MICA‐129 Met/Val polymorphism could be a genetic biomarker for Familial Breast Cancer in the Tunisian population

Identification of candidate genes associated with susceptibility of breast cancer can have a significant impact at a cancer management national healthcare systems level, making genetic testing more affordable and cost‐effective. We have previously shown that the major histocompatibility complex class I‐related chain A (MICA) was related to breast cancer and plays an important role in modulating immune response mechanisms through NKG2D receptor activation. Compared to our previous study, in this work, we recruited a new cohort composed of 354 unrelated Tunisian women affected by breast cancer and 380 age‐matched women as controls, all genotyped for MICA‐129 Met/Val (rs 1051792). Subsequently, we exanimated the distribution of this polymorphism in ten families. As a result, an association was found between the Val allele and Val/Val genotype and the risk of breast cancer (p = 2.5 × 10^–15; OR = 2.40; p = 6.5 × 10^–13; OR = 3.03, respectively). Stratified analysis with age and family history of cancer revealed an association between the Val/Val genotype and younger patients <40 years (p = .003; OR = 2.03). Among those patients having a family history of cancer, 68% had a Val/Val genotype (p = .02; OR = 1.82). In the family study, an analyse of pedigrees revealed that the majority of families showed the development of breast cancer at a young age. Moreover, all patients diagnosed with early‐onset breast cancer had a Val/Val genotype. Our results lead us to propose that this polymorphism may be an inherited genetic biomarker contributing to an increased breast cancer risk in Tunisian women.     

Biologically-Guided Isolation of Natural Lead Antithyroid Drug from Medicago sativa L. Sprouts and Its Toxic Profile in Comparison with Propylthiouracil

Hyperthyroidism is a common endocrine disorder associated with increased risk of cardiovascular complications and mortality. Although antithyroid drugs (ATDs) are approved as first line option for many hyperthyroidism cases, including pregnancy and childhood, they exert significant toxic profile. Medicago sativa L. (alfalfa) also called “The father of all food” was among the diet consumed by mares that gave birth to foals with congenital hypothyroidism. Since, greenfeed was accused for the development of such condition, alfalfa may possess constituents with promising antithyroid potential that could be a valuable substitute for the conventional ATDs. The current work was designed to identify the most biologically active antithyroid phytoconstituent separated from alfalfa sprouts and comparing its antithyroid mechanism, efficacy and toxic profile to the standard ATD; propylthiouracil (PTU). The most biologically active solvent fractions from alfalfa sprouts extract were identified by in vitro screening for anti-thyroid peroxidase (TPO) activity, from which different phytoconstituents were separated and identified by interpretation of spectroscopic data. These compounds were then in vitro screened for anti-TPO and virtually screened via GLIDE XP docking into the crystal structures of the enzymes; bovine lactoperoxidase, as an alternative to TPO, and mammalian selenocysteine-dependent iodothyronine deiodinase (IDI), that are both uniquely dually prohibited by PTU. The compound that showed the least TPO IC₅₀ and highest combined docking XP score was elected for comparing its antithyroid mechanism, efficacy, tendency to reverse hyperthyroidism-triggered complications and toxicity to PTU using L-thyroxine-induced hyperthyroidism model in rats. Seven compounds (1–7) were isolated from the most biologically active fraction, whilst, compounds (4–7) were reported for the first time from alfalfa sprouts. Compound 5 (apigenin) showed the least TPO IC₅₀ and highest in-silico combined score, thus, apigenin was selected for further in-vivo investigations. Apigenin was found to more effectively interfere with type 1-IDI than with TPO in vivo. Apigenin therapy resulted in nearly euthyroid state, without incidence of hypothyroidism, thyroid hypertrophy, hepatotoxity or WBCs count reduction. In addition, apigenin, but not PTU, corrected hyperthyroidism-induced left ventricular hypertyrophy. Therefore, apigenin is a natural lead antithyroid drug that represents a possible safer alternative to conventional ATDs.     

“We find what we look for,and we look for what we know”: factors interacting with a mental health training program to influence its expected outcomes in Tunisia

Background

Primary care physicians (PCPs) working in mental health care in Tunisia often lack knowledge and skills needed to adequately address mental health-related issues. To address these lacunas, a training based on the Mental Health Gap Action Programme (mhGAP) Intervention Guide (IG) was offered to PCPs working in the Greater Tunis area between February and April 2016. While the mhGAP-IG has been used extensively in low- and middle-income countries (LMICs) to help build non-specialists’ mental health capacity, little research has focused on how contextual factors interact with the implemented training program to influence its expected outcomes. This paper’s objective is to fill that lack.

Methods

We conducted a case study with a purposeful sample of 18 trained PCPs. Data was collected by semi-structured interviews between March and April 2016. Qualitative data was analyzed using thematic analysis.

Results

Participants identified more barriers than facilitators when describing contextual factors influencing the mhGAP-based training’s expected outcomes. Barriers were regrouped into five categories: structural factors (e.g., policies, social context, local workforce development, and physical aspects of the environment), organizational factors (e.g., logistical issues for the provision of care and collaboration within and across healthcare organizations), provider factors (e.g., previous mental health experience and personal characteristics), patient factors (e.g., beliefs about the health system and healthcare professionals, and motivation to seek care), and innovation factors (e.g., training characteristics). These contextual factors interacted with the implemented training to influence knowledge about pharmacological treatments and symptoms of mental illness, confidence in providing treatment, negative beliefs about certain mental health conditions, and the understanding of the role of PCPs in mental health care delivery. In addition, post-training, participants still felt uncomfortable with certain aspects of treatment and the management of some mental health conditions.

Conclusions

Findings highlight the complexity of implementing a mhGAP-based training given its interaction with contextual factors to influence the attainment of expected outcomes. Results may be used to tailor structural, organizational, provider, patient, and innovation factors prior to future implementations of the mhGAP-based training in Tunisia. Findings may also be used by decision-makers interested in implementing the mhGAP-IG training in other LMICs.

     

Superparamagnetic Iron Oxide–Loaded Lipid Nanocarriers Incorporated in Thermosensitive In Situ Gel for Magnetic Brain Targeting of Clonazepam

The objective of the study was to target clonazepam to the brain through the intranasal olfactory mucosa using nanolipid carriers loaded with superparamagnetic iron oxide nanoparticles (SPIONs) to allow nanocarrier guidance and retention with an external magnetic field. For improved delivery, the nanolipid carriers were incorporated in a thermosensitive mucoadhesive in situ gel. Different nanolipid carriers including solid lipid nanoparticles and nanostructured lipid carriers (NLC) were prepared and characterized with respect to particle size, zeta potential, entrapment efficiency, and in vitro release. The NLC composed of 3 solid lipids (Compritol^® 888, stearic acid, and glyceryl monostearate) and 2 liquid oils (oleic acid and glyceryl monooleate) showed the most satisfactory characteristics and was loaded with SPION (NLC/SPION). Both formulae (NLC and NLC/SPION) were incorporated in an optimized thermosensitive mucoadhesive in situ system composed of 15% pluronic 127 and 0.75% sodium alginate and evaluated for the anticonvulsant action in chemically induced convulsive Swiss Albino mice. The treatment of animals with NLC/SPION significantly prolonged the onset times for convulsion and considerably protected the animals from death. One can thus hope for the emergence of a new intranasal treatment of epilepsy with consequent decrease in peripheral side effects of clonazepam.