Acute hypocalcemia and metabolic alkalosis in children on cation-exchange resin therapy

Background. Sodium polystyrene sulfonate (SPS) is a chelating agent used for the treatment of hyperkalemia. SPS has a wide range of exchange capacity requiring close monitoring of serum electrolytes. We observed two patients who developed acute hypocalcemia and increased metabolic alkalosis after initiating SPS therapy. We report these cases to draw attention to the potential risk of this medication in pediatric patients. Case Diagnosis/Treatment. Two children with chronic kidney disease on dialysis were started on SPS for hyperkalemia. Within a week after initiation of the medication, both patients developed hypocalcemia on routine labs without overt clinical manifestations. The hypocalcemia was rapidly corrected with oral supplementation and discontinuation of SPS. Conclusions. Severe hypocalcemia can develop after SPS therapy. The metabolic alkalosis in these patients associated with the hypocalcemia put them at increased risk for complications. Hence, careful attention must be paid to the state of calcium metabolism in all patients receiving SPS. Often calcium supplementation is required to maintain normal calcium levels

RhoA: A therapeutic target for chronic myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL.</p> <p>Methods</p> <p>To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters.</p> <p>Results</p> <p>In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines.</p> <p>Conclusions</p> <p>RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML.</p

An Atypical Presentation of a Male with Oral-Facial-Digital Syndrome Type 1 Related Ciliopathy

Background. Oral-facial-digital syndrome type 1 (OFD1) is a rare condition with X-linked dominant inheritance caused by mutations in the Cxorf5 (OFD1) gene. This gene encodes the OFD1 protein located within centrosomes and basal bodies of primary cilia. Approximately 15–50% of patients with OFD1 progress to end-stage kidney disease following development of polycystic changes within the kidneys. This condition almost always causes intrauterine lethality in males. Description of Case Diagnosis and Treatment. A Caucasian male aged 9 years and 9 months presented with increased urinary frequency, increased thirst, and decreased appetite. Physical examination demonstrated short stature, hearing loss, photophobia, murmur, and hypogonadism. He had no other dysmorphic features. Laboratory results revealed anemia, renal insufficiency, and dilute urine with microscopic hematuria but no proteinuria. Ultrasound showed small kidneys with increased echogenicity but no evidence of cystic changes. A Ciliopathy Panel showed a novel and likely pathogenic deletion, approximately 7.9 kb, in the OFD1 gene encompassing exons 16, 17, and 19 (c.1654+833_2599+423del). Brain MRI did not demonstrate typical OFD1 findings. He is currently on chronic hemodialysis awaiting transplant from a living donor. Conclusions. We present a male patient with OFD1 mutation who lacks the classic OFD1 phenotype who presented with end-stage renal disease without evidence of polycystic changes within the kidneys

Claudin 19-based familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a sibling pair

Background: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare, autosomal recessive condition caused by mutations in CLDN16 or CLDN19, which encode for tight junction proteins, claudin-16 and claudin-19, respectively. This condition often has a delayed diagnosis in patients with no prior family history due to a lack of specific clinical symptoms. Description of case, diagnosis, and treatment: A 4-year, 10-month-old Caucasian boy presented with failure to thrive, developmental delay, and ocular findings consisting of horizontal nystagmus, bilateral macular staphylomas, and high myopia. Laboratory studies revealed hypercalciuria, hypomagnesemia, and renal insufficiency. Renal ultrasound showed bilateral small kidneys with medullary nephrocalcinosis. Candidate gene sequencing performed at age 7 years identified a novel, homozygous, frameshift mutation c.140_141delAT (p.Tyr47Stop) within CLDN19, confirming the molecular diagnosis of FHHNC. Due to rapid renal progression, the proband underwent renal transplant at age 10 years, 10 months. FHHNC was prenatally diagnosed in the proband's sister, who was found at birth to have ocular findings and hypomagnesemia. In addition, she had feeding intolerance and persistent hypoglycemia with hyperinsulinism that has required chronic diazoxide therapy. Conclusions: Although rare, FHHNC should be suspected in patients who present with nephrocalcinosis in the setting of congenital eye anomalies

Elucidation of the anticancer potential and tubulin isotype-specific interactions of β-sitosterol

<p>Beta-sitosterol (β-SITO), a phytosterol present in many edible vegetables, has been reported to possess antineoplastic properties and cancer treatment potential. We have shown previously that it binds at a unique site (the ‘SITO-site’) compared to the colchicine binding site at the interface of α- and β-tubulin. In this study, we investigated the anticancer efficacy of β-SITO against invasive breast carcinoma using MCF-7 cells. Since ‘isotypes’ of β-tubulin show tissue-specific expression and many are associated with cancer drug resistance, using computer-assisted docking and atomistic molecular dynamic simulations, we also examined its binding interactions to all known isotypes of β-tubulin in αβ-tubulin dimer. β-SITO inhibited MCF-7 cell viability by up to 50%, compared to vehicle-treated control cells. Indicating its antimetastatic potential, the phytosterol strongly inhibited cell migration. Immunofluorescence imaging of β-SITO-treated MCF-7 cells exhibited disruption of the microtubules and chromosome organization. Far-UV circular dichroism spectra indicated loss of helical stability in tubulin when bound to β-SITO. Docking and MD simulation studies, combined with MM-PBSA and MM-GBSA calculations revealed that β-SITO preferentially binds with specific β-tubulin isotypes (β_II and β_III) in the αβ-tubulin dimer. Both these β-tubulin isotypes have been implicated in drug resistance against tubulin-targeted chemotherapeutics. Our data show the tubulin-targeted anticancer potential of β-SITO, and its potential clinical utility against β_II and β_III isotype-overexpressing neoplasms.</p