Nested calcium dynamics support daily cell unity and diversity in the suprachiasmatic nuclei of free-behaving mice.

The suprachiasmatic nuclei (SCN) of the anterior hypothalamus host the circadian pacemaker that synchronizes mammalian rhythms with the day-night cycle. SCN neurons are intrinsically rhythmic, thanks to a conserved cell-autonomous clock mechanism. In addition, circuit-level emergent properties confer a unique degree of precision and robustness to SCN neuronal rhythmicity. However, the multicellular functional organization of the SCN is not yet fully understood. Indeed, although SCN neurons are well-coordinated, experimental evidences indicate that some neurons oscillate out of phase in SCN explants, and possibly to a larger extent in vivo. Here, to tackle this issue we used microendoscopic Ca2+ i imaging and investigated SCN rhythmicity at a single cell resolution in free-behaving mice. We found that SCN neurons in vivo exhibited fast Ca2+ i spikes superimposed upon slow changes in baseline Ca2+ i levels. Both spikes and baseline followed a time-of-day modulation in many neurons, but independently from each other. Daily rhythms in basal Ca2+ i were highly coordinated, while spike activity from the same neurons peaked at multiple times of the light cycle, and unveiled clock-independent coactivity in neuron subsets. Hence, fast Ca2+ i spikes and slow changes in baseline Ca2+ i levels highlighted how multiple individual activity patterns could articulate within the temporal unity of the SCN cell network in vivo, and provided support for a multiplex neuronal code in the circadian pacemaker.

Screening by single-molecule molecular inversion probes targeted sequencing panel of candidate genes of infertility in azoospermic infertile Jordanian males.

Infertility is a common health problem that affects around 1 in 6 couples in the United States, where half of these cases are attributed to male factors. Genetics play an important role in infertility and it is estimated that up to 50% of cases are due to genetic factors. Despite this, many male infertility cases are still idiopathic. This study aimed to identify the presence of possibly pathogenic rare variants in a set of candidate genes related to azoospermia in 69 Jordanian men using a next-generation sequencing-based panel covering more than a hundred male infertility related genes. A total of 9 variants were found and validated. Among them, two variants included reported pathogenic variants in CFTR and one novel pathogenic variant in the USP9Y gene. We also report the detection of 6 other variants with uncertain significance in other genes. Interestingly, male cases with CFTR variants did not show the expected cystic fibrosis phenotypes except for infertility. This work helps to uncover the contribution of additional genetic factors to the aetiology of male infertility and highlights the importance to obtain more reliable information about the presence of genetic variation in the Jordanian population.

Treatment of sebaceous gland hyperplasia: a review of the literature.

BACKGROUND: Sebaceous gland hyperplasia (SGH) is a benign cutaneous proliferation of the sebaceous glands that primarily affects the elderly group and frequently appears in individuals receiving long-term ciclosporin therapy such as organ transplant recipients. In the latter group, SGHs are usually multiple in number and occur predominantly on the face. Patients may find their appearance cosmetically undesirable and, in some cases, may result in significant negative psychological impact. There is, therefore, a demand for safe and effective treatment for SGH particularly in this patient group. A variety of treatment modalities have been previously described including electrodessication,surgery, cryotherapy, oral isotretinoin, lasers, and topical photodynamic therapy (PDT). METHODS: The objective of this paper is to review the various treatment modalities for SGH. We performed a systematic literature review using the National Library of Medicine's PubMed Database, whereby we included articles that met the following criteria: published in English, not focused on SGH in rhinophyma, studies with adult sample with SGH lesions, and studies with patients with SGH related to ciclosporin. RESULTS: Our findings show that the literature is categorized according to the treatment modalities ranging from conventional techniques such as oral isotretinoin and cryotherapy to more advanced topical PDT, lasers and a combination of both. We found that effectiveness does not depend on the technique itself but instead on the number of lesions, financial cost, psychological factors, skin phototype and age. CONCLUSIONS: Our work shows that SGH can be treated effectively by customizing the treatment modality according to different parameters, while effectively maintaining clearance of SGH lesions with best cosmetic outcome.

Combination Therapy of Ipilimumab and Nivolumab-associated Toxic Epidermal Necrolysis (TEN) in a Patient With Metastatic Melanoma: A Case Report and Literature Review.

Ipilimumab and nivolumab are immune checkpoint inhibitors used in the treatment of metastatic melanoma. The authors report the case of a 62-year-old white male individual with metastatic choroidal melanoma who had commenced adjuvant systemic treatment with combination checkpoint inhibitor therapy of intravenous ipilimumab (anti-cytotoxic T-lymphocyte antigen-4) and nivolumab (anti-programmed cell death-1) at 3-week cycle intervals. On day 4 after the second cycle, he developed an acute widespread rash. On examination there was confluent erythema with bullae and epidermal loss over 60% of the body surface area, with severe oral mucosal ulceration. A clinical diagnosis of toxic epidermal necrolysis (TEN) was made and he was transferred to the intensive care unit. Despite active treatment, he deteriorated systemically and died from multiorgan failure. This is the first reported case of TEN associated with nivolumab and ipilimumab dual therapy for metastatic uveal melanoma. Monotherapy improves survival in metastatic melanoma, but dual therapy has shown a greater mortality benefit at 3 years. Although the literature demonstrates case reports of Stevens-Johnson syndrome and TEN in association with nivolumab, ipilimumab has generally been regarded as a "safe" treatment with regard to severe cutaneous adverse reactions. With the increased use of immunotherapies, it is important to plan the management and early recognition of drug-related skin toxicity. This is of greatest concern during treatment initiation and with the higher risk associated with combination therapy. Reporting of adverse events and infrequently encountered complications with systemic biologic treatments will augment pharmacovigilance and improve the stratification of patients to treatments.

Molecular and Cellular Networks in The Suprachiasmatic Nuclei.

Why do we experience the ailments of jetlag when we travel across time zones? Why is working night-shifts so detrimental to our health? In other words, why can't we readily choose and stick to non-24 h rhythms? Actually, our daily behavior and physiology do not simply result from the passive reaction of our organism to the external cycle of days and nights. Instead, an internal clock drives the variations in our bodily functions with a period close to 24 h, which is supposed to enhance fitness to regular and predictable changes of our natural environment. This so-called circadian clock relies on a molecular mechanism that generates rhythmicity in virtually all of our cells. However, the robustness of the circadian clock and its resilience to phase shifts emerge from the interaction between cell-autonomous oscillators within the suprachiasmatic nuclei (SCN) of the hypothalamus. Thus, managing jetlag and other circadian disorders will undoubtedly require extensive knowledge of the functional organization of SCN cell networks. Here, we review the molecular and cellular principles of circadian timekeeping, and their integration in the multi-cellular complexity of the SCN. We propose that new, in vivo imaging techniques now enable to address these questions directly in freely moving animals.