A population based study of multiple myeloma patients with medication-related osteonecrosis of the jaw

Žurnāla mājaslapā pie raksta norādītas RSU afiliācijas, bet Scopus datubāzē Latvijas Universitātes afiliācijas.OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a rare complication of antiresorptive or antiangiogenetic therapy that manifests as an exposed bone with clinical signs of infection, persisting for more than 8 weeks, without history of radiation therapy or metastases to the jaws. The aim of the study was to describe the incidence, risk factors, staging process and clinical course of MRONJ in patients with multiple myeloma (MM). MATERIALS AND METHODS: We retrospectively analyzed all (126) newly diagnosed MM patients at Riga East Clinical University Hospital (Riga. Latvia) from June 2014 to June 2017. RESULTS: Among 88 MM patients treated with bisphosphonates (BP), 6 (6.8%) patients developed MRONJ. All six patients received intravenous nitrogen-containing BPs. The average time until MRONJ manifestation was under two years. For our patients the severity of MRONJ was stage I in two, stage II in three, and stage III in one patient. Five patients had MRONJ of mandibula and one of maxilla. All patients with MRONJ had undergone a dental extraction or a trauma before the development of MRONJ. CONCLUSION: We found that MRONJ correlated with the patient's age. The average time until MRONJ manifestation in reserach group is 2 years. One of triggerring MRONJ factors are tooth extraction or trauma.publishersversionPeer reviewe

Vitamin D status and its seasonal variations and association with parathyroid hormone concentration in healthy women in Riga

Copyright: Copyright 2020 Elsevier B.V., All rights reserved.The aim of the study was to describe the vitamin D status and its seasonal variations in women living in Riga, Latvia, to examine an association between the concentrations of plasma 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH), and to determine the threshold for plasma 25(OH)D above which there is no further suppression of PTH. Material and Methods: The data of 189 healthy Caucasian women were analyzed. The serum levels of 25(OH)D, PTH, and phosphorus were measured twice a year. All the participants were divided into 3 groups according to vitamin D supplementation and the reproductive status. Results: The overall mean level of 25(OH)D was 32.8 ng/mL with significantly lower levels being in winter when compared with those in summer (28.2 ng/mL vs. 37.5 ng/mL, respectively; P>0.05). PTH was negatively associated with 25(OH)D. A threshold level of plasma 25(OH)D above which no further suppression of PTH occurred was found to be 38 ng/mL. Postmenopausal women not taking vitamin D supplements and without exposure to sunlight had 25(OH)D deficiency in winter and summer (92% and 88%, respectively). The most significant seasonal fluctuations were seen in the women of the reproductive age not taking vitamin D supplements and without exposure to sunlight, of which 47% had 25(OH)D deficiency in summer and 69% in winter. Conclusions: An optimal concentration of 25(OH)D was found to be 38 ng/mL. According to this definition, 70.4% of all the healthy women were classified as vitamin D deficient in winter and 59.8% in summer. The highest proportion of vitamin D deficient individuals was found in the group representing the postmenopausal women not taking vitamin D supplements.publishersversionPeer reviewe

Toluidine Blue Test for Sperm DNA Integrity and Elaboration of Image Cytometry Algorithm

Background: Sperm DNA integrity is of paramount importance in the prognosis of fertility. We applied image cytometry to a toluidine blue (TB) test we recently proposed. Methods: Sperm samples from 33 men were assayed for standard sperm parameters and classified as normal or abnormal. Sperm smears were subjected to the TB test, DNA denaturation testing with acridine orange (AO), and terminal deoxyuridine triphosphate biotin nick end labeling (TUNEL). In CCD image analysis, TB-stained sperm cell heads were microscopically assigned to one of four color groups (dark, blue, light violet, and light blue). The optical densities of 6,600 cells in green and red CCD images were used to elaborate an algorithm for discrimination of these groups. Results: The proportions of sperm in TB color groups, as estimated with the developed image cytometry algorithm, correlated with microscopic features. The number of TB dark cells correlated with the number of AO-red and TUNEL+ cells. The proportion of TB dark cells in normal samples did not exceed 35%. Light-blue sperm cell heads prevailed in normal samples, whereas dark and blue sperm cell heads dominated in abnormal samples. Conclusions: The TB test was suitable for the assessment of sperm cell DNA integrity. The elaborated image cytometry algorithm can be used for this purpose and for finer determination of sperm nucleus status.publishersversionPeer reviewe

Insulin Signaling, Lifespan and Stress Resistance Are Modulated by Metabotropic GABA Receptors on Insulin Producing Cells in the Brain of Drosophila

Insulin-like peptides (ILPs) regulate growth, reproduction, metabolic homeostasis, life span and stress resistance in worms, flies and mammals. A set of insulin producing cells (IPCs) in the Drosophila brain that express three ILPs (DILP2, 3 and 5) have been the main focus of interest in hormonal DILP signaling. Little is, however, known about factors that regulate DILP production and release by these IPCs. Here we show that the IPCs express the metabotropic GABAB receptor (GBR), but not the ionotropic GABAA receptor subunit RDL. Diminishing the GBR expression on these cells by targeted RNA interference abbreviates life span, decreases metabolic stress resistance and alters carbohydrate and lipid metabolism at stress, but not growth in Drosophila. A direct effect of diminishing GBR on IPCs is an increase in DILP immunofluorescence in these cells, an effect that is accentuated at starvation. Knockdown of irk3, possibly part of a G protein-activated inwardly rectifying K+ channel that may link to GBRs, phenocopies GBR knockdown in starvation experiments. Our experiments suggest that the GBR is involved in inhibitory control of DILP production and release in adult flies at metabolic stress and that this receptor mediates a GABA signal from brain interneurons that may convey nutritional signals. This is the first demonstration of a neurotransmitter that inhibits insulin signaling in its regulation of metabolism, stress and life span in an invertebrate brain

Metabolic Stress Responses in Drosophila Are Modulated by Brain Neurosecretory Cells That Produce Multiple Neuropeptides

In Drosophila, neurosecretory cells that release peptide hormones play a prominent role in the regulation of development, growth, metabolism, and reproduction. Several types of peptidergic neurosecretory cells have been identified in the brain of Drosophila with release sites in the corpora cardiaca and anterior aorta. We show here that in adult flies the products of three neuropeptide precursors are colocalized in five pairs of large protocerebral neurosecretory cells in two clusters (designated ipc-1 and ipc-2a): Drosophila tachykinin (DTK), short neuropeptide F (sNPF) and ion transport peptide (ITP). These peptides were detected by immunocytochemistry in combination with GFP expression driven by the enhancer trap Gal4 lines c929 and Kurs-6, both of which are expressed in ipc-1 and 2a cells. This mix of colocalized peptides with seemingly unrelated functions is intriguing and prompted us to initiate analysis of the function of the ten neurosecretory cells. We investigated the role of peptide signaling from large ipc-1 and 2a cells in stress responses by monitoring the effect of starvation and desiccation in flies with levels of DTK or sNPF diminished by RNA interference. Using the Gal4-UAS system we targeted the peptide knockdown specifically to ipc-1 and 2a cells with the c929 and Kurs-6 drivers. Flies with reduced DTK or sNPF levels in these cells displayed decreased survival time at desiccation and starvation, as well as increased water loss at desiccation. Our data suggest that homeostasis during metabolic stress requires intact peptide signaling by ipc-1 and 2a neurosecretory cells

Insulin Production and Signaling in Renal Tubules of Drosophila Is under Control of Tachykinin-Related Peptide and Regulates Stress Resistance

The insulin-signaling pathway is evolutionarily conserved in animals and regulates growth, reproduction, metabolic homeostasis, stress resistance and life span. In Drosophila seven insulin-like peptides (DILP1-7) are known, some of which are produced in the brain, others in fat body or intestine. Here we show that DILP5 is expressed in principal cells of the renal tubules of Drosophila and affects survival at stress. Renal (Malpighian) tubules regulate water and ion homeostasis, but also play roles in immune responses and oxidative stress. We investigated the control of DILP5 signaling in the renal tubules by Drosophila tachykinin peptide (DTK) and its receptor DTKR during desiccative, nutritional and oxidative stress. The DILP5 levels in principal cells of the tubules are affected by stress and manipulations of DTKR expression in the same cells. Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted in increased survival at either stress, whereas over-expression of these components produced the opposite phenotype. Thus, stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP5 signaling. Manipulations of S6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locally on tubules, possibly in oxidative stress regulation. Our findings are the first to demonstrate DILP signaling originating in the renal tubules and that this signaling is under control of stress-induced release of peptide hormone

FOXO Regulates Organ-Specific Phenotypic Plasticity In Drosophila

Phenotypic plasticity, the ability for a single genotype to generate different phenotypes in response to environmental conditions, is biologically ubiquitous, and yet almost nothing is known of the developmental mechanisms that regulate the extent of a plastic response. In particular, it is unclear why some traits or individuals are highly sensitive to an environmental variable while other traits or individuals are less so. Here we elucidate the developmental mechanisms that regulate the expression of a particularly important form of phenotypic plasticity: the effect of developmental nutrition on organ size. In all animals, developmental nutrition is signaled to growing organs via the insulin-signaling pathway. Drosophila organs differ in their size response to developmental nutrition and this reflects differences in organ-specific insulin-sensitivity. We show that this variation in insulin-sensitivity is regulated at the level of the forkhead transcription factor FOXO, a negative growth regulator that is activated when nutrition and insulin signaling are low. Individual organs appear to attenuate growth suppression in response to low nutrition through an organ-specific reduction in FOXO expression, thereby reducing their nutritional plasticity. We show that FOXO expression is necessary to maintain organ-specific differences in nutritional-plasticity and insulin-sensitivity, while organ-autonomous changes in FOXO expression are sufficient to autonomously alter an organ's nutritional-plasticity and insulin-sensitivity. These data identify a gene (FOXO) that modulates a plastic response through variation in its expression. FOXO is recognized as a key player in the response of size, immunity, and longevity to changes in developmental nutrition, stress, and oxygen levels. FOXO may therefore act as a more general regulator of plasticity. These data indicate that the extent of phenotypic plasticity may be modified by changes in the expression of genes involved in signaling environmental information to developmental processes

Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila

Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan

Decoding the Regulatory Logic of the Drosophila Male Stem Cell System

The niche critically controls stem cell behavior, but its regulatory input at the whole-genome level is poorly understood. We elucidated transcriptional programs of the somatic and germline lineages in the Drosophila testis and genome-wide binding profiles of Zfh-1 and Abd-A expressed in somatic support cells and crucial for fate acquisition of both cell lineages. We identified key roles of nucleoporins and V-ATPase proton pumps and demonstrate their importance in controlling germline development from the support side. To make our dataset publicly available, we generated an interactive analysis tool, which uncovered conserved core genes of adult stem cells across species boundaries. We tested the functional relevance of these genes in the Drosophila testis and intestine and found a high frequency of stem cell defects. In summary, our dataset and interactive platform represent versatile tools for identifying gene networks active in diverse stem cell type