Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Objectives

This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.

Methods

Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.

Results

Fifty-six patients were defined as early-onset (n?=?23) if symptomatic?<?28 days of age, late-onset (n?=?23) if symptomatic later, or selectively screened perinatally due to a familial proband (n?=?10). The median follow-up was 12.4 years (range 0–53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n?=?19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.

Conclusions

Our study further defines the natural history of argininosuccinic aciduria and genotype–phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.

     

Hepatocellular adenoma: An update

Hepatocellular adenomas (HCA) are rare benign liver tumors. Recent technological advancements have helped in the early identification of such lesions. However, precise diagnosis of hepatocellular incidentalomas remains challenging. Studies at the molecular level have provided new insights into the genetics and pathophysiology of these lesions. These in turn have raised questions over their existing management modalities. However, the rarity of the tumor still restricts the quality of evidence available for current recommendations and guidelines. This article provides a comprehensive review on the etiology, molecular biology, patho-physiology, clinical manifestations, and complications associated with HCA. It also elaborates on the genetic advancements, existing diagnostic tools and current guidelines for management for such lesions.     

Total hip replacement for arthritis following tuberculosis of hip

AIM: To present the results of total hip arthroplasty (THA) for post tubercular arthritis of the hip joint.METHODS: Sixty-five patients (45 male, 20 female) with previously treated tuberculosis of the hip joint underwent cementless THA for post tubercular arthritis. The average age at the time of THA was 48 years (range 29 to 65 years). Erythrocyte sedimentation rate, C reactive protein, chest X-ray and contrast enhanced magnetic resonance imaging were done preoperatively to confirm resolution of the disease and to rule out any residual disease. Intra-operative samples were taken for microbiological examination, polymerase chain reaction (PCR) and histological examination. Patients were started on anti-tubercular drugs one week before the operation and continued for 6 mo post operatively. The patients were followed up clinically using the Harris hip score as well as radiologically for any loosening of the implants, osteolysis and any recurrence of tuberculosis. Any complications especially the recurrence of the infection was also recorded.RESULTS: The mean interval from completion of antitubercular therapy for tuberculosis to surgery was 4.2 years (range, 2-6 years). Preoperatively, 17 patients had ankylosis whereas 48 patients had functional but painful range of motion. The mean surgical time was 97 min (range, 65-125) whereas the mean blood loss was 600 mL (range, 400-900 mL). The average follow up was 8.3 years (range 6-11 years). The average Harris Hip score improved from 27 preoperatively to 91 at the final follow up. Seventeen patients had acetabular protrusion which was managed with impaction grafting and cementless acetabular cup. The bone graft had consolidated in all these 17 patients at the follow up. Two patients developed discharging sinuses at 9 and 11 mo postoperatively respectively. The discharge tested positive for tuberculosis on the PCR. Both these patients were put on antitubercular therapy for another year. Both of them recovered and had no evidence of any loosening or osteolysis on X-rays. There were no other complications recorded.CONCLUSION: Total hip replacement restores good function to patients suffering from post tubercular arthritis of the hip.     

Assessing the toxic effects of ethylene glycol ethers using Quantitative Structure Toxicity Relationship models

Experimental determination of toxicity profiles consumes a great deal of time, money, and other resources. Consequently, businesses, societies, and regulators strive for reliable alternatives such as Quantitative Structure Toxicity Relationship (QSTR) models to fill gaps in toxicity profiles of compounds of concern to human health. The use of glycol ethers and their health effects have recently attracted the attention of international organizations such as the World Health Organization (WHO). The board members of Concise International Chemical Assessment Documents (CICAD) recently identified inadequate testing as well as gaps in toxicity profiles of ethylene glycol mono-n-alkyl ethers (EGEs). The CICAD board requested the ATSDR Computational Toxicology and Methods Development Laboratory to conduct QSTR assessments of certain specific toxicity endpoints for these chemicals. In order to evaluate the potential health effects of EGEs, CICAD proposed a critical QSTR analysis of the mutagenicity, carcinogenicity, and developmental effects of EGEs and other selected chemicals.We report here results of the application of QSTRs to assess rodent carcinogenicity, mutagenicity, and developmental toxicity of four EGEs: 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, and 2-butoxyethanol and their metabolites. Neither mutagenicity nor carcinogenicity is indicated for the parent compounds, but these compounds are predicted to be developmental toxicants. The predicted toxicity effects were subjected to reverse QSTR (rQSTR) analysis to identify structural attributes that may be the main drivers of the developmental toxicity potential of these compounds.     

Quadriparesis and dysarthria due to tetrabenazine therapy in a child with rheumatic chorea

Tetrabenazine (TBZ) is widely used to treat hyperkinetic movement disorders in adults; however, published experience with the drug in children is limited. Common side effects of TBZ include drowsiness, sedation, weakness, Parkinsonism, depression, and acute akathisia, all of which are reversible with decreased doses. We report here a 7-year-old girl with rheumatic chorea who developed acute akinesia of all four limbs and dysarthria due to TBZ therapy. Withdrawal of the drug led to rapid improvement within 18 hours.     

Piperacillin-tazobactam-induced hypokalemia and metabolic alkalosis

Piperacillin/tazobactam is a commonly prescribed antibiotic and is generally considered safe. We report a case of a 2-year-old girl who developed hypokalemic metabolic alkalosis and bradycardia after receiving intravenous piperacillin-tazobactam for bronchopneumonia. Upon withdrawal of the drug, serum potassium normalized in 2 days. Hypokalemia is a serious adverse effect of piperacillin-tazobactam and should be suspected while treating patients with this drug. Early recognition and prompt withdrawal of the drug will result in lesser morbidity.     

A LC-MS analysis of acamprosate from human plasma: pharmacokinetic application

A rapid and highly sensitive method for the determination of acamprosate (ACM), in human plasma using ESI-LC-MS/MS (electrospray ionization liquid chromatography tandem mass spectrometry) in negative ionization polarity in multiple reactions monitoring (MRM) mode was developed and validated. The procedure involves a simple protein precipitation step. Chromatographic separation was carried out on a Hypersil BDS C(18) column (150 mm × 4.6 mm, 5 μm) with an isocratic mobile phase and a total run time of 2.5 min. The standard calibration curves were linear within the range of 7.04-702.20 ng/mL for ACM (r ≥ 0.990). This study briefly describes the role of ion source design on matrix effects. ACM shows matrix effects in z-spray ionization source design, whereas it has no matrix effects in orthogonal spray ion source design. This method was successfully applied to a pharmacokinetic study after oral administration of acamprosate 333 mg tablet in Indian healthy male volunteers.     

The promise of nanotechnology for solving clinical problems in breast cancer

Approaches for breast cancer treatment are invasive, disfiguring, have significant side-effects, and are not always curative. Nanotechnology is an emerging area which is focused on engineering of materials <100 × 10(-9) m. There is significant promise for advancing nanotechnology to improve breast cancer diagnosis and treatment including non-invasive therapy, monitoring response to therapy, advanced imaging, treatment of metastatic disease, and improved nodal staging. Current approaches and important future directions are discussed.