Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in T cells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.
Jonàs Juan-Mateu, Olatz Villate, and Décio L Eizirik
Edoarda V A Albuquerque, Renata C Scalco, and Alexander A L Jorge
Tall stature is defined as a height of more than 2 standard deviations (s.d.) above average for same sex and age. Tall individuals are usually referred to endocrinologists so that hormonal disorders leading to abnormal growth are excluded. However, the majority of these patients have familial tall stature or constitutional advance of growth (generally associated with obesity), both of which are diagnoses of exclusion. It is necessary to have familiarity with a large number of rarer overgrowth syndromes, especially because some of them may have severe complications such as aortic aneurysm, thromboembolism and tumor predisposition and demand-specific follow-up approaches. Additionally, endocrine disorders associated with tall stature have specific treatments and for this reason their recognition is mandatory. With this review, we intend to provide an up-to-date summary of the genetic conditions associated with overgrowth to emphasize a practical diagnostic approach of patients with tall stature and to discuss the limitations of current growth interruption treatment options.
Managing the symptoms of menopause after a diagnosis of breast cancer offers some unique clinical challenges. For some women, vasomotor symptoms can be severe and debilitating, and hormone therapy is at least relatively contraindicated. Non-oestrogen therapies for hot flushes include SSRIs, clonidine, gabapentin and perhaps black cohosh extracts. Vulvovaginal atrophy can usually be alleviated by simple moisturizers, although some may need specialized physiotherapy such as vaginal dilators. In a small number, topical oestrogens may be the only treatment that works. The CO2 laser may be a novel, non-oestrogen therapy to alleviate this unpleasant symptom. Bone loss can be accelerated in some patients on AIs or those who had early menopause induced by chemotherapy.
Stephan Petersenn, Albert Beckers, Diego Ferone, Aart van der Lely, Jens Bollerslev, Marco Boscaro, Thierry Brue, Paolo Bruzzi, Felipe F Casanueva, Philippe Chanson, Annamaria Colao, Martin Reincke, Günter Stalla, and Stelios Tsagarakis
A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease – including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence.
We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed.
Data from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0–96.6%; median, 77.9%) and recurrence (0–47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience.
The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.
Frederic Castinetti, Rachel Reynaud, Alexandru Saveanu, Nicolas Jullien, Marie Helene Quentien, Claire Rochette, Anne Barlier, Alain Enjalbert, and Thierry Brue
Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.
Vladimir Vasilev, Liliya Rostomyan, Adrian F Daly, Iulia Potorac, Sabina Zacharieva, Jean-François Bonneville, and Albert Beckers
Pituitary incidentalomas are a by-product of modern imaging technology. The term ‘incidentaloma’ is neither a distinct diagnosis nor a pathological entity. Rather, it is a collective designation for different entities that are discovered fortuitously, requiring a working diagnosis based on the input of the radiologist, endocrinologist and often a neurosurgeon. In addition to pathological conditions affecting the pituitary gland, a thorough knowledge of the radiological characteristics of normal variants and technical artifacts is required to arrive at an accurate differential diagnosis. After careful radiological and hormonal evaluation, the vast majority of pituitary incidentalomas turn out to be non-functioning pituitary microadenomas and Rathke’s cleft cysts (RCCs). Based on the low growth potential of non-functioning pituitary microadenomas and RCCs, periodic MRI surveillance is currently considered the optimal management strategy. Stricter follow-up is required for macroadenomas, as increases in size occur more frequently.