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Flood risk assessments are typically based on scenarios which assume homogeneous return periods of flood peaks throughout the catchment. This assumption is unrealistic for real flood events and may bias risk estimates for specific return periods. We investigate how three assumptions about the spatial dependence affect risk estimates: (i) spatially homogeneous scenarios (complete dependence), (ii) spatially heterogeneous scenarios (modelled dependence) and (iii) spatially heterogeneous but uncorrelated scenarios (complete independence). To this end, the model chain RFM (regional flood model) is applied to the Elbe catchment in Germany, accounting for the spatio-temporal dynamics of all flood generation processes, from the rainfall through catchment and river system processes to damage mechanisms. Different assumptions about the spatial dependence do not influence the expected annual damage (EAD); however, they bias the risk curve, i.e. the cumulative distribution function of damage. The widespread assumption of complete dependence strongly overestimates flood damage of the order of 100 % for return periods larger than approximately 200 years. On the other hand, for small and medium floods with return periods smaller than approximately 50 years, damage is underestimated. The overestimation aggravates when risk is estimated for larger areas. This study demonstrates the importance of representing the spatial dependence of flood peaks and damage for risk assessments.

Flood risk is impacted by a range of physical and socio-economic processes. Hence, the quantification of flood risk ideally considers the complete flood risk chain, from atmospheric processes through catchment and river system processes to damage mechanisms in the affected areas. Although it is generally accepted that a multitude of changes along the risk chain can occur and impact flood risk, there is a lack of knowledge of how and to what extent changes in influencing factors propagate through the chain and finally affect flood risk. To fill this gap, we present a comprehensive sensitivity analysis which considers changes in all risk components, i.e. changes in climate, catchment, river system, land use, assets, and vulnerability. The application of this framework to the mesoscale Mulde catchment in Germany shows that flood risk can vary dramatically as a consequence of plausible change scenarios. It further reveals that components that have not received much attention, such as changes in dike systems or in vulnerability, may outweigh changes in often investigated components, such as climate. Although the specific results are conditional on the case study area and the selected assumptions, they emphasize the need for a broader consideration of potential drivers of change in a comprehensive way. Hence, our approach contributes to a better understanding of how the different risk components influence the overall flood risk.

MEN1, an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1, manifests with co-occurrence of multiple endocrine/neuroendocrine neoplasms. An iPSC line derived from an index patient carrying the mutation c.1273C>T (p.Arg465*) was edited using a single multiplex CRISPR/Cas approach to create an isogenic control non-mutated line and a homozygous double mutant line. These cell lines will be useful for elucidating subcellular MEN1 pathophysiology and for screening to identify potential MEN1 therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dhruv Sareen has patent #US patent US 10,221,395 and 10,745,671 issued to Cedars Sinai Medical Center., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Forearm osteoporosis is a well-known complication of primary hyperparathyroidism (PHPT). However, measuring forearm bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at the distal radius is often neglected in clinical practice despite the fact that osteoporosis at any site is a criterion indicating surgery. We aimed to evaluate the importance and priority of forearm BMD and to determine its association with biochemical parameters., Material and Methods: Three hundred fourteen patients (272 females, 42 males) with PHPT who had BMD measurements at 3 sites were recruited for this retrospective study. The effect on surgical indications of osteoporosis only in the forearm was evaluated. Group 1 (n=151) with forearm osteoporosis and group 2 (n=163) without were compared in terms of biochemical and clinical parameters., Results: In the overall study population, 165 of the 314 patients had osteoporosis in at least 1 site. Twenty seven percent (n=86/314) had osteoporosis only in the forearm, while the other 2 sites (lumbar spine and femoral neck) were normal or osteopenic. Surgery was indicated based on osteoporosis only in the forearm in 10% of patients (n=30/314). Corrected calcium and parathyroid hormone levels were significantly higher in group 1 than group 2 (p=0.001 and p<0.001, respectively) and were also negatively correlated with distal radius BMD, T-score and Z-score in the whole study group., Conclusion: Including the distal radius in BMD measurement increased the number of patients diagnosed with osteoporosis and for whom surgery was indicated. Calcium and PTH were also more frequently elevated in patients with forearm osteoporosis. These results show that distal radius BMD is relevant to the management of PHPT., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate the effects of the pandemic process on those with an endocrinological disease that will require close follow-up from the last visit before the pandemic., Materials and Methods: Patients of 3,903 with thyroid, calcium-bone metabolism, adrenal gland, pituitary diseases, and neuroendocrine tumor (NET) were retrospectively scanned. The remaining 855 (656 females and 199 males) patients with active disease or who still needed multidisciplinary approaches were included. The number of patients who continued the disease-related medical procedures and could complete these procedures on time in the pandemic period was determined, and medical deprivation rate (MDR) was calculated., Results: The prepandemic period of our patients with thyroid disease (n = 594), calcium-bone metabolism disorder (n = 130), adrenal disease (n = 85), pituitary disease, and NET (n = 46) had MDRs of 85%, 56%, 81%, and 89%, respectively. For each subgroup of patients, the lowest MDR (67%) was in medullary thyroid carcinoma, the highest MDR (89%) was in differentiated thyroid carcinoma; the lowest MDR (6%) was in osteoporosis, the highest MDR (100%) was in the active Paget's disease; the lowest MDR (0%) was in primary adrenocortical insufficiency, the highest MDR (100%) was in hyperfunctional adrenal adenomas; the lowest MDR (81%) was in pituitary nonfunctional adenomas, and the highest MDR (100%) was in Cushing's disease, active prolactinoma, TSHoma, and NET, respectively., Conclusion: This study showed that not only those who had COVID-19 but also those who had medical deprivation due to their current endocrinological disease were not to be underestimated during the pandemic period.

Background: Acromegaly is a disease that occurs as a result of excessive growth hormone caused by pituitary adenomas. Some acromegaly patients show resistance to somatostatin analog (SSA) treatment. Filamin-A (FLNA) and β-arrestins are thought to play a role in the response to SSAs. We aimed to investigate the relationship between FLNA-rs782079491 and β-arrestin-2-rs34230287 single-nucleotide polymorphisms and disease risk, as well as treatment response in patients with acromegaly in the Turkish population., Methods: The genotypes of 110 acromegaly patients and 99 controls were determined by realtime PCR. The genotype distributions were compared with clinical data on the disease., Results: There was no association between the β-arrestin-2 gene polymorphism and the response to SSA treatment in acromegaly patients. For responder patients to SSAs, the β-arrestin-2-rs34230287 CT+TT genotype was associated with higher microadenoma as compared with the CC genotype (p = 0.017). The FLNA polymorphism was not observed in the study group., Conclusions: We showed that there was no association between the polymorphic genotypes of FLNA and β-arrestin-2 genes with acromegaly disease and SSAs response in the Turkish population. However, there was a relationship between β-arrestin-2 and some of the clinical characteristics. Furthermore, the CC genotype and the C allele are risk factors associated with tumor growth rate in acromegaly patients.

The anterior pituitary is derived from Rathke's pouch precursors, which differentiate into specific hormone-secreting cell lineages. Sustained low postnatal and adult pituitary cell turnover is governed by stem/progenitor cells that undergo slow mitotic activity and give rise to hormone-secreting cells in response to physiological demands and feedback loops. Pituitary cell populations exhibit stem cell properties, which include stem cell marker expression, non-hormone expression, and the ability to self-renew and to potentially differentiate into any of five hormone-secreting cell lineages. Specific signaling pathways underlie differentiated pituitary cell development and regulation. Several validated pituitary stem cell models have been reported and have the potential for functional regeneration of pituitary hormone-secreting cell functions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As most of the unenriched cages will soon switch to enriched cages, it is important to characterize all the effects in the laying hens for sustainable production. Laying hens can be used in several production periods by applying molting. The aim of this study was to determine the cage type (unenriched and enriched) on performance, welfare, and microbiological properties of laying hens during the molting period and the second production cycle. Overall, 840 brown laying hybrids were used in the experiment. Laying hens were reared on two different cage types (unenriched cage (UEC) and enriched cage (EC)) in the same poultry house. When the hybrids were 75 weeks old, they were subjected to force molting with whole grain barley. Performance, welfare, microbiological, and serological data of laying hens were obtained from 73 to 107 weeks of age. Egg production, egg weight, feed conversion ratio, breaking strength, albumen and yolk index, Haugh unit, feather condition, and breaking force of femur and metatarsus were better in the post-molting period. However, keel bone deformities and Newcastle disease virus antibody titers are the worst in the post-molting period. Stiffness of femur and metatarsus was increased with period. These results indicate that necessary precautions should be taken against the problems that may occur in the direction of bone and health. During the molting period, hens kept in EC had lower egg production but they returned to egg production at a high rate. EC type had a positive effect on egg production, feed conversion ratio, feather and foot condition, and breaking force of metatarsus.

The molecular mechanisms underlying the formation of nonfunctioning pituitary adenomas (NFAs) are largely unknown. In this study, we aimed to understand the relationship between NFAs and functional pituitary adenomas and the possible role of proteins involved in cell cycle, senescence, and DNA damage control mechanisms in the etiology of NFA. We analyzed pATM-S1981, pRb-S608, Rb, pE2F1-S364, p16, E2F1, p73, cyclin D1, and CHEK2 protein expression (in a group of 20 patients with acromegaly, 18 patients with Cushing's disease (CD), and 29 NFA patients) by immunohistochemistry and their relevant mRNA expression by qRT-PCR (in a group of 7 patients with acromegaly, 7 patients with CD, and 7 NFA patients). The clinical and histopathological results on the patients were statistically evaluated. pE2F1-S364 protein expression in the CD group was significantly lower than that in the NFA and acromegaly groups (p = 0.025, p = 0.034, respectively). However, the expression of the p16 protein was lower than in the NFA group than in the CD and acromegaly groups (p = 0.030, p = 0.033, respectively), and E2F1 protein expression was significantly higher in the NFA group than in the CD group (p = 0.025). p73 protein expression in patients with acromegaly was significantly higher (p = 0.031) than that in the CD group. CHEK2 mRNA expression in the CD group was significantly higher than that in the acromegaly group (p = 0.012). The selective and tumor-specific associations between E2F1, pE2F1-S364, CHEK2, and p73 mRNA and protein levels indicate their involvement in pituitary adenoma formation in NFA, CD, and acromegaly patients.

Hyperphosphorylation of tau leading to neurofibrillary tangles (NFT) is one of the key pathological hallmarks in neurodegenerative disorders such as Alzheimer disease (AD). Peptidyl-prolyl cis-trans isomerase (Pin1) regulates the phosphorylation of Ser/Thr sites of tau protein, and promotes microtubule assembly. In this study, we aimed to determine the effect of tau hyperphosphorylation on Pin1 expression in primary cortical neurons in order to investigate the results of the pathological process on Pin1, an important enzyme involved in various cellular mechanisms. Primary cortical neurons were prepared from embryonic day 16 -Sprague Dawley rat embryos. The cultures were treated with 25 nM okadaic acid (OKA) on day 7 in order to promote tau hyperphosphorylation. The cytotoxicity was determined with LDH release and measured by ELISA. Tau phosphorylation was confirmed by western blot using anti-tau antibodies Thr231 and Tau-1. Pin1 mRNA expression level was determined by qRT-PCR at 8 and 24 h. Pin1 protein expression was analyzed with immunofluorescent labeling at 8 and 24 h. Tau phosphorylation on Thr231 was increased and non-phosphorylated Tau-1 was decreased in OKA treated group compared with the untreated control at 8 h of treatment. While Pin1 mRNA expression levels at 8 h post-OKA treatment were lower than that of control groups, there were no differences between OKA-treated group and control groups in Pin1 protein expression. Whereas no significant differences for Pin1 mRNA expression, protein expression levels were decreased OKA-treated group compared to control groups at 24 h of treatment. The LDH release of OKA-treated group was significantly increased at 24 h. Our study indicates that although OKA treatment suppressed Pin1 mRNA expression and induced tau phosphorylation at 8 h of treatment, its influence on Pin1 protein expression has 16 h phase delay. Given the important role of Pin1 in many cellular mechanisms these results might indicate that tau hyperphosphorylation involved in many neurodegenerative disorders may cause some alterations in brain microenvironment via Pin1.This is the first demonstration of the alteration of the Pin1 mRNA and protein expression in OKA induced model in primary cortical neurons., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intracellular aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is a major neuropathological hallmark of taupathies such as Alzheimer's disease. Okadaic acid (OKA) is a potent inhibitor of PP2A, leading to abnormal tau phosphorylation. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is selectively downregulated in AD. In this study, we investigated the effects of OKA induced tau hyperphosphorylation on secreted and cellular levels of BDNF in primary cortical neurons that were treated with 25nM OKA. Tau phosphorylation at threonine 231 (Thr231) sites was assessed by Western blot using antibodies against phospho-Thr231. Non-phosphorylated tau protein was detected with the Tau-1 antibody. Levels of BDNF secreted to the culture medium were determined by ELISA at the 8th and 24th hours of treatment. Cellular localization and protein expression of BDNF and tau were assessed by immunofluorescent labeling and fluorescent intensity measurements at 24h of treatment. Tau hyperphosphorylation was confirmed with increase in Thr231 and the decrease in Tau-1 signals after 8h of OKA treatment, compared with the control groups, secreted BDNF levels in the OKA-treated group were significantly lower after 24h of treatment but were not significantly different at 8h of treatment. BDNF immunoreactivity was seen in cytoplasm and neurites of the neurons in control group. BDNF immunoreactivity significantly decreased in the OKA treated group and this attenuation was significant especially at neurites. Our results suggest that the decrease in BDNF secretion and the BDNF expression might depend on the disruption of microtubule structure caused by tau hyperphosphorylation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Preiser's disease, also known as idiopathic avascular necrosis of the scaphoid, and five-fingered hand are rare hand conditions. In this report, we present a case of a 25 year old female patient who had avascular necrosis of the scaphoid and five-fingered hand.

Empirical antifungal therapy is most often given to patients with leukemia. However breakthrough fungal infections under antifungal therapy are not uncommon. Four children, with hematologic malignant disease developed mycotic breakthrough infections while on empirical caspofungin treatment for a median of 14 (range 11-19) days. Trichosporon asahii was detected in the blood culture of two patients and Geotrichum capitatum in the other two (one patient also had positive cerebrospinal fluid culture). Because the patients' clinical situation worsened, voriconazole was empirically added for two patients three and five days before the agent was detected. The first sterile blood culture was obtained 3-7 days of voriconazole treatment. All patients reached clear cultures but one patient died. One patient with central nervous system infection with G. capitatum had severe neurological sequelae. Very severe fungal infections can occur during empirical caspofungin therapy. Therefore, patients should be followed closely., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

Background: Fungal sepsis is becoming more frequent in neonatal intensive care units (NICU) and has a high mortality rate due to the invasive nature of the disease and to the insufficiency of low doses and high incidence of renal problems with effective doses of amphotericin B. New generation lipid formulated amphotericin B preparations may be more efficient because they are less toxic to be applied in target doses. However, there is limited experience in neonates and preterm infants., Methods: The charts of 917 patients admitted to NICU between 2001 and 2003 were reviewed and the data of 21 patients with systemic Candida infection, requiring different amphotericin B therapy, were analyzed., Results: Infants with fungal septicemia were treated with amphotericin B lipid complex (Abelcet)(n = 10) and liposomal amphotericin B (AmBisome)(n = 9) for a mean duration of 21 and 18 days. The mean gestational age of the patients was 30.9 +/- 4.2 weeks and mean birth weight was 1536 +/- 714 g. Two patients in the Abelcet group and one patient in the AmBisome group died during therapy. Fungal eradication was achieved in 16 surviving infants and mean eradication time was 8.1 +/- 2.6 days and mean duration of therapy was 19.2 +/- 4.1 days. Mortality rates related to treatment failure were similar being 20% in the Abelcet group and 11% in the AmBisome group. No patient showed severe side-effects from the antifungal therapy; the incidence of minimal side-effects were similar in both groups and they were elevated serum transaminase levels in six patients, increased serum creatinine in one patient and hypokalemia in one patient., Conclusion: Both preparations have the same benefits for the treatment of neonatal fungal sepsis and they can be used safely in neonates including very low birth weight infants. However, the clinician must keep in mind the cost of treatment.

Species of the genus Acremonium (Cephalosporium) are opportunistic micro-organisms that are environmentally widespread saprophytes in soil and can, very rarely, be pathogenic in humans. Disseminated infection has been described in patients with immunodeficiency, but has previously been reported in only one neonate. A preterm infant with Acremonium strictum fungaemia is reported here. The patient was born at 27 weeks gestation and weighed 870 g at birth. She needed intensive respiratory management and became septic on day 11 of life. Blood and cerebrospinal fluid (CSF) cultures were positive for A. strictum. The patient did not respond to therapy with amphotericin B plus fluconazole and died on day 25 of life. The autopsy showed foci due to A. strictum in the brain, liver and heart.