Circadian rhythmicity and photobiological mechanisms of light sensitivity and discomfort glare in humans

Discomfort glare is a common visual sensation, which is generally reported when being exposed to a brighter lit environment. In certain clinical conditions, this sensation is abnormally amplified, and is commonly named photophobia. Despite the frequent appearance of this sensation in everyday life or in pathological conditions, the underlying mechanisms remain poorly understood. We show here, in highly controlled laboratory constant routine conditions, that light-induced discomfort glare is rhythmic over the 24-hour day. We reveal a strong circadian drive, with a sinusoidal rhythmicity, with maximal discomfort glare in the middle of the night and minimal in the afternoon. We also find a modest sleep-related homeostatic drive of visual discomfort, with a linear increase in discomfort glare over 34 hours of prolonged wakefulness. Our study reveals that discomfort glare is primarily driven by the ipRGC pathway, and that mid and/or long wavelengths cones are involved as well. The 6.5-hour phase lag between the rhythms of photoreceptors' sensitivity, assessed through pupillary light reflex, and of glare discomfort, suggests two independent underlying mechanisms. In conclusion, our findings highlight the need to take time-of-day and biological rhythmicity into account in the evaluation of light-induced discomfort glare. Apprehending these mechanisms may help understand photophobia in clinical populations, such as in migraine patients, and should be taken into account to optimize light quality at home and at the workplace, both for day and night work

Prolactin immunoassay: does the high-dose hook effect still exist?

International audiencePurpose: Measurement of prolactin in clinical laboratories is an important component in the management of patients with pituitary adenoma. Prolactin measurement is known to be sensitive to the high-dose hook effect, in the presence of extremely high prolactin concentrations. This interference is referred to in most recent articles discussing prolactin assays and the management of prolactin-secreting pituitary adenomas. The objective of our study was to evaluate if the high-dose hook effect remains relevant in current practice, when using currently available assays.Methods: Serum from a patient with a giant macroprolactinoma was assayed using all of the available prolactin assays in France in 2020, using native serum and after dilution. Technical inserts from assays were reviewed to assess the information on analytical principles, numbers of steps, and any reference to high dose hook effect.Results: Fourteen assay kits were studied by 16 laboratories; all were two-site immunometric assays, mostly using one step (11/14). Results obtained after dilution varied from 17,900 µg/L to 86,900 µg/L depending on the assay used. One tested assay was sensitive to the high-dose hook effect leading to a falsely lower prolactin concentration when measuring native serum (150 µg/L compared to 17,900 µg/L after dilution).Conclusion: The high-dose hook effect still exists in a very small minority of prolactin assays. The evolution of assay methods may lead to new assays that remain sensitive to this effect in the future. We therefore advise that the hook effect should still be mentioned in prolactin assay recommendations

Is Gross Total Resection Reasonable in Adults with Craniopharyngiomas with Hypothalamic Involvement?

International audienceObjective: The treatment of hypothalamus-invading craniopharyngiomas, based on pediatric experience, is subtotal resection (STR) with radiotherapy. This strategy sometimes leads to uncontrollable tumor progression. In adults, with the use of endoscopic endonasal surgery (EES), does removing the hypothalamic part of the tumor-whenever possible-compromise the outcome of the patients?Methods: We included adults with craniopharyngioma treated by a first EES in 2008-2016 by senior neurosurgeon (E.J.). Endocrine, ophthalmologic, and hypothalamic data were retrospectively collected, including body mass index (BMI), cognitive and social status, with a systematic follow-up interview. Magnetic resonance imaging scans were graded according to Puget classification: 0, no hypothalamic involvement; 1, hypothalamic displacement; and 2, hypothalamic involvement. Grade 2 tumors were separated into gross total resection (GTR) or STR.Results: We included 22 patients aged 18-79 years. Presenting symptoms were visual (14, 64%), endocrine dysfunction (10, 45%), BMI >30 (8, 36%), and cognitive/psychiatric impairment (9, 41%). Fourteen (64%) were grade 2 craniopharyngiomas. GTR was performed in 14 (64%) patients. Postoperatively, 12/14 (86%) cases improved visually, and 20 (91%) needed hormone replacement therapy. There was no difference in BMI evolution in the GTR versus STR group, cognitive status was stable or improved in all patients except 1; 4/8 patients with STR experienced progression needing adjuvant treatment versus no patient with GTR.Conclusions: EES GTR of grade 2 craniopharyngiomas does not cause major hypothalamic worsening, in contrast with children operated by cranial approaches. The surgeon's experience is key in deciding when to stop the dissection. Offering GTR whenever possible aims at avoiding tumor progression and radiotherapy

Multi-System Deconditioning in 3-Day Dry Immersion without Daily Raise

Dry immersion (DI) is a Russian-developed, ground-based model to study the physiological effects of microgravity. It accurately reproduces environmental conditions of weightlessness, such as enhanced physical inactivity, suppression of hydrostatic pressure and supportlessness. We aimed to study the integrative physiological responses to a 3-day strict DI protocol in 12 healthy men, and to assess the extent of multi-system deconditioning. We recorded general clinical data, biological data and evaluated body fluid changes. Cardiovascular deconditioning was evaluated using orthostatic tolerance tests (Lower Body Negative Pressure + tilt and progressive tilt). Metabolic state was tested with oral glucose tolerance test. Muscular deconditioning was assessed via muscle tone measurement.Results: Orthostatic tolerance time dropped from 27 ± 1 to 9 ± 2 min after DI. Significant impairment in glucose tolerance was observed. Net insulin response increased by 72 ± 23% on the third day of DI compared to baseline. Global leg muscle tone was approximately 10% reduced under immersion. Day-night changes in temperature, heart rate and blood pressure were preserved on the third day of DI. Day-night variations of urinary K+ diminished, beginning at the second day of immersion, while 24-h K+ excretion remained stable throughout. Urinary cortisol and melatonin metabolite increased with DI, although within normal limits. A positive correlation was observed between lumbar pain intensity, estimated on the second day of DI, and mean 24-h urinary cortisol under DI. In conclusion, DI represents an accurate and rapid model of gravitational deconditioning. The extent of glucose tolerance impairment may be linked to constant enhanced muscle inactivity. Muscle tone reduction may reflect the reaction of postural muscles to withdrawal of support. Relatively modest increases in cortisol suggest that DI induces a moderate stress effect. In prospect, this advanced ground-based model is extremely suited to test countermeasures for microgravity-induced deconditioning and physical inactivity-related pathologies

GHRH excess and blockade in X-LAG syndrome

X-linked acrogigantism (X-LAG) syndrome is a newly-described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated growth hormone (GH) and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GH-releasing hormone (GHRH) levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(D-Arg²)-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome

Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP) on diagnosis of Cushing's syndrome

International audienceCushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section

2018 Consensus of the French Society of Endocrinology: endocrine toxicities of cancer immunotherapies

Immunotherapy induced side effects: Are frequent, usually well-tolerated, and can lead to thyroid, pituitary, and less frequently adrenals and pancreas (fulminant diabetes) disease,. Do not contra-indicate immunotherapy, and rarely require high dose glucocorticoids; Need to be screened for, as there are acute manifestations, and replacement treatments can be given lifelong; Require a pre-immunotherapy evaluation; Require a careful follow-up at least during the first 6 months of immunotherapy

Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences.

Context: Responses of GH-secreting adenomas to multimodal management of acromegaly varies widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying predictive factors of their evolution is a research priority. Objective: To clarify the relationship between adenoma T2-weighted signal on diagnostic MRI in acromegaly and clinical and biological features at diagnosis. Design: International, multicenter, retrospective analysis. Setting: 10 endocrine tertiary referral centers. Patients: 297 acromegalic recently diagnosed patients with available diagnostic MRI evaluations were included in the study. Main outcome measure: Clinical, biochemical characteristics and MRI signal findings. Results: T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyper- and isointense counterparts (p<0.0001), were associated with higher IGF1 levels (p=0.0001), invaded the cavernous sinus less frequently (p=0.0002) and rarely caused optic chiasm compression (p<0.0001). Acromegalic men tended to be younger at diagnosis than women (p=0.067) and presented higher IGF1 values (p=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (p<0.0001), whereas in women optic chiasm compression of macroadenomas occurred more often (p=0.0067). Most adenomas (45.1%) measured between 11-20mm in maximal diameter and bigger adenomas were diagnosed at younger ages (p=0.0001). Conclusions: T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies