLX ? SLN was 74.9 ± 3.0 %, 186.3 ± 69.26 nm and ?22.8 ± 7.78 mv, respectively. After vein injection of VLX formulations, the brain uptake amount of VLX from VLX ? SLN was significantly higher than that of VLX solution, VLX solution with empty SLN (VLX+ empty SLN) and VLX solution with Verapamil (VLX + Ver), respectively. Furthermore, the protein mass of P-gp in VLX ? SLN treated group was the lowest among all the investigated groups. These results indicated that SLN could overcome P-gp and achieve brain target by intravenous administration.     

Enhancement of solubility and dissolution of cilostazol by solid dispersion technique

Cilostazol is practically insoluble in water and thus results in poor bioavailability. Only a few approaches have been reported for improving the bioavailability of cilostazol. Solid dispersion technique via solvent evaporation method was applied to improve the solubility and dissolution of cilostazol. Various polymers, mixture of polymer and surfactant, and mixture of polymers were screened as a carrier for the solid dispersion. Solubility of cilostazol was improved significantly when Eudragit^® L100 was used as a carrier. However, addition of surfactant to Eudragit^® L100 decreased the solubility slightly. Whereas, the mixture of Eudragit^® L100 and Eudragit^® S100 as a carrier system further increased the solubility. Based on the highest solubility obtained among the carriers screened, 1:1 ratio of Eudragit^® L100 and Eudragit^® S100 was selected as a carrier, and drug to carrier ratio was optimized to 1:5. Differential scanning calorimetry and X-ray diffraction studies showed that the characteristic peak of cilostazol disappeared in the solid dispersion, indicating that cilostazol existed in amorphous form in this formulation. Spray drying method was superior to vacuum drying method in terms of dissolution rate. Meanwhile, it was observed that the disintegration rate and the concentration of polymer had some effect on the crystallization of cilostazol in dissolution medium. Tablet formulation containing spray dried solid dispersion showed significant improvement in dissolution as compared to the commercial tablet.     

Ethnic Background,Socioeconomic Status,and Problem Severity as Dropout Risk Factors in Psychotherapy with Youth

Background

Dropout from child and adolescent psychotherapy is a common phenomenon which can have negative consequences for the individual later in life. It is therefore important to gain insight on dropout risk factors.

Objective

Several potential risk factors [ethnic minority status, a lower socioeconomic status (SES), and higher problem severity] were analyzed in present study. Innovations are that these risk factors were examined for children and adolescents separately, and a distinction was made in termination status between referred patients, dropouts and completers.

Methods

For ethnic majority and minority outpatient children (age 5–11, n = 399) and adolescents (age 12–20, n = 352) problem severity, ethnic background, SES, and treatment termination status (completer, dropout, referral) were specified. Multinomial logistic regression models were used as main method of analysis.

Results

For children, a Moroccan/Turkish ethnicity and higher externalizing scores were risk factors for being referred. For adolescents, a Surinamese/Antillean ethnicity, being female, being older, and lower parental SES occupation levels were risk factors for dropout.

Conclusions

Different dropout risk profiles emerged for children versus adolescents, and for dropouts versus referrals. Also, it depended on the specific ethnic background whether ethnic minority status was a predictor for dropout, and the relationship between SES and termination status differed by whether parental SES occupation or parental SES education were used as SES indicator. Professionals should thus be aware of these potential risk factors for dropout or referral when treating children and adolescents.