ENDOCRINOLOGY IN THE TIME OF COVID-19 Clinical management of neuroendocrine neoplasms (NENs)

In viral pandemics, most specifically Covid-19, many patients with neuroendocrine neoplasms (NENs), including phaeochromocytomas, paragangliomas and medullary thyroid carcinoma, may develop Covid-19 in a mild or severe form, or be concerned about the influence of viral infection relative to their anti-tumoral therapy. In general, newly presenting patients should be assessed, and patients recently receiving chemotherapy, targeted therapy or radionuclide therapy, or showing tumour growth, should be closely followed. For previously diagnosed patients, who have indolent disease, some delay in routine follow-up or treatment may not be problematic. However, patients developing acute secretory syndromes due to functional neuroendocrine neoplasms (such as of the pancreas, intestine or lung), phaeochromocytomas and paragangliomas, will require prompt treatment. Patients with life-threatening Covid-19-related symptoms should be urgently treated and long-term anti-tumoral treatments may be temporarily delayed. In patients with especially aggressive NENs, a careful judgement should be made regarding the severity of any Covid-19 illness, tumour grade, and the immunosuppressant effects of any planned chemotherapy, immunotherapy (e.g. interferon-alpha), targeted therapy or related treatment. In other cases, especially patients with completely resected NENs, or who are under surveillance for a genetic disorder, a telephone or delayed consultation may be in order, balancing the risk of a delay against that of the possible development of Covid-19.Peer reviewe

Prolyl oligopeptidase inhibition reduces oxidative stress via reducing NADPH oxidase activity by activating protein phosphatase 2A

Oxidative stress (OS) is a common toxic feature in various neurodegenerative diseases. Therefore, reducing OS could provide a potential approach to achieve neuroprotection. Prolyl oligopeptidase (PREP) is a serine protease that is linked to neurodegeneration, as endogenous PREP inhibits autophagy and induces the accumulation of detrimental protein aggregates. As such, inhibition of PREP by a small-molecular inhibitor has provided neuroprotection in preclinical models of neurodegenerative diseases. In addition, PREP inhibition has been shown to reduce production of reactive oxygen species (ROS) and the absence of PREP blocks stress-induced ROS production. However, the mechanism behind PREP-related ROS regulation is not known. As we recently discovered PREP's physiological role as a protein phosphatase 2A (PP2A) regulator, we wanted to characterize PREP inhibition as an approach to reduce OS. We studied the impact of a PREP inhibitor, KYP-2047, on hydrogen peroxide and ferrous chloride induced ROS production and on cellular antioxidant response in HEK-293 and SHSY5Y cells. In addition, we used HEK-293 and SH-SY5Y PREP knock-out cells to validate the role of PREP on stress-induced ROS production. We were able to show that absence of PREP almost entirely blocks the stressinduced ROS production in both cell lines. Reduced ROS production and smaller antioxidant response was also seen in both cell lines after PREP inhibition by 10 mu M KYP-2047. Our results also revealed that the OS reducing mechanism of PREP inhibition is related to reduced activation of ROS producing NADPH oxidase through enhanced PP2A activation. In conclusion, our results suggest that PREP inhibition could also provide neuroprotection by reducing OS, thus broadening the scope of its beneficial effects on neurodegeneration

Protein kinase C-activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations

Abnormal protein kinase C (PKC) function contributes to many pathophysiological processes relevant for Alzheimer's disease (AD), such as amyloid precursor protein (APP) processing. Phorbol esters and other PKC activators have been demonstrated to enhance the secretion of soluble APP alpha (sAPP alpha), reduce the levels of beta-amyloid (A beta), induce synaptogenesis, and promote neuroprotection. We have previously described isophthalate derivatives as a structurally simple family of PKC activators. Here, we characterised the effects of isophthalate derivatives HMI-1a3 and HMI-1b11 on neuronal viability, neuroinflammatory response, processing of APP and dendritic spine density and morphology in in vitro. HMI-1a3 increased the viability of embryonic primary cortical neurons and decreased the production of the pro-inflammatory mediator TNF alpha, but not that of nitric oxide, in mouse neuron-BV2 microglia co-cultures upon LPS- and IFN-gamma-induced neuroinflammation. Furthermore, both HMI-1a3 and HMI-1b11 increased the levels of sAPPa relative to total sAPP and the ratio of A beta 42/A beta 40 in human SH-Sv5v neuroblastoma cells. Finally, bryostatin-1, but not HMI-1a3, increased the number of mushroom spines in proportion to total spine density in mature mouse hippocampal neuron cultures. These results suggest that the PKC activator HMI-1a3 exerts neuroprotective functions in the in vitro models relevant for AD by reducing the production of TNF alpha and increasing the secretion of neuroprotective sAPPa.Peer reviewe

Using the nonlinear control of anaesthesia-induced hypersensitivity of EEG at burst suppression level to test the effects of radiofrequency radiation on brain function

Background In this study, investigating the effects of mobile phone radiation on test animals, eleven pigs were anaesthetised to the level where burst-suppression pattern appears in the electroencephalogram (EEG). At this level of anaesthesia both human subjects and animals show high sensitivity to external stimuli which produce EEG bursts during suppression. The burst-suppression phenomenon represents a nonlinear control system, where low-amplitude EEG abruptly switches to very high amplitude bursts. This switching can be triggered by very minor stimuli and the phenomenon has been described as hypersensitivity. To test if also radio frequency (RF) stimulation can trigger this nonlinear control, the animals were exposed to pulse modulated signal of a GSM mobile phone at 890 MHz. In the first phase of the experiment electromagnetic field (EMF) stimulation was randomly switched on and off and the relation between EEG bursts and EMF stimulation onsets and endpoints were studied. In the second phase a continuous RF stimulation at 31 W/kg was applied for 10 minutes. The ECG, the EEG, and the subcutaneous temperature were recorded. Results No correlation between the exposure and the EEG burst occurrences was observed in phase I measurements. No significant changes were observed in the EEG activity of the pigs during phase II measurements although several EEG signal analysis methods were applied. The temperature measured subcutaneously from the pigs' head increased by 1.6°C and the heart rate by 14.2 bpm on the average during the 10 min exposure periods. Conclusion The hypothesis that RF radiation would produce sensory stimulation of somatosensory, auditory or visual system or directly affect the brain so as to produce EEG bursts during suppression was not confirmed.BioMed Central Open acces

MGMT Promoter Methylation and Parathyroid Carcinoma

Peer reviewe

Allelic Variants of Melanocortin 3 Receptor Gene (MC3R) and Weight Loss in Obesity: A Randomised Trial of Hypo-Energetic High- versus Low-Fat Diets

INTRODUCTION: The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets. SUBJECTS AND METHODS: This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat) diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes. RESULTS: No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04) and dominant models (p = 0.03). These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103-rs1543873 (p = 0.06), rs6014646-rs6024730 (p = 0.05) and rs3746619-rs3827103 (p = 0.10) displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes. CONCLUSION: The study provided overall sufficient evidence to support that there is no major effect of genetic variants of MC3R and differential weight loss after a 10-week dietary intervention with hypo-energetic diets in obese Europeans

Maisemarakenteen vaikutus maakotkan poikastuottoon Suomessa

Maisemaekologia tutkii maisemarakenteen ja ekologisten prosessien vuorovaikutuksia, joiden ymmärtäminen vaatii maisematason mittakaavan tarkastelun. Lajien ja ympäristömuuttujien välisiä suhteita voidaan tutkia tilastollisilla analyysi-, GIS- ja kaukokartoitusmenetelmillä. Maankäytön suunnittelulla pyritään poistamaan maisemarakenteen muutosten negatiiviset vaikutukset eliöihin. Tässä tutkielmassa selvitetään onko maisemarakenteella vaikutusta maakotkan poikastuottoon Suomessa. Menetelminä käytetään yleistettyjä additiivisia malleja (generalized additive models, GAM) ja hierarkkista ositusta. GAM-mallinnuksessa vastemuuttuja on binaarisena tietona (”hyvä reviiri = 1” ja ”huono reviiri = 0”), joka on luokiteltu maakotkareviirien (n = 469) poikastuoton perusteella käyttäen raja-arvoa 0,5. Vastemuuttujia on yhteensä 469 reviiriä, joita selittävät maanpeitettä, ihmistoimintaa ja topografiaa kuvaavat ympäristömuuttujat. GAM:lla laaditaan malleja kolmella eri etäisyysvyöhykkeellä (200, 2500 ja 6000 metriä). Laadittuja malleja arvioidaan tilastollisilla testeillä. Hierarkkisella osituksella selvitetään ympäristömuuttujien suhteelliset selitysvoimat. GAM-mallinnuksessa maakotkan poikastuottoa selittivät 6000 metrin vyöhykkeellä havumetsät, avoimet alueet ja keskikorkeus (selitysaste 2,99 %). Hierarkkisessa osituksessa keskikorkeus oli selvästi tärkein muuttuja ja avoimet alueet toiseksi tärkein. 2500 metrin vyöhykkeen GAM-mallin hyvien ja huonojen reviireiden vaihtelua selitti keskikorkeus (selitysaste 0,41 %). Myös hierarkkisessa osituksessa keskikorkeuden suhteellinen selitysvoima oli selvästi suurin. 200 metrin vyöhykkeen GAM-mallissa poikastuottoa selittivät lehtimetsät, havumetsät ja avosuot (selitysaste 3,34 %). Hierarkkisessa osituksessa selvästi suurimmat suhteelliset selitysvoimat olivat avoimilla alueilla ja keskikorkeudella. Tämän tutkielman tulosten perusteella maisemarakenteella ei näytä olevan vaikutusta maakotkan poikastuottoon Suomessa, koska (1) ympäristömuuttujien erot hyvin ja huonosti tuottavien reviireiden välillä eivät olleet tilastollisesti merkitseviä, (2) GAM-mallien selitysasteet olivat alhaiset ja (3) jokaisen vyöhykkeen GAM-mallilla oli huono kyky erotella reviirit poikastuoton perusteella toisistaan