Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design

Introduction: Mutations introduce diversity into genomes, leading to selective changes and driving evolution. These changes have contributed to the emergence of many of the current major health concerns of the 21st century, from the development of genetic diseases and cancers to the rise and spread of drug resistance. The experimental systematic testing of all mutations in a system of interest is impractical and not cost-effective, which has created interest in the development of computational tools to understand the molecular consequences of mutations to aid and guide rational experimentation.

Areas covered: Here, the authors discuss the recent development of computational methods to understand the effects of coding mutations to protein function and interactions, particularly in the context of the 3D structure of the protein.

Expert opinion: While significant progress has been made in terms of innovative tools to understand and quantify the different range of effects in which a mutation or a set of mutations can give rise to a phenotype, a great gap still exists when integrating these predictions and drawing causality conclusions linking variants. This often requires a detailed understanding of the system being perturbed. However, as part of the drug development process it can be used preemptively in a similar fashion to pharmacokinetics predictions, to guide development of therapeutics to help guide the design and analysis of clinical trials, patient treatment and public health policy strategies.     

Luteinizing hormone beta mutation and hypogonadism in men and women

Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism. We describe the clinical features of a consanguineous family in which three siblings, two men and one woman, had hypogonadism related to isolated luteinizing hormone deficiency. These subjects have a newly discovered homozygous mutation of a 5' splice site in LHB: IVS2+1G-->C. This mutation disrupts the splicing of messenger RNA (mRNA), generating a gross abnormality in the processing of the luteinizing hormone beta-subunit mRNA, which abrogates the secretion of luteinizing hormone. We also determined that the female phenotype of this LHB mutation is characterized by normal pubertal development, secondary amenorrhea, and infertility.     

Natural history of intraventricular meningiomas: systematic review

Review the data published on the subject to create a more comprehensive natural history of intraventricular meningiomas (IVMs). A Medline search up to March 2018 using “intraventricular meningioma” returned 98 papers. As a first selection step, we adopted the following inclusion criteria: series and case reports about IVMs, as well as papers written in other languages, but abstracts written in English were evaluated. Six hundred eighty-one tumors were evaluated from 98 papers. The majority of the tumors were located in the lateral ventricles (602–88.4%), fourth ventricle (59–8.7%), and third ventricle (20–2.9%). These tumors accounted for a mortality rate of 4.0% (25 deaths) and a recurrence rate of 5.3% (26 recurrences). The majority of the tumors were grade I (89.8%) and consisted of the following subtypes: fibrous, 39.7% (n = 171); transitional, 22.0% (n = 95); meningothelial, 18.6% (n = 80); angiomatosus, 3.2% (n = 14); psammomatous, 2.6% (n = 11); and others, 13.9% (n = 60). Forty-five patients (7.4%) presented with grade II (GII) tumors, and 17 patients (2.8%) presented with grade III (GIII) tumors. These tumors follow the histopathological distribution of meningiomas in general, with the exception of the higher prevalence of the fibrous subtype, possibly due to its embryonic origin. Recurrence and mortality were lower than in other localizations likely due to a complete surgical resection rate than in the convexity and skull base, which suggests that GTR is the gold standard for the management of IVMs.     

Minimally invasive percutaneous plate osteosynthesis for ankle fractures: a prospective observational cohort study

Background

The gold standard for the surgical management of ankle fractures is through open reduction and internal fixation. The rate of wound problems has been reported to be as high as 18 %, especially in patients with poor vascular supply or in diabetics. Minimally invasive percutaneous plate osteosynthesis (MIPPO) has been described as a potential solution for these patients.

Patients and methods

This is a prospective observational cohort study. From October 2009 to February 2010, and following ethical approval of our research, adult patients admitted at our level I trauma center with a closed lateral malleolar displaced unstable fracture (Lauge-Hansen supination-external rotation) with or without a medial-sided injury and patients with an undisplaced fracture associated with medial clear space opening on external rotation stress radiographs were recruited and managed using MIPPO technique. All patients were followed up for a minimum of 12 months post-surgery (12–20 with a mean of 16.5 months). Trauma mechanism, comorbidities, classifications, trauma-surgery interval, image intensifier duration, surgery duration, complications, and function American Orthopaedic Foot and Ankle Society (AOFAS) were analyzed.

Results

Thirty-two patients were recruited of which 20 fulfilled the inclusion criteria (16 females, 4 males) and were available for follow-up. Ten fractures (50 %) were classified as 44-B1, 7 fractures (35 %) as 44-B2, and 3 fractures (15 %) as 44-B3 according to the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification (100 % were supination-external rotation injuries). At 8 weeks post-surgery, all fractures had healed. The duration of surgery ranged between 15 and 73 min (average 32.8) from skin incision to closure. There were 2 complications (1 malunion and 1 skin necrosis requiring implant removal). At 12-month follow-up, AOFAS average was 88.3 (72–100 standard deviation of 6.8 points).

Conclusion

MIPPO technique proved to be a viable option for lateral malleolar fracture treatment with a low complication rate and high functional outcome at 1 year. It is particularly useful in patients with a high risk of wound complication.     

Mineral density changes in bovine carious dentin after treatment with bioactive dental cements: a comparative micro-CT study

Objectives

To evaluate the potential of conventional glass ionomer cement (GIC), Biodentine™, MTA, and Portland cement to induce mineral density changes in carious dentin compared to zinc oxide eugenol control cement (ZOE).

Materials and methods

Fifty blocks of bovine root dentin were prepared and a biofilm model using ATCC strains of S.mutans, S.sobrinus, and L.casei was used to promote artificial dentin lesions. After demineralization, the blocks were randomly divided into the five cement groups. Half of the surface of each specimen received the tested material and the other half was covered with wax (control). Samples were stored in phosphate buffered saline solution for 30 days and after that were scanned in a micro-CT with standardized parameters. Dentin mineral density changes were calculated using differences in plot profiles of the exposed and control carious dentin. Friedman’s test, followed by Wilcoxon signed-rank test was used with 5% significance.

Results

Mean ΔZ values for the cements were 48.63 ± 19.09 for the control (ZOE), 63.31 ± 32.59 for Biodentine™, 114.63 ± 72.92 for GIC, 109.56 ± 66.28 for MTA, and 106.88 ± 66.02 for Portland cement. All cements showed a statistically significant increase in ΔZ values compared to the control, but Biodentine™ values were statistically significantly lower compared to GIC and the other calcium silicate cements.

Conclusions

Tested materials present potential to induce mineral density changes in carious bovine dentin. MTA, Portland, and GIC showed higher bioactivity potential than Biodentine™.

Clinical relevance

Based on minimally invasive concept, materials with remineralization potential can be used to preserve diseased but still repairable dental tissue.

     

Sociodemographic,sexual, and reproductive variables associated with pregnancy among adolescents from low socioeconomic background

Adolescent pregnancy remains a public health concern in both developed and developing countries. Portugal and Brazil represent some of the best examples of this phenomenon. The present study aimed to identify sociodemographic, sexual, and reproductive health-related variables associated with adolescent pregnancy among students from low socioeconomic backgrounds in both countries. The sample included 984 female adolescents, among whom 215 became pregnant. Living with a partner and lack of information about sex and contraception from the family were the best explicative factors for pregnancy occurrence in both countries. Country-specific variables were also identified. Our results may contribute to developing global preventive interventions, addressing the school as an ideal setting for primary intervention and considering culture-specific characteristics of high-risk populations.