Aim
Children with brain and cervical medulla tumours may experience circadian abnormalities and poor health. We aimed to examine their circadian rhythm, fatigue and quality of life (QoL).
Methods
...Children with a brain or cervical medulla tumour were recruited from the Paediatric Department, Rigshospitalet, Copenhagen, Denmark, between 2016 and 2020. They were grouped by tumour location involving the circadian regulatory system, defined as diencephalon, pineal gland, brain stem and cervical medulla, or other areas. Saliva melatonin and cortisol concentrations were measured. Sleep diaries and actigraphy assessed sleep‐wake patterns. The Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale measured fatigue and QoL.
Results
We included 68 children (62% males) with a median age (25th‐75th percentiles) of 12.2 (7.7–16.3) years. Children with tumours involving the circadian regulatory system typically had a lower melatonin peak (p=0.06) and experienced significantly more fatigue and poorer QoL. Low melatonin profiles were observed in 31% and 4% had a phase‐shifted daytime peak, compared with 14% and 0%, respectively, in children with tumours located elsewhere. Children with low melatonin profiles had significantly lower inter‐daily stability than those with normal profiles.
Conclusion
Tumours involving the circadian regulatory system adversely affected circadian function, fatigue and QoL.
Objective
Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies.
Design
A nationwide cohort study including all incident cases of acromegaly (1978–2010, ...n = 596) and a meta‐analysis on sex differences in active acromegaly (40 studies) were performed.
Method
Sex‐dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin‐like growth factor 1 (IGF‐I) and growth hormone (GH) concentrations were estimated.
Results
The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5–49.8 (males) vs. 47.2 CI95% 45.5–48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R2 = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF‐ISDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females.
In the meta‐analysis, the weighted percentage female was 53.3% (CI95% 51.5–55.2) with considerable heterogeneity (I2 = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9–4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% −0.4 to 2.1). Serum IGF‐I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable.
Conclusion
There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF‐I concentrations and a longer diagnostic delay.
The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the ...p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance.
We performed a systematic review of peer‐reviewed publications and case‐reports on individuals and populations harbouring the p.Asp313Tyr variant.
Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha‐galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb3) and sphingosine‐globotriaosylceramide (lyso‐Gb3) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non‐elevated lysoGb3/Gb3 concentrations and lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders.
p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels.
Objective
The occurrence of thyroid disease varies among populations. While the iodine nutrition level of the Faroese seems to have been decreasing over the past decades, there is no systematic ...evaluation of the thyroid disease pattern in the Faroe Islands. Such knowledge of thyroid disease occurrence in the North Atlantic region may support healthcare planning and prevention. To investigate incidence rates, including subtypes of thyroid diseases, and demographic characteristics of thyroid disease patients in the Faroe Islands, to improve understanding of the patterns and trends of these disorders.
Design and Method
A registry‐based observational study was conducted over 10 years, encompassing all adult Faroese individuals. Patients and Measurements: Health records from general practitioners and hospitals were used to identify incident cases of thyroid diseases. Validation was performed using multiple data sources. The incidence rates were standardised using population data from the middle of the study period 2006–2018.
Results
Among the 1152 individuals diagnosed with thyroid disease, the standardised incidence rates per 100,000 person‐years were 55 for hyperthyroidism and 112 for hypothyroidism, and around four times higher in women than in men. Hashimoto's thyroiditis was the dominant cause of hypothyroidism, while Graves' disease was the leading cause of hyperthyroidism. The incidence of hypothyroidism increases with age. A decreasing trend was observed over time for both hypothyroidism and hyperthyroidism.
Conclusion
Considering the decrease in iodine nutrition levels over the past decades, we were surprised by the high incidence of autoimmune thyroid disease. The findings highlight the need for continuous monitoring of thyroid disease occurrence in coastal areas of the North Atlantic Ocean.
Objective
Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF‐I) patterns as well as clinical features but whether this also pertains to ...controlled disease is unclear.
Design
In a cross‐sectional, multi‐centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined.
Methods
Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF‐I and completion of two HR‐Qol questionnaires (acromegaly quality of life questionnaire AcroQol and Patient‐assessed Acromegaly Symptom Questionnaire PASQ).
Results
The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF‐I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF‐I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04).
Conclusion
In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF‐I levels, which also translated into impaired metabolic health and well‐being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease‐specific sex differences prevail after treatment.
Objective
To estimate the proportion of patients with persistent normoprolactinaemia following dopamine agonist (DA) withdrawal and to identify predictors of successful withdrawal in patients with ...hyperprolactinaemia.
Design, patients, and measurements
A systematic review of observational eligible studies were identified by searching PubMed and Embase. The primary outcome was the proportion of patients with normoprolactinaemia after cessation of DA treatment. Secondary outcome included the proportion of patients with normoprolactinaemia after DA withdrawal using individual patient data. Risk of bias was assessed by using Newcastle‐Ottawa Scale. Pooled proportions were estimated using a random effects model in case I2 ≤ 75% or by reporting range of effects if I2 > 75%.
Results
Thirty‐two observational studies enroling 1563 patients were included. The proportion of patients with persistent normoprolactinaemia ranged from 0% to 75% (I2 = 84%). Heterogeneity was partly explained by age with more successful withdrawal in patients of higher age. Individual patient data analyses suggested that the proportion of patients with persistent normoprolactinaemia 6 months after DA withdrawal with a low maintenance dose and full regression of the prolactinoma was 87.7% (95% confidence interval CI = 60.7–97.1; I2 = 0%) and 58.4% (95% CI = 23.8–86.3; I2 = 75%) for microadenomas and macroadenomas, respectively.
Conclusions
The proportion of patients with persistent normoprolactinaemia following DA withdrawal treatment varied greatly, partly explained by the mean age of participants of the individual studies. Individual patient data analysis suggested that successful withdrawal was likely in patients with full regression of prolactinomas using a low maintenance dose before cessation.
Injury to the glomerular podocyte is a key mechanism in human glomerular disease and podocyte repair is an important therapeutic target. In Fabry disease, podocyte injury is caused by the ...intracellular accumulation of globotriaosylceramide. This study identifies in the human podocyte three endocytic receptors, mannose 6-phosphate/insulin-like growth II receptor, megalin, and sortilin and demonstrates their drug delivery capabilities for enzyme replacement therapy. Sortilin, a novel α-galactosidase A binding protein, reveals a predominant intracellular expression but also surface expression in the podocyte. The present study provides the rationale for the renal effect of treatment with α-galactosidase A and identifies potential pathways for future non-carbohydrate based drug delivery to the kidney podocyte and other potential affected organs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context
Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor‐interacting protein (AIP) gene are associated with familial pituitary adenoma ...predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved.
Objective
To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant.
Methods
The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants.
Results
We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin‐like growth factor‐I (IGF‐I) levels in all family members were above the mean for age and sex (IGF‐I SDS: +0.6 CI95% +0.4‐0.9, P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons.
Conclusions
This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.
The endocrinology of pregnancy involves endocrine and metabolic changes as a consequence of physiological alterations at the foetoplacental boundary between mother and foetus. The vast changes in ...maternal hormones and their binding proteins complicate assessment of the normal level of most hormones during gestation. The neuroendocrine events and their timing in the placental, foetal and maternal compartments are critical for initiation and maintenance of pregnancy, for foetal growth and development, and for parturition. As pregnancy advances, the relative number of trophoblasts increase and the foeto-maternal exchange begins to be dominated by secretory function of the placenta. As gestation progresses toward term, the number of cytotrophoblasts again declines and the remaining syncytial layer becomes thin and barely visible. This arrangement facilitates transport of compounds including hormones and their precursors across the foeto-maternal interface. The endocrine system is the earliest system developing in foetal life, and it is functional from early intrauterine existence through old age. Regulation of the foetal endocrine system relies, to some extent, on precursors secreted by placenta and/or mother.
► Humans are exposed to a large number of suspected thyroid disrupting chemicals. ► Exposure to PCBs and perchlorate has negative effects on thyroid function. ► BPA, UV-filters and phthalates are ...also suspected to be thyroid disrupting chemicals. ► Long term studies on thyroid effects in humans are currently lacking.
In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties.
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