Disturbed Calcium Research Articles

A combined CaMKII inhibition and mineralocorticoid receptor antagonism via eplerenone inhibits functional deterioration in chronic pressure overloaded mice.

In the diseased and remodelled heart, increased activity and expression of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), an excess of fibrosis, and a decreased electrical coupling and cellular excitability leads to disturbed calcium homeostasis and tissue integrity. This subsequently leads to increased arrhythmia vulnerability and contractile dysfunction. Here, we investigated the combination of CaMKII inhibition (using genetically modified mice expressing the autocamtide‐3‐related‐peptide (AC3I)) together with eplerenone treatment (AC3I‐Epler) to prevent electrophysiological remodelling, fibrosis and subsequent functional deterioration in a mouse model of chronic pressure overload. We compared AC3I‐Epler mice with mice only subjected to mineralocorticoid receptor (MR) antagonism (WT‐Epler) and mice with only CaMKII inhibition (AC3I‐No). Our data show that a combined CaMKII inhibition together with MR antagonism mitigates contractile deterioration as was manifested by a preservation of ejection fraction, fractional shortening, global longitudinal strain, peak strain and contractile synchronicity. Furthermore, patchy fibrosis formation was reduced, potentially via inhibition of pro‐fibrotic TGF‐β/SMAD3 signalling, which related to a better global contractile performance and a slightly depressed incidence of arrhythmias. Furthermore, the level of patchy fibrosis appeared significantly correlated to eplerenone dose. The addition of eplerenone to CaMKII inhibition potentiates the effects of CaMKII inhibition on pro‐fibrotic pathways. As a result of the applied strategy, limiting patchy fibrosis adheres to a higher synchronicity of contraction and an overall better contractile performance which fits with a tempered arrhythmogenesis.

Characteristics of calcium and phosphorous metabolism in patients after bariatric surgery and the role of vitamin d supplementation in the prevention and treatment of postoperative bone and mineral disorders

This article provides a review of current literature on the effect of various doses of vitamin D on the parameters of calcium and phosphorus metabolism in patients after bariatric surgery.
 The decrease of bone mineral density is one of the most frequent complications of the bariatric surgery, which increases the risk of fractures. There are many different mechanisms for impaired mineral metabolism after bariatric surgery, but a decrease in the absorption of calcium and vitamin D plays a key role in this process. Vitamin D is the most important endocrine regulator of calcium homeostasis in the body, which provides the absorption of 90% of calcium in the gut. Patients with morbid obesity have a high risk of vitamin D deficiency even before surgery, which may worsen after operation and in the absence of timely treatment lead to severe disturbances of calcium and phosphorus metabolism.
 It was found that high doses of vitamin D after bariatric surgery can improve parameters of bone metabolism, and, as a result, prevent fractures after surgery, which generally has a beneficial effect on the quality of life and labor prognosis. The results of the studies available to date open up new opportunities for the prevention and treatment of postoperative complications associated with impaired bone metabolism.

Electrolyte Disorders Induced by Antineoplastic Drugs.

The use of antineoplastic drugs has a central role in treatment of patients affected by cancer but is often associated with numerous electrolyte derangements which, in many cases, could represent life-threatening conditions. In fact, while several anti-cancer agents can interfere with kidney function leading to acute kidney injury, proteinuria, and hypertension, in many cases alterations of electrolyte tubular handling and water balance occur. This review summarizes the mechanisms underlying the disturbances of sodium, potassium, magnesium, calcium, and phosphate metabolism during anti-cancer treatment. Platinum compounds are associated with sodium, potassium, and magnesium derangements while alkylating agents and Vinca alkaloids with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Novel anti-neoplastic agents, such as targeted therapies (monoclonal antibodies, tyrosine kinase inhibitors, immunomodulators, mammalian target of rapamycin), can induce SIADH-related hyponatremia and, less frequently, urinary sodium loss. The blockade of epidermal growth factor receptor (EGFR) by anti-EGFR antibodies can result in clinically significant magnesium and potassium losses. Finally, the tumor lysis syndrome is associated with hyperphosphatemia, hypocalcemia and hyperkalemia, all of which represent serious complications of chemotherapy. Thus, clinicians should be aware of these side effects of antineoplastic drugs, in order to set out preventive measures and start appropriate treatments.

Calcific aortic stenosis: known facts and promising studies

Calcific aortic stenosis is a common heart disease and the most common cause of surgical interventions on heart valves in old age. Eliminated course, nonspecific clinical symptoms, and late patients seeking surgical help, lead to high mortality, reaching 50 % over the next 5 years. Despite the frequent occurrence, our knowledge of this type of aortic defect remains incomplete. About 300 years ago A. Bonnet first described defect as a random isolated pathological finding in the corpse of a Parisian tailor. Later, R. Virchow designated ectopic calcification / ossification as the main cause of the development of the disease and put forward the theory of hematogenous drift. In 1904, J. G. Monckeberg considered calcific aortic stenosis a manifestation of “senile degeneration” of valves and blood vessels. W. S. Roberts retrospectively correlated the classic triad of symptoms with the time of death of patients with aortic stenosis. The progress of cardiac surgery in the middle of the 20 th century made it possible to describe in detail ectopic calcification as an active, progressive, recurrent and potentially modifiable process. In the works of the staff of the Nesterov’s department of facultative therapy demonstrated a high incidence of the disease in the population of the Russia. The main reason for the development of symptoms is a progressive obstruction of the exit tract of the left ventricle of the heart, its uneven hypertrophy, rhythm and conduction disturbances in combination with concomitant arterial hypertension and other comorbidities. A change in the nature of systolic murmur, underestimation of symptoms by doctors and patients themselves, the ambiguity of echocardiography data lead to late diagnosis of the disease and untimely surgical treatment. Disturbances of calcium and bone metabolism significantly reduce the functional status of patients, including due to an adverse effect on cardiac hemodynamics. Modern molecular genetic studies are aimed at finding possible ways to control a systemic inflammatory reaction, suppress lipid peroxidation, inhibit calcification and modify the osteogenic potential of interstitial cells of heart valves.

Electrocardiological effects of ranolazine and lidocaine on normal and diabetic rat atrium.

Cellular changes occurring in diabetic cardiomyopathy include disturbances of calcium and sodium homeostasis. Voltage-gated sodium channels are responsible for the initiation of cardiac action potentials, and the excitability would create relevance. The effect of ranolazine as a sodium channel blocker on atrium electromechanical parameters is investigated and compared with lidocaine in streptozocin-treated diabetic rats. After an 8-week induction of diabetes type I, the effect of cumulative concentrations of ranolazine and lidocaine on the electrophysiology of isolated atrium was studied. Ranolazine's effects were evaluated on cardiac sodium current in normal- and high-glucose medium, with whole-cell patch-clamp technique. Ranolazine at therapeutic concentrations had no significant statistical effect on refractory period in normal and diabetic isolated heart. Ranolazine (10μM) caused a hyperpolarizing shift of V1/2 for steady-state inactivation in normal media, while it significantly elicited a depolarizing shift in high-glucose media (p < 0.05). It is concluded that in the isolated rat atrium preparation, ranolazine and lidocaine have no beneficial on diabetic cardiomyopathy. Although refractoriness and contractility were not much different in normal and diabetic atria, there was a definite effect of ranolazine and lidocaine on sodium current in varying concentrations. This may have significance in future therapeutics.

Usefulness of X-rays in the Differential Diagnosis of Hypophosphataemic Rickets.

Rickets and osteomalacia are two related conditions linked by the lack of mineralization of bone tissue due to a disturbance of calcium and phosphate homeostasis. Some of the most characteristic features of rickets are skeletal deformities, fractures, linear and continuous periosteal reaction, and enlargement of the metaphyseal space in an irregular and frayed form. However, these radiological findings are not exclusive to these diseases, but may also originate in children who were born prematurely or in those who have suffered physical abuse or an accident. Hence, it is important to establish a differential diagnosis. All these observations can be evidenced by radiological images using a simple X-ray. The aim of this article is to show the main radiological findings that can be found in rickets and how to establish a differential diagnosis of X-linked hypophosphataemic (XLH) rickets.

Pravastatin alleviates intracellular calcium dysregulation induced by Interleukin-6 via the mitochondrial ROS pathway in adult ventricular myocytes

Acute inflammation often contributes to the increased arrhythmogenesis in the cardiomyocytes. We investigated the protective effects of pravastatin on calcium disorders induced by acute administration of pro-inflammatory cytokines in isolated ventricular myocytes and its underlying mechanisms. Wild-type mice were intraperitoneally injected for five days with either pravastatin 20 mg/kg per day or an equal volume of normal saline. Cytosol Ca2+ handling was studied in freshly isolated ventricular myocytes after acute exposure of interleukin-6 (IL-6) (1 ng/ml) for 120 min by Ionoptix and confocal microscopy. Acute administration of clinically relevant concentrations of IL-6 disturbed calcium handling in ventricular myocytes, which presented as decreased amplitudes, prolonged decay times of Ca2+ transients, and reduced sarcoplasmic reticulum (SR) calcium stores. The frequency of spontaneous Ca2+ release, including calcium sparks and spontaneous calcium waves, was dramatically enhanced in the setting of IL-6. Notably, the pretreatment of pravastatin alleviated disturbed Ca2+ cycling, reduced spontaneous Ca2+ leakage induced by IL-6. Mitochondrial ROS pathway may constitute the underlying mechanism of the protective effects of pravastatin. Pravastatin protected the cardiomyocytes against calcium disorders induced by IL-6 via the mitochondrial ROS pathway, which suggests that pravastatin may represent a promising auxiliary therapeutic strategy for cardiac injury under acute inflammation.

A Visual FRET Immunofluorescent Biosensor for Ratiometric Parathyroid Hormone (1-84) Antigen Point-of-Care Detection.

Excessive secretion of PTH leads to disturbance of calcium and phosphorus metabolism in the body, which promotes bone, kidney, digestive system and nervous system diseases. Due to the short half-life of PTH, it becomes a difficult issue for PTH detection in the clinical diagnosis field. We explored a competitive immunofluorescent sensing mode based on FRET of two-color CdTe QDs for ratiometric PTH 1-84 antigen detection. The FRET effect and ratiometric fluorescence between the two-color CdTe QDs motivated accurate quantification of PTH 1-84 antigen concentration from 0.01ngmL-1 to 0.08ngmL-1 with a limit of detection of 3pgmL-1. More importantly, under UV irradiation, samples with different concentrations of PTH 1-84 antigen achieved fluorescence visualization, which provides huge possibility for the practical application of PTH 1-84 antigen point-of-care detection.

The Pathogenic Role of Very Low Density Lipoprotein on Atrial Remodeling in the Metabolic Syndrome.

Atrial fibrillation (AF) is the most common persistent arrhythmia, and can lead to systemic thromboembolism and heart failure. Aging and metabolic syndrome (MetS) are major risks for AF. One of the most important manifestations of MetS is dyslipidemia, but its correlation with AF is ambiguous in clinical observational studies. Although there is a paradoxical relationship between fasting cholesterol and AF incidence, the benefit from lipid lowering therapy in reduction of AF is significant. Here, we reviewed the health burden from AF and MetS, the association between two disease entities, and the metabolism of triglyceride, which is elevated in MetS. We also reviewed scientific evidence for the mechanistic links between very low density lipoproteins (VLDL), which primarily carry circulatory triglyceride, to atrial cardiomyopathy and development of AF. The effects of VLDL to atria suggesting pathogenic to atrial cardiomyopathy and AF include excess lipid accumulation, direct cytotoxicity, abbreviated action potentials, disturbed calcium regulation, delayed conduction velocities, modulated gap junctions, and sarcomere protein derangements. The electrical remodeling and structural changes in concert promote development of atrial cardiomyopathy in MetS and ultimately lead to vulnerability to AF. As VLDL plays a major role in lipid metabolism after meals (rather than fasting state), further human studies that focus on the effects/correlation of postprandial lipids to atrial remodeling are required to determine whether VLDL-targeted therapy can reduce MetS-related AF. On the basis of our scientific evidence, we propose a pivotal role of VLDL in MetS-related atrial cardiomyopathy and vulnerability to AF.

Osteodystrophies of jaws

Bone is a dense, semi rigid, porous, calcified connective tissue forming the major portion of the skeleton of most vertebrates. It consists of a dense organic matrix and an inorganic mineral component. Bone remodelling is a complex process by which old bone is continuously replaced by new tissue, which requires interaction between different cell phenotypes and is regulated by a variety of biochemical and mechanical factors. In a homeostatic equilibrium, the process of resorption and formation are balanced so that old bone is continuously replaced by new tissue and it adapts to mechanical load and strain. Several local and systematic factors which cause disturbances in bone resorption and deposition leads to abnormal or defective development of bone commonly termed as osteodystrophy - A defective ossification of bone usually is associated with disturbed calcium and phosphorus metabolism. The better understanding of molecular cellular biology and pathogenic mechanism aids to define the abnormalities in osteoblastic and osteoclastic lineages and to develop new therapeutic approaches.

DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson's disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

Hypertrophic cardiomyopathy: genetics and clinical perspectives.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and defined by unexplained isolated progressive myocardial hypertrophy, systolic and diastolic ventricular dysfunction, arrhythmias, sudden cardiac death and histopathologic changes, such as myocyte disarray and myocardial fibrosis. Mutations in genes encoding for proteins of the contractile apparatus of the cardiomyocyte, such as β-myosin heavy chain and myosin binding protein C, have been identified as cause of the disease. Disease is caused by altered biophysical properties of the cardiomyocyte, disturbed calcium handling, and abnormal cellular metabolism. Mutations in sarcomere genes can also activate other signaling pathways via transcriptional activation and can influence non-cardiac cells, such as fibroblasts. Additional environmental, genetic and epigenetic factors result in heterogeneous disease expression. The clinical course of the disease varies greatly with some patients presenting during childhood while others remain asymptomatic until late in life. Patients can present with either heart failure symptoms or the first symptom can be sudden death due to malignant ventricular arrhythmias. The morphological and pathological heterogeneity results in prognosis uncertainty and makes patient management challenging. Current standard therapeutic measures include the prevention of sudden death by prohibition of competitive sport participation and the implantation of cardioverter-defibrillators if indicated, as well as symptomatic heart failure therapies or cardiac transplantation. There exists no causal therapy for this monogenic autosomal-dominant inherited disorder, so that the focus of current management is on early identification of asymptomatic patients at risk through molecular diagnostic and clinical cascade screening of family members, optimal sudden death risk stratification, and timely initiation of preventative therapies to avoid disease progression to the irreversible adverse myocardial remodeling stage. Genetic diagnosis allowing identification of asymptomatic affected patients prior to clinical disease onset, new imaging technologies, and the establishment of international guidelines have optimized treatment and sudden death risk stratification lowering mortality dramatically within the last decade. However, a thorough understanding of underlying disease pathogenesis, regular clinical follow-up, family counseling, and preventative treatment is required to minimize morbidity and mortality of affected patients. This review summarizes current knowledge about molecular genetics and pathogenesis of HCM secondary to mutations in the sarcomere and provides an overview about current evidence and guidelines in clinical patient management. The overview will focus on clinical staging based on disease mechanism allowing timely initiation of preventative measures. An outlook about so far experimental treatments and potential for future therapies will be provided.

Severity of Ionized Hypercalcemia and Hypocalcemia Is Associated With Etiology in Dogs and Cats.

Background: Calcium disorders are common in small animals, but few studies have investigated the etiology of ionized hypercalcemia and hypocalcemia in large populations. This study aimed to determine the incidence of ionized calcium disorders in dogs and cats treated at a tertiary referral clinic and to describe the associated diseases.Methods: An electronic database of electrolyte analyses conducted at the Cornell University Hospital for Animals from 2007 to 2017 was searched. Dogs and cats with ionized hypercalcemia or hypocalcemia were identified based on institution reference intervals. Duplicate case entries were removed. Medical records were reviewed to identify the cause of the calcium abnormality. Chi-squared analysis with Bonferroni adjustment was performed to compare frequencies of disease processes between mild and moderate-severe disturbances.Results: The database included 15,277 dogs and 3,715 cats. Hypercalcemia was identified in 1,641 dogs and 119 cats. The incidence of canine and feline hypercalcemia was 10.7 and 3.2%, respectively. Hypocalcemia was identified in 1,467 dogs and 450 cats. The incidence of canine and feline hypocalcemia was 9.6% and 12.1%, respectively. The most common pathologic causes of hypercalcemia in dogs were malignancy-associated (12.9%), parathyroid-dependent (4.6%) and hypoadrenocorticism (1.7%). In cats, malignancy-associated hypercalcemia (22.7%), kidney injury (13.4%) and idiopathic hypercalcemia (12.6%) were most common. Dogs presenting with moderate-severe hypercalcemia vs. mild hypercalcemia were significantly more likely to have hyperparathyroidism, malignancy-associated hypercalcemia or hypervitaminosis D, whereas cats were significantly more likely to have malignancy-associated hypercalcemia or idiopathic hypercalcemia. The most common pathologic causes of hypocalcemia in dogs were critical illness (17.4%), kidney injury (10.4%) and toxicity (7.5%). In cats, kidney injury (21.6%), urethral obstruction (15.1%), and critical illness (14.7%) were most frequent. Dogs presenting with moderate-severe hypocalcemia were significantly more likely to have hypoparathyroidism, kidney injury, eclampsia or critical illness, whereas cats were significantly more likely to have kidney injury, soft tissue trauma or urethral obstruction.Conclusions: Mild calcium disturbances are most commonly associated with non-pathologic or transient conditions. Malignancy-associated hypercalcemia is the most common cause of ionized hypercalcemia in dogs and cats. Critical illness and kidney injury are frequent causes of ionized hypocalcemia in both species.

Rapid regression of calciphylaxis in a hemodialysis patient after intensive management of disturbance of calcium and phosphate metabolism: a case report with literature review

BackgroundCalciphylaxis, a multifactorial cutaneous vascular disease, is a rare but therapy-resistant and life-threatening disorder that usually occurs in patients with end-stage kidney disease (ESKD). Although there have been many reports regarding calciphylaxis, its pathophysiology is not fully understood and strong evidence for its treatment is lacking.Case presentationA 63-year-old woman with a 20-year history of hemodialysis (HD) for ESKD of unknown etiology was admitted because of severe painful cutaneous ulcers on the right lower leg. She underwent artificial heart valve replacement surgery for infective endocarditis 13 years earlier, following which warfarin was prescribed. Laboratory findings on admission showed elevation of the calcium (Ca)-phosphorus (P) product due to hyperphosphatemia, and parathyroid hormone (PTH) levels were above the target range. Additionally, the efficiency of HD, based on Kt/V urea, was reduced because of vascular access (VA) failure. Furthermore, there was no evidence of inflammation, and the ankle-brachial index was within the normal range. Skin biopsy specimens showed thrombosis of the small vessels and marked Ca deposition in the media of the arterioles, which were compatible with a diagnosis of calciphylaxis. Hence, in addition to surgical repair of VA failure and prolongation of HD treatment time, we discontinued administration of the synthetic vitamin D3, calcitriol, and switched treatment from cinacalcet to etelcalcetide, which is a novel peptide agonist of the Ca-sensing receptor. Consequently, serum Ca, P, and Ca-P product levels decreased immediately, although her PTH levels remained high. Her painful severe skin ulcers regressed completely within 3 months.ConclusionIn this patient, although the influence of oral warfarin therapy and secondary hyperparathyroidism, which are known risk factors for calciphylaxis, was not removed, her ulcers appeared to respond to the optimization of disturbed Ca-P metabolism. Our experience suggests that intensive management of serum Ca and P levels is essential to prevent the development of calciphylaxis. Hypercalcemia and hyperphosphatemia due to excess vitamin D receptor activators could be risk factors for calciphylaxis.

TRPM4 channel and cancer.

The TRPM4 channel has been extensively studied in cerebral diseases such as stroke, head injury and multiple sclerosis. In the heart, gain-of-function mutations of TRPM4 are a cause of familial cardiac block. Recently, evidence has emerged to support the role of TRPM4 in certain types of cancer, such as prostate cancer and large B cell lymphoma. The expression of TRPM4 could mediate certain behaviors of cancer cells such as migration and invasion. However, the mechanisms are largely unknown. As a nonselective monovalent cation channel, TRPM4 upregulation and activation enhance sodium entry, which leads to depolarization of the membrane potential. The membrane potential is critical in regulating calcium influx, and a disturbed calcium homeostasis is always associated with cancer cell behaviors. Research on TRPM4 channels in cancer is at a very early stage. In this review, we summarize the expression of TRPM4 in various cancers as well as our current understanding of TRPM4 in cancer. The potential mechanisms of the TRPM4 channel in regulating calcium homeostasis in cancer cells are further discussed in detail. Targeting the TRPM4 channel can be a novel way of managing cancer metastasis via disrupting calcium signaling pathways.

Epileptic seizure in a cocker spaniel associated with hypocalcaemia, hypovitaminosis D and a protein-losing enteropathy

Disturbances in calcium and vitamin D homeostasis can cause neurological disturbances. Protein-losing enteropathies (PLEs) are an important cause of hypocalcaemia in dogs and can be associated with epileptic seizures. Hypocalcaemic...

Effect of Sodium-Glucose Co-transporter 2 Inhibitors on Bone Metabolism and Fracture Risk.

The effect of anti-diabetic medications on bone metabolism has received increasing attention, considering that type 2 diabetes mellitus is a common metabolic disorder with adverse effects on bone metabolism. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel anti-diabetic medications that prevent glucose resorption at the proximal convoluted tubules in the kidney, increasing urinary glucose excretion, and decreasing the blood glucose level. The superiority of SGLT2 inhibitors shows in reducing the glucose level independent of insulin secretion, lowering the risk of hypoglycemia, and improving cardiovascular outcomes. SGLT2 inhibitors have been associated with genital mycotic infections, increased risk of acute kidney injury, dehydration, orthostatic hypotension, and ketoacidosis. Moreover, the effect of SGLT2 inhibitors on bone metabolism and fracture risk has been widely taken into consideration. Our review summarizes the results of current studies investigating the effects of SGLT2 inhibitors on bone metabolism (possibly including increased bone turnover, disrupted bone microarchitecture, and reduced bone mineral density). Several mechanisms are probably involved, such as bone mineral losses due to the disturbed calcium and phosphate homeostasis, as confirmed by an increase in fibroblast growth factor 23 and parathyroid hormone levels and a decrease in 1,25-dihydroxyvitamin D levels. SGLT2 inhibitors might indirectly increase bone turnover by weight loss. Lowering the blood glucose level might ameliorate bone metabolism impairment in diabetes. The effect of SGLT2 inhibitors on bone fractures remains unclear. Evidence indicating the direct effect of SGLT2 inhibitors on fracture risk is lacking and increased falls probably contribute to fractures.

Disturbances in Calcium and Zinc Homeostasis During Testicular Damage Induced by Citrus aurantifolia Juice in Wistar Rats.

Infertility rate is high globally and in Nigeria. The reported spermicidal activity of Citrus aurantifolia juice (CAJ)and its popular consumption may be a contributing factor to the rise in male infertility. This study examined the effects ofCAJ on testis and evaluated the role of calcium and zinc in these effects. Twenty-eight male rats (200-220g) were groupedinto four (n=7). Group I (control) received 0.5ml normal saline, while groups II, III and IV received 600mg/kg, 900mg/kgand 1200mg/kg of CAJ, respectively, orally for 35 days. Sperm analysis, testicular histology, testicular zinc and calciumconcentrations were evaluated. The results showed a significant decrease (P < 0.001) in body weight and gonad-somaticindex (GSI) of the rats in group IV. No sperm cells were found in the sperm samples of all the treatment groups in contrastto control. There was a significant decrease (P < 0.001) in zinc concentration of group III and IV animals and a significantincrease (P < 0.001) in testicular calcium content of group III and IV animals. Derangement of testicular cyto-architecture,shrinkage or complete destruction of seminiferous tubules as well as absence of spermatogenic cells were observed in thetreatment groups. It was concluded that CAJ induced a destructive effect on testes of rats as evidenced by damaged testiculartissue, reduced gonado-somatic index, azospermia and disruption in testicular electrolyte homeostasis. It was concluded thatCAJ caused hypercalcaemia and hypozincaemia in the testicular tissue of the treated rats. Concurrently, CAJ also causeddamage to testicular histology, azospermia and decreased GSI. Citrus aurantifolia juice should be consumed with cautiondue to its potential to cause infertility in males.

Bone health in chronic kidney disease-mineral and bone disorder: a clinical case seminar and update.

The metabolic abnormalities affecting bone in the setting of chronic kidney disease (CKD) are complex with overlapping and interacting aetiologies and have challenging diagnostic and management strategies. Disturbances in calcium, phosphate, fibroblast growth factor 23, parathyroid hormone concentrations and vitamin D deficiency are commonly encountered and contribute to the clinical syndromes of bone disorders in CKD, including hyperparathyroidism, osteomalacia, osteoporosis and adynamic bone disease. Mineral and bone abnormalities may also persist or arise de novo post-renal transplantation. The Kidney Disease Improving Global Outcomes organisation describes these mineral metabolism derangements and skeletal abnormalities as 'CKD Mineral and Bone Disorder'. Patients with this disorder have an increased risk of fracture, cardiovascular events and overall increased mortality. In light of the recently updated 2017 guidelines from the Kidney Disease Improving Global Outcomes, we present a clinical case-based discussion to highlight the complexities of investigating and managing the bone health of patients with CKD with a focus on these updates.

CKD-MBD: from the Pathogenesis to the Identification and Development of Potential Novel Therapeutic Targets.

Although we have seen tremendous advances in the comprehension of CKD-MBD pathophysiology during the last few years, this was not accompanied by a significant change in mortality rate and quality of life. This review will address the traditional and updated pathophysiology of CKD-MBD along with the therapeutic limitations that affect CKD-MBD and proposed alternative treatment targets. An innovative concept brings the osteocyte to the center of CKD-MBD pathophysiology, in contrast to the traditional view of the skeleton as a target organ for disturbances in calcium, phosphate, parathyroid hormone, and vitamin D. Osteocytes, through the synthesis of FGF-23, sclerostin, among others, are able to interact with other organs, making bone an endocrine organ. Thus, osteocyte dysregulation might be an early event during the course of CKD. This review will revisit general concepts on the pathophysiology of CKD-MBD and discuss new perspectives for its treatment.