Changes In Calcium Homeostasis Research Articles

The protective effect of silver nanoparticles' on epithelial cornea cells against ultraviolet is accompanied by changes in calcium homeostasis and a decrease of the P2X7 and P2Y2 receptors

PurposeThe aim of the study was to evaluate the effect of silver nanoparticles hydrocolloids (AgNPs) on human corneal epithelial cells. Epithelial cells form the outermost and the most vulnerable to environmental stimuli layer of the cornea in the eye. Mechanical stress, UV radiation, and pathogens such as bacteria, viruses, and parasites challenge the fragile homeostasis of the eye. To help combat stress, infection, and inflammation wide portfolio of interventions is available. One of the oldest treatments is colloidal silver. Silver nanoparticle suspension in water is known for its anti-bacterial anti-viral and antiprotozoal action. However, AgNPs interact also with host cells, and the character of the interplay between corneal cells and silver seeks investigation. MethodsThe human epithelial corneal cell line (HCE-2) was cultured in vitro, treated with AgNPs, and subjected to UV. The cell’s viability, migration, calcium concentration, and expression/protein level of selected proteins were investigated by appropriate methods including cytotoxicity tests, “wound healing” assay, Fluo8/Fura2 AM staining, qRT-PCR, and western blot. ResultsIncubation of human corneal cells (HCE-2) with AgNP did not affect cells viability but limited cells migration and resulted in altered calcium homeostasis, decreased the presence of ATP-activated P2X7, P2Y2 receptors, and enhanced the expression of PACAP. Furthermore, AgNPs pretreatment helped restrain some of the deleterious effects of UV irradiation. Interestingly, AgNPs had no impact on the protein level of ACE2, which is important in light of potential SARS-CoV-2 entrance through the cornea. ConclusionsSilver nanoparticles are safe for corneal epithelial cells in vitro.

SAT250 A Case Of Hypercalcemia In Pregnancy - A Diagnostic And Management Challenge

Abstract Disclosure: W. Cheng: None. Y. Kuan: None. Hypercalcemia in pregnancy is rare and poses significant diagnostic and management challenges especially in a low resource setting. Although primary hyperparathyroidism (PHPT) is the main cause, physiological changes in calcium homeostasis make it difficult to distinguish from familial hypocalciuric hypercalcemia (FHH) unless genetic testing is done. Furthermore uncertainty exists on the safety of pharmacotherapy for hypercalcemia in pregnancy which if untreated, can be detrimental to both mother and child. Described herein a 17 year-old primigravida who presented at 32 weeks of gestation for asthma exacerbation precipitated by COVID-19 infection. She was incidentally found to have PTH-dependent hypercalcemia with albumin-corrected calcium 3.42 mmol/L [2.10-2.55] associated with raised intact parathyroid hormone (iPTH) 15 pmol/L [1.6 - 6.0] and deficient serum 25OH Vitamin D at 19.95 nmol/L [50-125]. She was given IV saline of 3-3.5L/day but to no avail as her serum calcium was persistently above 3 mmol/L with an episode of premature uterine contraction. Calcitonin was given in short courses and withheld once albumin-corrected calcium dropped below 3 mmol/L but rebound within three days. As bisphosphonates is contraindicated in pregnancy, we introduced cinacalcet, up to 75mg/day after discussion with the patient and her family. Meanwhile, investigations were done to ascertain underlying cause. Fractional urine calcium excretion ranged from 0.0068 (spot urine sample) to 0.0568 (24-hour urine sample). Ultrasound neck did not reveal enlarged parathyroid glands or an adenoma. Sestamibi scan was contraindicated in pregnancy. Genetic testing for FHH was too costly but all her first-degree relatives tested to have normocalcemia. Blood pressure remained normal throughout pregnancy. She was discharged with cinacalcet at calcium level of 2.7 mmol/L. However she defaulted follow-up and medications and presented at 36 weeks of gestation for preterm labour. She gave birth to a healthy, 2.46kg baby girl. The baby had neonatal jaundice but normal calcium level. Postpartum, the patient was asymptomatic despite persistent hypercalcemia 3.12 - 3.15nmol/L. As she was non-compliant to cinacalcet it was stopped and serum calcium did not worsen. Sestamibi scan is planned after she stops breastfeeding and a reassessment of the urine calcium once vitamin D is adequately replenished. She refused exploratory parathyroidectomy. She continued to be followed up at the endocrine clinic while her baby at primary care. Contraception is advised untill definitive diagnosis and treatment of hypercalcemia. This case illustrates the challenges in managing hypercalcemia in pregnancy and difficulty in distinguishing PHPT vs FHH without genetic testing. Presentation: Saturday, June 17, 2023

SAT195 A Curious Case Of Severe Reversible PTH-mediated Hypercalcemia Of Pregnancy

Abstract Disclosure: I. Albanese: None. N. Nicolas: None. S.S. Wing: Grant Recipient; Self; Pfizer Global R&D. Other; Self; Almac Discovery (Independent Contractor). E. Mitmaker: None. L. Vautour: None. Background: Primary hyperparathyroidism is rarely diagnosed in pregnancy as symptoms may overlap with those of pregnancy and biochemical diagnosis may be masked by physiologic changes in calcium homeostasis. Hyperparathyroidism in pregnancy is associated with increased maternal and fetal complications. While mild disease is treated conservatively, moderate to severe disease is generally treated surgically in the second trimester. Safe pharmacotherapy options are limited in pregnancy. Case: A 35-year-old woman G3P1 at 10 weeks presented to our institution with polyuria, bone pain and weakness with labs demonstrating severe hypercalcemia (Calcium total: 3.82mmol/L (normal: 2.12-2.62); PTHi: 12pmol/L (normal: 1.5-9.3)). PTHrP was suppressed. She had a prior history of PTH-mediated hypercalcemia in her first pregnancy. She previously underwent three exploratory surgeries in which only three parathyroid glands were found and removed. The hyperparathyroidism and hypercalcemia persisted post-operatively thus she also required intravenous fluids, calcitonin and cinacalcet. The pregnancy was otherwise uncomplicated. Post-partum, she developed hypoparathyroidism and hypocalcemia. Throughout this current pregnancy, multiple imaging modalities were used (ultrasound, MRI and parathyroid sestamibi), none of which were unable to localize any hyperfunctioning parathyroid tissue. Thus, management was limited to medical therapy. Despite aggressive hydration, calcitonin and cinacalcet, total calcium and PTH levels consistently rose reaching peaks of 4.06mmol/L and 45.4pmol/L, respectively. Given hypercalcemia severity and associated neurological symptoms, she was also given bisphosphonates (pamidronate 60mg and zoledronic acid 4mg). She underwent C-section at 25+3 weeks due to fetal decelerations and placental insufficiency. She again developed hypoparathyroidism and hypocalcemia 1-week post-partum. Genetic testing was negative for any causes of hyperparathyroidism. Discussion: This is a unique case of severe PTH-mediated hypercalcemia in that the exact mechanism is unknown but appears to be pregnancy-mediated and reversible such that it only occurs in pregnancy with subsequent hypoparathyroidism post-partum. Investigations to better elucidate the mechanism of this are ongoing. Presentation: Saturday, June 17, 2023

Exploring Neuroprotective Agents for Sepsis-Associated Encephalopathy: A Comprehensive Review.

Sepsis is a life-threatening condition resulting from an inflammatory overreaction that is induced by an infectious factor, which leads to multi-organ failure. Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that can lead to acute cognitive and consciousness disorders, and no strict diagnostic criteria have been created for the complication thus far. The etiopathology of SAE is not fully understood, but plausible mechanisms include neuroinflammation, blood-brain barrier disruption, altered cerebral microcirculation, alterations in neurotransmission, changes in calcium homeostasis, and oxidative stress. SAE may also lead to long-term consequences such as dementia and post-traumatic stress disorder. This review aims to provide a comprehensive summary of substances with neuroprotective properties that have the potential to offer neuroprotection in the treatment of SAE. An extensive literature search was conducted, extracting 71 articles that cover a range of substances, including plant-derived drugs, peptides, monoclonal antibodies, and other commonly used drugs. This review may provide valuable insights for clinicians and researchers working in the field of sepsis and SAE and contribute to the development of new treatment options for this challenging condition.

Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.

The endoplasmic reticulum (ER) is a major organelle involved in protein quality control and cellular homeostasis. ER stress results from structural and functional dysfunction of the organelle, along with the accumulation of misfolded proteins and changes in calcium homeostasis, it leads to ER stress response pathway such as unfolded protein response (UPR). Neurons are particularly sensitive to the accumulation of misfolded proteins. Thus, the ER stress is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion disease and motor neuron disease (MND). Recently, the complex involvement of ER stress pathways has been demonstrated in experimental models of amyotrophic lateral sclerosis (ALS)/MND using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive response to ER stress. Here, we aim to provide recent evidence demonstrating that the ER stress pathway is an essential pathological mechanism of ALS. In addition, we also provide therapeutic strategies that can help treat diseases by targeting the ER stress pathway.

Эффекты кардиотоксинов кобры на папиллярной мышце и сердце крысы, перфузируемом по Лангендорфу, не связаны с выбросом адреналина

In a study of the effects of cobra cardiotoxins on myocardial tissue, both right ventricular (papillary muscle) and left ventricular contractility (isovolumic recording of left ventricular pulse pressure during Langendorff perfusion of the heart) were assessed. In papillary muscle, both toxins, at a concentration of 5 μg/mL, caused short-term increases in contractility to 200±25% and 171±15% for CTX-1 and CTX-2, respectively, at the point of maximum effect. At the same time, for CTX-1 and CTX-2, the time to peak tension (TPT) increased from 104±2 to 111±2 and from 96±2 to 104±5 ms, the relaxation time to 50%(TR50%) from 64±4 to 70±6 and from 64±6 to 69±7 ms, and the relaxation time to 95%(TR95%) from 163±10 to 190±22 and from 148±16 to 155±20 ms, respectively. This significantly differs from the positive inotropic effect of the β-adrenomimetic isoproterenol (170±31%), which causes acceleration of TPT from 106±5 to 89±4 ms, TR50% from 58±6 to 43±4 ms, and TR95% from 145±15 to 90±14 ms. When the whole heart was exposed to cardiotoxins, an increase in contractility was also observed, followed by its suppression and contracture, in contrast to isoproterenol, which caused a steady increase in contractility coupled with an increase in heart rate. Pretreatment of papillary muscles with the β-blocker propranolol 
 (10 μM) did not prevent the development of cardiotoxin effects, but completely blocked the effects of isoproterenol. Our data indicate that the temporary increase in contractility under the action of cardiotoxins is not associated with the release of endogenous adrenaline, but rather is caused by changes in calcium homeostasis in cardiomyocytes.

ODP123 Severe Hypercalcemia During Lactation In A Patient With Pre-Existing Hypoparathyroidism

Abstract Background Pregnancy and lactation are associated with profound changes in calcium homeostasis that can complicate the management of primary hypoparathyroidism. Clinical Case A 35-year-old woman with a history of post-operative hypoparathyroidism aftertotal thyroidectomy for metastatic papillary thyroid carcinomawas found to have hypercalcemia during lactation, two months after delivery of her first pregnancy. She was taking calcitriol 0.5mcgtwo times daily prepartum, which she continued throughout pregnancy and postpartum. Two weeks prior to delivery, her serum calcium was 9.7 mg/dL (n: 8.6-10.3 mg/dL). However, testingtwo months postpartum revealed a markedly elevated serum calcium 13.7 mg/dL and ionized calcium 1.70 mmol/L (n: 1. 09-1.29 mmol/L). Subsequent workup was notable for low parathyroid hormone (PTH) 4 pg/mL (n: 11-51 pg/mL), and normal PTH-related protein (PTHrP) 0.3 pmol/L (n: <2 pmol/L), 25-hydroxy-vitamin D 60 ng/mL (n: 30-80 ng/mL), and 1,25-dihydroxy-vitamin D 38. 0 pg/mL (n: 19.9-79.3 pg/mL). Her calcitriol was reducedto 0.25mcg once daily, and her serum and ionized calcium improved to 10.2 mg/dL and 1.18 mmol/L, respectively, within 10 days. Two years later, after her second pregnancy, she again developed hypercalcemia during lactation. One month prior to delivery, her serum calcium was 8. 0 mg/dL and her ionized calcium was 1. 04 mmol/L on a regimen of calcium carbonate 1000mg three times daily and calcitriol 0.5mcg twice daily. However, two months after delivery and during lactation, her serum and ionized calcium increased to 10.4 mg/dL and 1.31 mmol/L, respectively. Evaluation of her PTHrP levels revealed an increase from 13 pg/mL (n: 14-27 pg/mL) one-year prepartum to 22 pg/mL during her third trimester, and then to17 pg/mL two months postpartum. In addition, her 1,25-dihydroxy-vitamin D increased from 60.2 pg/mL one-year prepartum to 108. 0 pg/mL during her third trimester and decreased to 70.2 pg/mL two months postpartum. Reductions in her calcium and calcitriol regimen improved her serum and ionized calcium levels. Conclusion This rare case highlights the changes in calcium physiology during pregnancy and lactation that can significantly alter calcium and calcitriol requirements in women with primary hypoparathyroidism. During pregnancy, calcium demand is met by increased placental and fetal PTHrP secretion and increased 1,25-dihydroxy-vitamin D production from placental 1-alpha-hydroxylase activity. Conversely, during lactation, this demand is met by increased net bone resorption from PTHrP produced by the mother's mammary tissue and decreased estrogen levels postpartum. As illustrated in this case, continuation of prepartum calcium and calcitriol regimens during pregnancy and lactation can result in maternal hypercalcemia. Thus, close monitoring of calcium levels during pregnancy and lactation in women with hypoparathyroidism is essential to adjust calcium and calcitriol supplementation and maintain adequate calcium homeostasis in the mother and fetus. Presentation: No date and time listed

Acute and Delayed Effects of Mechanical Injury on Calcium Homeostasis and Mitochondrial Potential of Primary Neuroglial Cell Culture: Potential Causal Contributions to Post-Traumatic Syndrome.

In vitro models of traumatic brain injury (TBI) help to elucidate the pathological mechanisms responsible for cell dysfunction and death. To simulate in vitro the mechanical brain trauma, primary neuroglial cultures were scratched during different periods of network formation. Fluorescence microscopy was used to measure changes in intracellular free Ca2+ concentration ([Ca2+]i) and mitochondrial potential (ΔΨm) a few minutes later and on days 3 and 7 after scratching. An increase in [Ca2+]i and a decrease in ΔΨm were observed ~10 s after the injury in cells located no further than 150–200 µm from the scratch border. Ca2+ entry into cells during mechanical damage of the primary neuroglial culture occurred predominantly through the NMDA-type glutamate ionotropic channels. MK801, an inhibitor of this type of glutamate receptor, prevented an acute increase in [Ca2+]i in 99% of neurons. Pathological changes in calcium homeostasis persisted in the primary neuroglial culture for one week after injury. Active cell migration in the scratch area occurred on day 11 after neurotrauma and was accompanied by a decrease in the ratio of live to dead cells in the areas adjacent to the injury. Immunohistochemical staining of glial fibrillary acidic protein and β-III tubulin showed that neuronal cells migrated to the injured area earlier than glial cells, but their repair potential was insufficient for survival. Mitochondrial Ca2+ overload and a drop in ΔΨm may cause delayed neuronal death and thus play a key role in the development of the post-traumatic syndrome. Preventing prolonged ΔΨm depolarization may be a promising therapeutic approach to improve neuronal survival after traumatic brain injury.

Age-Dependent Changes in the Function of Mitochondrial Membrane Permeability Transition Pore in Rat Liver Mitochondria

Mitochondria play an important role in the cell aging process. Changes in calcium homeostasis and/or increased reactive oxygen species (ROS) production lead to the opening of mitochondrial permeability transition pore (MPTP), depolarization of the inner mitochondrial membrane, and decrease of ATP production. Our work aimed to monitor age-related changes in the Ca2+ ion effect on MPTP and the ability of isolated rat liver mitochondria to accumulate calcium. The mitochondrial calcium retention capacity (CRC) was found to be significantly affected by the age of rats. Measurement of CRC values of the rat liver mitochondria showed two periods when 3 to17-week old rats were tested. 3-week and 17-week old rats showed lower CRC values than 7-week old animals. Similar changes were observed while testing calcium-induced swelling of rat liver mitochondria. These findings indicate that the mitochondrial energy production system is more resistant to calcium-induced MPTP opening accompanied by the damaging effect of ROS in adult rats than in young and aged animals.

The acute effects of milk intake on calcium homeostasis and cardiovascular outcome: A randomized crossover trial in postmenopausal women.

ObjectiveThe importance of calcium intake from dairy in regard to cardiovascular health has been investigated in several studies with discrepant results. Hence, we aim to investigate the immediate effects of milk intake on cardiovascular function.DesignA randomized crossover study with at least 10 days for washout between the two interventions, 500 ml of water with 200 µg of cholecalciferol or 500 ml of semi‐skimmed milk containing approximately 600 mg of calcium with 200 µg of cholecalciferol.PatientsTwenty community‐based postmenopausal women aged 60–80 years.MeasurementsParathyroid hormone and ionized calcium were measured at baseline and after 2 and 4 h on each study day. Pulse wave analysis and velocity were measured at baseline and after 4 h on each study day.ResultsCompared to water, milk intake increased ionized calcium levels by 0.02 mmol/L (p = .029) and decreased parathyroid hormone levels by 1.78 pmol/L (p < .001). The two interventions caused no changes as measured 4 h after the intervention in the following indices of cardiovascular health; pulse wave velocity, brachial diastolic or systolic blood pressure, central diastolic or systolic blood pressure, mean arterial pressure, pulse pressure, augmentation pressure, augmentation index, heart rate or pulse transit time.ConclusionsDespite significant changes in calcium homeostasis with increased levels of ionized calcium following milk intake, no acute effects seem to occur on measures of cardiovascular health.

Age-Dependent Changes in the Function of Mitochondrial Membrane Permeability Transition Pore in Rat Liver Mitochondria.

Mitochondria play an important role in the cell aging process. Changes in calcium homeostasis and/or increased reactive oxygen species (ROS) production lead to the opening of mitochondrial permeability transition pore (MPTP), depolarization of the inner mitochondrial membrane, and decrease of ATP production. Our work aimed to monitor age-related changes in the Ca2+ ion effect on MPTP and the ability of isolated rat liver mitochondria to accumulate calcium. The mitochondrial calcium retention capacity (CRC) was found to be significantly affected by the age of rats. Measurement of CRC values of the rat liver mitochondria showed two periods when 3 to 17-week old rats were tested. 3-week and 17-week old rats showed lower CRC values than 7-week old animals. Similar changes were observed while testing calcium-induced swelling of rat liver mitochondria. These findings indicate that the mitochondrial energy production system is more resistant to calcium-induced MPTP opening accompanied by the damaging effect of ROS in adult rats than in young and aged animals.

Polymorphisms Contributing to Calcium Status: A Systematic Review.

This systematic review assessed genotypes and changes in calcium homeostasis. A literature search was performed in EMBASE, Medline and CENTRAL on 7 August 2020 identifying 1012 references. Studies were included with any human population related to the topic of interest, and genetic variations in genes related to calcium metabolism were considered. Two reviewers independently screened references, extracted relevant data and assessed study quality using the Q-Genie tool. Forty-one studies investigating Single Nucleotide Polymorphisms (SNPs) in relation to calcium status were identified. Almost half of the included studies were of good study quality according to the Q-Genie tool. Seventeen studies were cross-sectional, 14 case-control, seven association and three were Mendelian randomization studies. Included studies were conducted in over 18 countries. Participants were mainly adults, while six studies included children and adolescents. Ethnicity was described in 31 studies and half of these included Caucasian participants. Twenty-six independent studies examined the association between calcium and polymorphism in the calcium-sensing receptor (CASR) gene. Five studies assessed the association between polymorphisms of the Vitamin D receptor (VDR) gene and changes in calcium levels or renal excretion. The remaining ten studies investigated calcium homeostasis and other gene polymorphisms such as the CYP24A1 SNP or CLDN14. This study identified several CASR, VDR and other gene SNPs associated with calcium status. However, to provide evidence to guide dietary recommendations, further research is needed to explore the association between common polymorphisms and calcium requirements.

Changes in Serum Calcium and Treatment of Hypoparathyroidism During Pregnancy and Lactation: A Single-center Case Series.

Hypoparathyroidism (hypo-PT) is rare, and studies on hypo-PT, especially during pregnancy and lactation, are limited. This was a retrospective study on a relatively large case series in a single center from mainland China. A total of 19 patients with 25 pregnancies, diagnosed with hypo-PT before pregnancy, were enrolled. Data on clinical characteristics and treatment strategies at onset time and around pregnancy period were collected. During pregnancy, except for 2 patients with missing data, 5 patients with 6 pregnancies (6/23, 26.1%) experienced improved hypo-PT condition, defined as an increased serum calcium level; 4 patients with 4 pregnancies (4/23, 17.4%) experienced worsened hypo-PT condition, defined as a more than 0.2 mmol/L decline in the serum calcium level; and 3 patients with 3 pregnancies (3/23, 13.0%) remained in stable hypo-PT condition. The prevalence of adverse pregnancy outcomes was 30.4% (4/23 for preterm delivery; 3/23 for miscarriage). The serum calcium and 24-hour urine calcium levels significantly increased during lactation compared with pregnancy (2.57 ± 0.34 vs 1.99 ± 0.11 mmol/L, P < 0.001; 12.28 ± 5.41 vs 8.63 ± 3.22 mmol/L, P = 0.013), and 5 patients with 5 lactations (5/12, 41.7%) developed hypercalcemia in the first 2 months after delivery. Female patients with hypo-PT had different changes in calcium homeostasis and a high prevalence of adverse outcomes during pregnancy. Thus, they should be monitored closely to maintain the optimal serum calcium level. Decreasing drug dosage during the lactation period should be considered to avoid hypercalcemia.

The acute effects of milk intake on calcium homeostasis and cardiovascular outcome: A randomized, crossover trial in postmenopausal women

OBJECTIVE The importance of calcium intake from dairy in regard to cardiovascular health has been investigated in several studies with discrepant results. Hence, we aim to investigate the immediate effects of milk intake on cardiovascular function. DESIGN A randomized crossover study with at least 10 days for washout between the two interventions, 500 ml of water with 200 µg of cholecalciferol or 500 ml of semi-skimmed milk containing approximately 600 mg of calcium with 200 µg of cholecalciferol. PATIENTS Twenty community-based postmenopausal women aged 60-80 years. MEASUREMENTS Parathyroid hormone and ionized calcium were measured at baseline and after 2 and 4 h on each study day. Pulse wave analysis and velocity were measured at baseline and after 4 h on each study day. RESULTS Compared to water, milk intake increased ionized calcium levels by 0.02 mmol/L (p = .029) and decreased parathyroid hormone levels by 1.78 pmol/L (p < .001). The two interventions caused no changes as measured 4 h after the intervention in the following indices of cardiovascular health; pulse wave velocity, brachial diastolic or systolic blood pressure, central diastolic or systolic blood pressure, mean arterial pressure, pulse pressure, augmentation pressure, augmentation index, heart rate or pulse transit time. CONCLUSIONS Despite significant changes in calcium homeostasis with increased levels of ionized calcium following milk intake, no acute effects seem to occur on measures of cardiovascular health.

Effects of electromagnetic fields on neuronal ion channels: a systematic review.

Many aspects of chemistry and biology are mediated by electromagnetic field (EMF) interactions. The central nervous system (CNS) is particularly sensitive to EMF stimuli. Studies have explored the direct effect of different EMFs on the electrical properties of neurons in the last two decades, particularly focusing on the role of voltage-gated ion channels (VGCs). This work aims to systematically review published evidence in the last two decades detailing the effects of EMFs on neuronal ion channels as per the PRISM guidelines. Following a predetermined exclusion and inclusion criteria, 22 papers were included after searches on three online databases. Changes in calcium homeostasis, attributable to the voltage-gated calcium channels, were found to be the most commonly reported result of EMF exposure. EMF effects on the neuronal landscape appear to be diverse and greatly dependent on parameters, such as the field's frequency, exposure time, and intrinsic properties of the irradiated tissue, such as the expression of VGCs. Here, we systematically clarify how neuronal ion channels are particularly affected and differentially modulated by EMFs at multiple levels, such as gating dynamics, ion conductance, concentration in the membrane, and gene and protein expression. Ion channels represent a major transducer for EMF-related effects on the CNS.

Hypercalcemia during pregnancy: management and outcomes for mother and child

Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins.

Mitochondria represent the fundamental system for cellular energy metabolism, by not only supplying energy in the form of ATP, but also by affecting physiology and cell death via the regulation of calcium homeostasis and the activity of Bcl-2 proteins. A lot of research has recently been devoted to understanding the interplay between Bcl-2 proteins, the regulation of these interactions within the cell, and how these interactions lead to the changes in calcium homeostasis. However, the role of Bcl-2 proteins in the mediation of mitochondrial calcium homeostasis, and therefore the induction of cell death pathways, remain underestimated and are still not well understood. In this review, we first summarize our knowledge about calcium transport systems in mitochondria, which, when miss-regulated, can induce necrosis. We continue by reviewing and analyzing the functions of Bcl-2 proteins in apoptosis. Finally, we link these two regulatory mechanisms together, exploring the interactions between the mitochondrial Ca2+ transport systems and Bcl-2 proteins, both capable of inducing cell death, with the potential to determine the cell death pathway—either the apoptotic or the necrotic one.

Pathophysiological mechanisms of neurological disorders in experimental animals exposed to vibration

The review presents an analysis of literature on the study of nervous system changes in experimental animals exposed to vibration. The hypoxic type of cellular metabolism against the background of vibration is the result of vascular mechanoreceptors stimulation and spasm of blood vessels as well as intravascular pressure phase fluctuations and impaired blood and lymph outflow. Hemodynamic disorders and microangiopathy in the central nervous system can reach the level of cerebral vascular impairment and capillary-trophic insufficiency of the brain. Changes in calcium homeostasis at the cellular and tissue levels is a key mechanism of neuronal destruction occurring alongside with impaired blood supply to the nervous tissue in patients with vibrational disease. Long-term exposure to vibration results in reduced tissue respiration in the brain structures of experimental animals, that is most pronounced in the cortex and leads to a pathological change of spontaneous electrical activity of brain structures. Acute vibration stress stimulated the synthesis and excretion of serotonin not only in the hippocampus and hypothalamus but also in the cerebellum, which explains the disturbances of the oculomotor reactions observed in vibration exposure in the control system of the vertical vestibular ocular reflex. A decrease in the total number of neurons as well as an increase in the number of astroglia cells against the background of paravascular tissue edema were revealed against the background of changes in neurotransmitters levels. An increase in the concentration of the biomarker of structural and functional damage to brain tissue specific protein S-100B accompanies the development of professional sensorineural hearing loss and dysfunction of cerebral level vegetative regulation.

MYASTHENIA & RELATED DISORDERS: P.37 Autophagy affected in patients with hypokalemic periodic paralysis

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant rare disorder that is caused by mutations in the genes for voltage gated calcium channel CaV1.1 (CACNA1S) and NaV1.4 (SCN4A). Patients with hypoPP may suffer from periodic paralysis alone, periodic paralysis with weakness or permanent weakness. HypoPP has been known to be associated with vacuolar myopathy for decades but the cause of this has not been known. We have investigated a cohort of 14 hypoPP patients with the R528H mutation in the CACNA1S gene for vacuoles and their content. The R528H mutation has previously been demonstrated to cause a Ca2+ leak through CaV1.1 into the cytoplasm, possibly causing disturbance in the calcium homeostasis. Histology and transmission electron microscopy revealed that vacuoles had a very heterogenous content of glycogen, fibrils and autophagosomes/endosomes. Further investigation demonstrated autophagosomes and endosomes were arrested in the autophagic processing pathway between the early and late stages of maturation, as well as large non-fused lysosomes. Expression analysis of proteins associated with endosomes, autophagosomes and lysosomes showed a significant decrease in levels of proteins involved in autophagy such as Rab5, Rab7, p62/SQSTM1, LC3I, Atg5 and LAMP1 in patients with hypoPP suggesting a systemic effect on the protein expression at the gene level, which decreased mRNA expression levels confirmed, possibly through a master regulator of autophagy gene expression. The findings suggest that changes in calcium homeostasis leads to disruptions in autophagic flux and abnormally large endosomes, autophagosomes and lysosomes that contribute to the vacuoles seen in patients with hypoPP.

The role of L-type calcium channels in neuronal excitability and aging

Over the last two decades there has been significant progress towards understanding the neural substrates that underlie age-related cognitive decline. Although many of the exact molecular and cellular mechanisms have yet to be fully understood, there is consensus that alterations in neuronal calcium homeostasis contribute to age-related deficits in learning and memory. Furthermore, it is thought that the age-related changes in calcium homeostasis are driven, at least in part, by changes in calcium channel expression. In this review, we focus on the role of a specific class of calcium channels: L-type voltage-gated calcium channels (LVGCCs). We provide the reader with a general introduction to voltage-gated calcium channels, followed by a more detailed description of LVGCCs and how they serve to regulate neuronal excitability via the post burst afterhyperpolarization (AHP). We conclude by reviewing studies that link the slow component of the AHP to learning and memory, and discuss how age-related increases in LVGCC expression may underlie cognitive decline by mediating a decrease in neuronal excitability.