Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis

Objective: Disorders of sexual development (DSD) are a heterogeneous group of genital defects affecting chromosomal, gonadal and anatomical sex. 46,XY DSD is a subset of DSD which covers a wide range of phenotypes in which 46,XY gonadal dysgenesis (GD) is the most severe form. In this study, we report on the clinical and molecular cytogenetic findings of a study on a Tunisian girl with the syndromic form of 46,XY DSD. Methods: This case was a phenotypic female patient having several congenital anomalies including growth retardation. Karyotype, fluorescence in situ hybridization and array Comparative Genome Hybridization (array CGH) were performed. Results: The proband exhibited a de-novo 46,X,der(Y) karyotype. Array CGH revealed a pathogenic 27.5Mb gain of an Xp21.2 chromosome segment leading to Xp functional disomy. No deletion was observed in the Y-chromosome. The duplicated region encompassed the NR0B1 (DAX1) and MAGEB genes, located within the dosage sensitive sex (DSS) reversal locus, known as promote genes responsible for human sex reversal and testis repression. The extra-dosage and interactions of these genes with different specific genes could result in the impairment of the male sex pathway. Over-dosage of KAL1 and IL1RAPL1 genes fall within the somatic features observed in the patient. Conclusion: To the best of our knowledge, we report on the fourth case of Xp21.2-pter duplication within Xp;Yp translocation associated with XY GD. Our findings suggest that when duplicated, the NR0B1 and MAGEB genes could be a major cause of XY GD. Therefore, we emphasize the usefulness of a combined cytogenetic approach in order to provide an accurate genetic diagnosis for those patients having syndromic XY DSD in a clinical setting.

Medical experimentation on prisoners (part 6): Situation in Africa, Middle East and part of the Arab world (Tunisia in particular).

The developing World has the largest number of prisoners globally, but their situation is considered «opaque¼. In recent years, there has been a growing interest from pharmaceutical companies in this part of the world. A growing number of voices is denouncing the spectrum of medical exploitation of prisoners. In Tunisia, there is a great legislative effort to ensure the protection of this vulnerable population. The present history note, the sixth in a series on medical experimentation on prisoners, intended to discuss the situation of medical experimentation in prisons in Africa, the Middle East and part of the Arab world, Tunisia in particular.

Medical experimentation on prisoners (part 1): historical milestones.

The exploitation of prisoners in medical research is an ancient phenomenon. However, the history of the XXth century was marked by major events that reached the peak of horror during the second world war. Although the collective mind has remembered the outrages of the Nazi regime, the truth is that these practices were adopted by the majority of the military powers of that time, and continued after the end of the war. This history note is the first in a series that aims to review the circumstances and implications of these dark moments in the history of medical research in order to pay tribute to the countless victims who paid with their lives for «scientific progress¼ and to understand the reasons for current ethical considerations in biomedical experimentation on persons deprived of liberty.

Medical experimentation on prisoners (part 2): role of doctors in research abuses.

The involvement of physicians as an executive tool in the excesses of medical experimentation in prisons continues to raise questions and incomprehension. From the depths of the extermination camps under the Nazi regime to the iterative exploitation scandals after the Second World War, the ability of certain physicians to overstep the foundations of the Hippocratic Oath of «do no harm¼ and associate themselves with so many atrocities will always surprise. The answers to this question seem ambiguous because the excesses of medical experimentation in prisons should be reconsidered in their associated historical-political context. This history note, the second in a series on medical experimentation in prisons, aims to relieve the excesses attributed to physicians during medical experimentation on prisoners.

Medical experimentation on prisoners (part 3): the main milestones of the evolving ethical' texts and codes.

Ethical foundations related to the use of human beings in medical research, already existed in the oldest texts. The historical evolution of regulations (in terms of texts and codes) had always drawn its legitimacy and its logic from the historical context. The main aim of these regulations was to satisfy a need to restore moral or physical prejudices, by hoping by means of the law, that these abuses would not be repeated. Although they were the main victims of medical experimentation, prisoners were rarely specifically identified in these legislations. This history note, the third in a series on medical experimentation on prisoners, aims to describe the major founding texts of ethics in medical experimentation, drawing attention to the historical context as well as the issues that shaped these documents.

[Medical experimentation on prisoners (part 4): the dilemma of 'pros' and 'cons'.]

Given the long history of abuse of prisoners in medical experimentation, it is understandable that additional safeguards have been established to protect this social category. However, the debate between the detractors and the supporters of the medical experimentation in the prison environment is still going on. The present history note, the fourth in a series on medical experimentation on prisoners, intended to relate the main arguments of both sides: ie; the detractors and supporters of medical experimentation on prisoners.

[Medical experimentation on prisoners (part 5): ethical considerations].

Medical experimentation on prisoners is one of the most difficult ethical issues because it brings many principles into conflict with the reality of the practice. These ethical principles, which are universal and timeless, are accepted as elementary rights for every human being. However, in a detention setting, these principles are easily lost. Moreover, the scope of this problem goes far beyond the walls of the penitentiary to touch on conflicting issues of scientific publication, social discrimination, and even political decisions sometimes. The present history note, the fifth in a series on medical experimentation on prisoners, intended to discuss the main ethical considerations regarding prisoners, and to highlight the difficulty of their implementation.

Reversibility of pancreatic ß-cells dysfunction after vitamin D and calcium supplementation: a pilot study in a population of obese and prepubescent North-African children.

The mechanisms of diabetogenesis in children remain largely obscure. This study aimed to determine the impact of vitamin D and calcium supplementation on pancreatic ß-cells function in terms of insulin secretion and sensitivity. This was a quasi-experimental study involving 30 obese and prepubescent Tunisian children (57% boys). During three months, the children received calcium and vitamin D supplementation at therapeutic doses. An oral glucose tolerance test (OGTT) was performed at the beginning and at the end of the study. The following metabolic definitions were applied: i) hyperinsulinism: insulinemia sum > 300 µ UI/ml during OGTT, ii) insulin-resistance: homeostatic model assessment of insulin-resistance > 2, iii) normal glycaemic profile: normal plasma levels during OGTT without any spike, and iv) pancreatic ß-cells dysfunction reversibility: disappearance of the aforementioned disorders. The means ± standard-deviation of age and body mass index were 10.87 ± 1.9 years, and 30.17 ± 4.99 kg/m2, respectively. All children were at the stage of hyperinsulinism associated with insulin-resistance. These disturbances were noted even in children having a normal glycaemic profile at OGTT. After calcium and vitamin D supplementation, glycaemic profile as well as insulin-secretion improved significantly (p < 0.0001). Hyperinsulinism and insulin-resistance decreased significantly by 56.67% (p < 0.0001) and 70.00% (p < 0.0001), respectively. Complete reversibility of these two disorders was noted in 26.6% of children. To conclude, in obese and prepubescent children, vitamin D and calcium supplementation led to the reversibility of the pancreatic ß-cells dysfunction.

In COVID-19 context : a look back at the transition to exclusive e-learning experiment and the engagement of medical students.

In a context of unprecedented pandemic, e-learning has emerged as the only possible alternative to pursue higher education. In this work, we carried out an experiment consisting in completely transforming a fundamental science course into e-learning via the tools offered by Moodle platform. The results were generally encouraging in terms of learning outcomes and evaluation. However, the lack of motivation and adhesion observed in part of the promotion remains the main obstacle universally criticized in this type of teaching.

Evaluation of IGF1/IGFBP3 Molar Ratio as an Effective Tool for Assessing the Safety of Growth Hormone Therapy in Small-for-gestational-age, Growth Hormone-Deficient and Prader-Willi Children

Objective: IGF1 concentration is the most widely used parameter for the monitoring and therapeutic adaptation of recombinant human growth hormone (rGH) treatment. However, more than half the variation of the therapeutic response is accounted for by variability in the serum concentrations of IGF1 and IGFBP3. We therefore compared the use of IGF1/IGFBP3 molar ratio with that of IGF1 concentration alone. Methods: We selected 92 children on rGH for this study and assigned them to three groups on the basis of growth deficiency etiology: small for gestational age (SGA), GH deficiency (GHD) and Prader-Willi syndrome (PWS). Plasma IGF1 and IGFBP3 concentrations and their molar ratio were determined. Results: Before rGH treatment, mean IGF1/IGFBP3 molar ratio in the SGA, GHD and PWS groups was 0.14±0.04, 0.07±0.01 and 0.12±0.02, respectively. After the initiation of rGH treatment, these averages were 0.19±0.07, 0.20±0.08 and 0.19±0.09, within the normal range for most children, even at puberty and despite some significant increases in serum IGF1 levels. Conclusion: We consider IGF1/IGFBP3 molar ratio to be a useful additional parameter for assessing therapeutic safety in patients on rGH, and for maintaning the values within the normal range for age and pubertal stage.