Exploring ND-011992, a quinazoline-type inhibitor targeting quinone reductases and quinol oxidases.

Bacterial energy metabolism has become a promising target for next-generation tuberculosis chemotherapy. One strategy to hamper ATP production is to inhibit the respiratory oxidases. The respiratory chain of Mycobacterium tuberculosis comprises a cytochrome bcc:aa and a cytochrome bd ubiquinol oxidase that require a combined approach to block their activity.

Chemical Genetics Screen of EVP4593 Sensitivity in Budding Yeast Identifies Effects on Mitochondrial Structure and Function.

Mitochondria are essential eukaryotic organelles. Mitochondrial dysfunction can lead to mitochondrial myopathies and may contribute to neurodegenerative diseases, cancer, and diabetes. EVP4593, a 6-aminoquinazoline derivative with therapeutic potential, has been shown to inhibit NADH-ubiquinone oxidoreductase (Complex I) of the mitochondrial electron transport chain, causing the release of reactive oxygen species (ROS) and a reduction in ATP synthesis.

Concise Synthesis of 1,4-Benzoquinone-Based Natural Products as Mitochondrial Complex I Substrates and Substrate-Based Inhibitors.

A short, efficient one-step synthesis of 2-methyl-5-(3-methyl-2-butenyl)-1,4-benzoquinone, a natural product from Pyrola media is described. The synthesis is based on a direct late C-H functionalization of the quinone scaffold. The formation of the natural product was confirmed by means of 2D-NMR spectroscopy.

A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment.

In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation εL221F.

Clinical features in a series of fast channel congenital myasthenia syndrome.

Fast channel congenital myasthenic syndromes are rare, but frequently result in severe weakness. We report a case of 12 fast channel patients to highlight clinical features and management difficulties. Patients were diagnosed through genetic screening and identification of mutations shown to cause fast channel syndrome.

Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia.

Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico-pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis.

Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7.

Background: Mutations in the postsynaptic adaptor protein Dok-7 underlie congenital myasthenic syndrome (CMS) with a characteristic limb girdle pattern of muscle weakness. Patients usually do not respond to or worsen with the standard CMS treatments: cholinesterase inhibitors and 3,4-diaminopyridine. However, anecdotal reports suggest they may improve with ephedrine.

Congenital myasthenic syndromes and the formation of the neuromuscular junction.

The congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders affecting neuromuscular transmission. Underlying mutations have been identified in at least 11 different genes. The majority of CMS patients have disorders due to mutations in postsynaptic proteins.

Aortic arch morphology and late systemic hypertension following correction of coarctation of aorta.

Objective: To reproduce in an adult population a pediatric study that found an association between aortic arch geometry and late systemic hypertension following successful repair of aortic coarctation.

Design And Results: Fifty-one patients with successful repair of coarctation of the aorta had blood pressure measurement at rest and during exercise. After cross-sectional imaging of the aortic arch, patients were assigned to 1 of 3 previously defined morphological categories: normal, gothic, or crenel.

Clinical features of the DOK7 neuromuscular junction synaptopathy.

Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships.

Minimal tethered cord syndrome associated with thickening of the terminal filum.

Object: The authors investigated the occurrence of anatomical abnormalities of the terminal filum in children undergoing surgical filum lysis for minimal tethered cord syndrome (TCS).

Methods: Five consecutive children (age range 6-12 years) with medically refractory voiding dysfunction but no magnetic resonance (MR) imaging-documented lumbosacral abnormality on 1.5-tesla sequences underwent preoperative urodynamic studies consisting of calibrated uroflowmetry, cystometrography, and voiding cystourethrography.

Tumour-induced polarization of tumour vaccine-draining lymph node T cells to a type 1 cytokine profile predicts inherent strong immunogenicity of the tumour and correlates with therapeutic efficacy in adoptive transfer studies.

Previously we have shown that vaccination with the poorly immunogenic B16BL6-D5 melanoma (D5) elicits a dominant type 2 (T2) cytokine response that fails to protect the host from a subsequent tumour challenge. Here we investigated whether the inherent immunogenicity of a tumour can be correlated with its ability to bias the anti-tumour cytokine response towards either a type 1 (T1) or a T2 profile. The immune response to six tumours of different inherent immunogenicity was assayed.

Ipsilateral ureteroureterostomy for the treatment of vesicoureteral reflux or obstruction associated with complete ureteral duplication.

Purpose: We reviewed our experience with ureteroureterostomy as definitive treatment for vesicoureteral reflux or obstruction associated with ureteral duplication to determine the efficacy and morbidity of this procedure and identify factors that affect outcome.

Materials And Methods: We performed a total of 100 ureteroureterostomies in 94 children with an average age of 28 months during the 23-year period ending May 1999. Four patients (4 kidneys) failed to return for postoperative evaluation.

Megacystis microcolon intestinal hypoperistalsis syndrome: bladder distension and pyelectasis in the fetus without anatomic outflow obstruction.

We report a case of a 46,XY male infant with a history of normal amniotic fluid levels who was delivered by elective cesarean section at 38.5 weeks' gestation because of progressive bladder distension, hydroureteronephrosis, and what was thought to be a dilated posterior urethra. The child died at 19 days of age of cardiovascular complications.

Unenhanced computerized axial tomography to detect retained calculi after percutaneous ultrasonic lithotripsy.

Purpose: We report our experience with unenhanced computerized axial tomography (CT) after percutaneous ultrasonic lithotripsy in patients thought to be at high risk for retained calculi.

Materials And Methods: CT was obtained in 121 patients (124 kidneys) within 12 to 36 hours of percutaneous ultrasonic lithotripsy for staghorn or large nonstaghorn renal calculi. Cases were grouped according to the CT findings as no retained calculi, insignificant retained calculi (fragments 1 to 3 mm.

Kidney transplantation in children: a single center experience.

Purpose: We reviewed our most recent 10-year experience with kidney transplantation in children to determine the morbidity and mortality of the procedure, and to identify factors that affected outcome.

Materials And Methods: A total of 107 renal transplants were done in 95 children 1 to 17 years old (mean age 10.9) during the 10-year period ending January 1, 1997.

Examining the immune response in sentinel lymph nodes of mice and men.

Recently, it was recognized that an immune response develops along one of two major pathways. One leads to a destructive immune response (type 1), while the alternative leads to a nondestructive immune response (type 2). Our studies in animal models suggest that therapeutic vaccines induce a tumor-specific type 1 immune response while ineffective vaccines induce a type 2 response.

A rational approach to managing stage I nonseminomatous germ cell cancer.

Regardless of the treatment option selected for management of low-stage germ cell cancer, ultimate survival is nearly identical. Treatment-related morbidity is very low regardless of management modality and the individual patient can expect similar physical limitations owing to therapy. The overall difference in loss of productivity between treatment programs varies by little more than 1 week.