Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.

Value of genetic testing for pediatric epilepsy: Driving earlier diagnosis of ceroid lipofuscinosis type 2 Batten disease.

This study assessed the effectiveness of genetic testing in shortening the time to diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Individuals who received epilepsy gene panel testing through Behind the Seizure , a sponsored genetic testing program (Cohort A), were compared to children outside of the sponsored testing program during the same period (Cohort B). Two cohorts were analyzed: children aged ≥24 to ≤60 months with unprovoked seizure onset at ≥24 months between December 2016 and January 2020 (Cohort 1) and children aged 0 to ≤60 months at time of testing with unprovoked seizure onset at any age between February 2019 and January 2020 (Cohort 2).

Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.

Epilepsy is one of the most common childhood-onset neurological conditions with a genetic etiology. Genetic diagnosis provides potential for etiologically-based management and treatment. Existing research has focused on early-onset (<24 months) epilepsies; data regarding later-onset epilepsies is limited.

Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants.

Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. We collected, analyzed, and uniformly summarized all published GALNS gene variants, thus updating the previous mutation review (published in 2014). In addition, new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States.

Opto-Microfluidic System for Absorbance Measurements in Lithium Niobate Device Applied to pH Measurements.

The aim of Lab-on-a-chip systems is the downscaling of analytical protocols into microfluidic devices, including optical measurements. In this context, the growing interest of the scientific community in opto-microfluidic devices has fueled the development of new materials. Recently, lithium niobate has been presented as a promising material for this scope, thanks to its remarkable optical and physicochemical properties.

The polysaccharide and low molecular weight components of Opuntia ficus indica cladodes: Structure and skin repairing properties.

The Opuntia ficus-indica multiple properties are reflected in the increasing interest of chemists in the identification of its natural components having pharmaceutical and/or cosmetical applications. Here we report the structural elucidation of Opuntia ficus-indica mucilage that highlighted the presence of components differing for their chemical nature and the molecular weight distribution. The high molecular weight components were identified as a linear galactan polymer and a highly branched xyloarabinan.

Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis.

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most commonly presents with seizures and/or ataxia in the late-infantile period (ages 2-4), often in combination with a history of language delay, followed by progressive childhood dementia, motor and visual deterioration, and early death.

Inhibition of melanogenesis by the pyridinyl imidazole class of compounds: possible involvement of the Wnt/β-catenin signaling pathway.

While investigating the role of p38 MAPK in regulating melanogenesis, we found that pyridinyl imidazole inhibitors class compounds as well as the analog compound SB202474, which does not inhibit p38 MAPK, suppressed both α-MSH-induced melanogenesis and spontaneous melanin synthesis. In this study, we demonstrated that the inhibitory activity of the pyridinyl imidazoles correlates with inhibition of the canonical Wnt/β-catenin pathway activity. Imidazole-treated cells showed a reduction in the level of Tcf/Lef target genes involved in the β-catenin signaling network, including ubiquitous genes such as Axin2, Lef1, and Wisp1 as well as cell lineage-restricted genes such as microphthalmia-associated transcription factor and dopachrome tautomerase.

Ion channel blockers for the treatment of neuropathic pain.

Neuropathic pain, a severe chronic pain condition characterized by a complex pathophysiology, is a largely unmet medical need. Ion channels, which underlie cell excitability, are heavily implicated in the biological mechanisms that generate and sustain neuropathic pain. This review highlights the biological evidence supporting the involvement of voltage-, proton- and ligand-gated ion channels in the neuropathic pain setting.

Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARgamma activation.

Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne. It has also been shown to be effective in rosacea; however, the mechanism of action has not been clarified. Because inflammation is a common feature of both conditions, we investigated the effects of azelaic acid on the inflammatory response of normal human keratinocytes to ultraviolet B light, which is a photosensitizer agent in rosacea.

GSK3beta inhibition promotes melanogenesis in mouse B16 melanoma cells and normal human melanocytes.

Glycogen synthase kinase 3beta (GSK3beta) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and the insulin response. GSK3beta also plays a key role in the Wnt/beta-catenin pathway. The master regulator of the pigmentation microphthalmia-associated transcription factor (MITF) is a target for the Wnt pathway, however, to date, the regulatory role of GSK3beta in the control of melanogenesis has not been elucidated.

Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys.

Increased glutamatergic activity is believed to play a significant role in the development of levodopa-induced dyskinesias (LID). LID may therefore be attenuated by a reduction in glutamatergic function. This was tested pharmacologically in MPTP monkeys by increasing the formation of kynurenic acid (KYNA), a tryptophan metabolite that inhibits glutamate release and also blocks NMDA receptors directly.

Impairment of dopaminergic system function after chronic treatment with corticotropin-releasing factor.

Mounting evidence suggests that chronic stress may have a detrimental effect on dopaminergic function and, in certain individuals, could contribute to the pathophysiology of central nervous system disorders like depression, schizophrenia, and Parkinson's disease. Therefore, the effects of chronic elevated brain levels of corticotropin-releasing factor (CRF), a crucial mediator of the behavioral stress response, on dopaminergic function were investigated. Rats treated intracerebroventricularly (i.

Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys.

Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa-induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID.

Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus.

Kynurenine 3-mono-oxygenase (KMO, kynurenine hydroxylase) inhibitors increase brain kynurenic acid (KYNA) synthesis and cause pharmacological actions possibly mediated by a reduced activity of excitatory synapses. We used in vivo microdialysis and passive avoidance to study the effects of local KYNA or systemic KMO inhibitor administration on glutamate (GLU) neurotransmission. Local application of KYNA (30-100 nM) through reverse microdialysis reduced GLU content in caudate and cortical dialysates by 75 and 55%, respectively.

Repair of acute ascending aorta-arch dissection with continuous body perfusion: a case report.

An approach for the replacement of the distal ascending aorta-proximal arch and acute dissection is described. During the operation, the patient's entire body was continuously perfused, the aortic arch was excluded from the arterial circulation, and the aorta was not clamped at any time. To achieve continuous body perfusion, we independently cannulated the right axillary and the left femoral arteries.

Neural plasticity and addiction: PI3-kinase and cocaine behavioral sensitization.

Drug addiction has been linked to protracted functional changes in neural circuits involved in motivation that can lead to drug dependence, craving and relapse. Here we investigated the role of the phosphatidylinositol 3 kinase (PI3K) signal transduction pathway in long-lasting behavioral sensitization to cocaine in rats, an animal model of the long-lasting functional changes induced by repeated drug use. Our results show that PI3K is required for the expression, but not the induction, of behavioral sensitization to cocaine.

Blockade of nitric oxide synthesis reduces responding for cocaine self-administration during extinction and reinstatement.

Nitric oxide is a gaseous neurotransmitter that plays a significant role in various forms of synaptic plasticity and may play a role in the behavioral effects of psychostimulant drugs and in cocaine addiction. The course of drug addiction consists of different phases. Relapse into drug-seeking behavior following a period of abstinence is believed to represent one of the major factors leading to the perpetuation of the addictive cycle.

A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule.

A recently characterized class of compounds, dopamine partial agonists, have been suggested as potential therapeutic candidates for pharmacological intervention in psychostimulant addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are thought to behave as functional antagonists in conditions of high dopaminergic tone, and as agonists in conditions of low receptor occupancy by dopamine. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the D2 receptor subtype, on intravenous self-administration of amphetamine in a progressive ratio schedule and to compare it with the effects produced by the dopamine D2 antagonist eticlopride and the dopamine D2 full agonist quinpirole.

Long-term results of the bioprosthesis in elderly patients: impact on quality of life.

Background: A wealth of data exists on acceptable mortality and morbidity for valve operations in older patients, yet information documenting quality of life is lacking.

Methods: From October 1974 to May 1998, 2,075 patients aged 65 years and older underwent valve replacement using a porcine bioprosthesis. There were 1,126 men (54.

Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines.

Protracted administration of diazepam elicits tolerance, whereas discontinuation of treatment results in signs of dependence. Tolerance to the anticonvulsant action of diazepam is present in an early phase (6, 24, and 36 h) but disappears in a late phase (72-96 h) of withdrawal. In contrast, signs of dependence such as decrease in open-arm entries on an elevated plus-maze and increased susceptibility to pentylenetetrazol-induced seizures were apparent 96 h (but not 12, 24, or 48 h) after diazepam withdrawal.

Antagonism of heroin and morphine self-administration in rats by the morphine-6beta-glucuronide antagonist 3-O-methylnaltrexone.

In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6beta-glucuronide and heroin at doses which are inactive against morphine. We found a similar selectivity in rats. 3-O-Methylnaltrexone antagonized the analgesic actions of 6-acetylmorphine in Sprague-Dawley rats and heroin in Wistar rats at doses that were inactive against morphine.

Unusual presentation of aortic pseudoaneurysm: middle lobe pneumonia.

Pseudoaneurysms of the aorta are rare. We report an unusual presentation of an ascending thoracic pseudoaneurysm found with atypical presenting symptoms.

Comparison of secretion of a hepatitis C virus glycoprotein in Saccharomyces cerevisiae and Kluyveromyces lactis.

A C-terminally truncated form of the hepatitis C virus (HCV) putative envelope glycoprotein E2 was expressed in two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis, using a yeast signal peptide sequence to direct the viral glycoprotein to the endoplasmic reticulum (ER) pathway of secretion. Characterization of secreted E2 showed that the protein is endoglycosidase-H-sensitive in both yeasts. Moreover, in vivo inhibition of glycosylation with tunicamycin prevented secretion of E2 and showed that, of its 11 putative N-linked glycosylation sites, at least eight were core-glycosylated.

Risk factors for acute hepatitis B: a case-control study.

Over the period 1989-1991 a case-control study was carried out in the area of Naples comparing 162 subjects with acute hepatitis B and 788 hospitalized control subjects. The results of multivariate analysis showed that surgical intervention (odds ratio 3.8; 95% CI 1.