Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, ...and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.
Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, thus requiring rapid treatment.
A post-hoc analysis of two ...retrospective studies analysed the efficacy of carglumic acid ± ammonia (NH
) scavengers compared with scavengers alone for reducing plasma NH
levels in patients with OAs and hyperammonaemia (plasma NH
> 60 μmol/L) during decompensation episodes. NH
was analysed in 12-h periods at 0-48 h and 24-h periods at 48-120 h. Treatment-emergent adverse events (TEAEs) were recorded.
Of 98 episodes, 38 were treated with carglumic acid (34 patients), 33 with NH
scavengers (22 patients) and 27 with carglumic acid combined with NH
scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH
scavengers group) and 74% (combination group) of episodes occurred in neonates. Median episode duration was 6 days for the carglumic acid and combination groups, and 9 days for the NH
scavenger group. Median baseline NH
level was: 199 μmol/L, carglumic acid; 122 μmol/L, NH
scavengers; and 271 μmol/L, combination; 13, 30 and 11% of episodes required extracorporeal detoxification (ED), respectively. Data were censored at ED initiation. While baseline NH
levels were higher in the combination and carglumic acid groups, mean reduction in NH
levels to 72 h in both groups was greater than the NH
scavengers' group; reductions were greatest in the combination group. Mean change in plasma NH
vs baseline in the carglumic acid, NH
scavengers and combination groups, respectively, was - 13, + 12% and - 27% at 0-12 h (p < 0.05 NH
scavengers vs combination); - 47, - 22% and - 52% at 12-24 h (not significant); - 44, - 5% and - 61% at 24-48 h; and - 66, - 16% and - 76% at 48-72 h (p < 0.05 carglumic acid/combination groups vs NH
scavengers for both timepoints). The number of TEAEs was similar between groups and mainly related to the disease/condition.
Carglumic acid is a well-tolerated and efficacious treatment for OA decompensation episodes. When given alone or combined with NH
scavengers, the reduction in NH
was greater than with NH
scavengers alone in the first 72 h.
Highlights • LY2603618 (LY) is a selective checkpoint kinase 1 inhibitor. • LY was added to standard first-line treatment for patients with nonsquamous NSCLC. • Primary endpoint of significantly ...improved PFS was met with addition of LY. • No statistically significant improvement in secondary efficacy endpoints with LY. • There was a numerical increase in the rate of thromboembolic events with LY
Purpose
To describe the retinal structure of a group of patients affected by methylmalonic aciduria with homocystinuria cblC type, caused by mutations in the MMACHC gene, using spectral domain ...optical coherence tomography (SD‐OCT).
Methods
Young patients (n = 11, age 0–74 months) with cblC disease, detected by newborn screening or clinically diagnosed within 40 days of life, underwent molecular analysis and complete ophthalmic examination, including fundus photography and SD‐OCT. In one case, we also performed fluorescein angiography (FA) and standard electroretinography (ERG).
Results
Molecular analysis of the MMACHC gene fully confirmed cblC disease in nine of 11 patients. Two patients harboured only a single heterozygous pathogenic MMACHC mutation and large unbalanced rearrangements were excluded by array‐CGH analysis in both. All patients except two showed a bilateral maculopathy. In general, retinal changes were first observed before one year of age and progressed to a well‐established maculopathy. Measurable visual acuities ranged from normal vision, in keeping with age, to bilateral, severe impairment of central vision. Nystagmus was present in six patients. Spectral domain optical coherence tomography (SD‐OCT) showed macular thinning with severe alterations in outer, and partial sparing of inner, retinal layers.
Conclusion
Patients affected by cblC disease may frequently show an early onset maculopathy with variable ophthalmoscopic appearance. Spectral domain optical coherence tomography (SD‐OCT) broadens the knowledge of subtle retinal alterations during the disease's progression and helps to shed light on the pathological mechanism of maculopathy development.
•Bisphosphonates are increasingly used in children with DMD.•Bisphosphonate-induced rhabdomyolysis has not previously been described in children.•We observed two pediatric cases of apparent ...rhabdomyolysis after zoledronate infusion.•Hypophosphatemia or myotoxicity are likely explanations for this possible side effect.•Nitrogen-containing bisphosphonates are likely to be concerned by this hazard.
Rhabdomyolysis with myoglobinuria is a recognized complication of dystrophinopathies. It can be triggered by infections, exercise or volatile anesthetics. To our knowledge, it has never been reported in boys with Duchenne muscular dystrophy (DMD) after the administration of bisphosphonates. We report two patients with DMD who presented an apparent transient rhabdomyolysis with myoglobinuria after zoledronate administration. Possible mechanisms could involve hypophosphatemia, a known dose-dependent side effect of bisphosphonates, and/or direct myotoxicity of biphosphonates. Physicians and families should be aware of rhabdomyolysis with myoglobinuria as a potential uncommon side effect of bisphosphonates in DMD, in particular of zoledronate.
Abstract Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel CaV 2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic ...hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant CaV 2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.
Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this ...study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients.
We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients. Such liver involvement led us to retrospectively collect liver (clinical, laboratory and ultrasound) data of MMA (N = 12) or PA patients (N = 16) from 2003 to 2016.
Alpha-fetoprotein (αFP) levels were increased in 8/16 and 3/12 PA and MMA patients, respectively, and tended to increase with age. Moderate and recurrent increase of GGT was observed in 4/16 PA patients and 4/12 MMA patients. Abnormal liver ultrasound with either hepatomegaly and/or hyperechoic liver was observed in 7/9 PA patients and 3/9 MMA patients.
These data demonstrate that approximately half of the patients affected by MMA or PA had signs of liver abnormalities. The increase of αFP with age suggests progressive toxicity, which might be due to the metabolites accumulated in PA and MMA. These metabolites (e.g., methylmalonic acid and propionic acid derivatives) have previously been reported to have mitochondrial toxicity; this toxicity is confirmed by the results of histological and biochemical mitochondrial analyses of the liver in two of our MMA patients. In contrast to the moderate clinical, laboratory or ultrasound expression, severe pathological expression was found for three of the 4 patients who underwent liver biopsy, ranging from fibrosis to cirrhosis. These results emphasize the need for detailed liver function evaluation in organic aciduria patients, including liver biopsy when liver disease is suspected.
MMA and PA patients exhibit long-term liver abnormalities.
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We present a patient who developed, after an early‐onset, a stable course of spastic paraplegia and ataxia for 4 decades and eventually succumbed to two episodes of postinfectious lactic acidosis. ...Diagnostic workup including muscle biopsy and postmortem analysis, oxymetric analysis, spectrophotometric enzyme analysis, and MitoExome sequencing revealed a necrotizing leukoencephalomyelopathy due to the so far unreported biallelic variant of the NDUFV1 gene (p.(Pro122Leu)). This case extends our understanding of NDUFV1 variants with a 14‐fold longer lifetime than so far reported cases, and will foster sensitivity toward respiratory chain disease also in adult patients with sudden deteriorating neurological deficits.
The objective is to evaluate Grifols' DG-PT L Rec liquid reagent for prothrombin time (PT) determination in comparison to the laboratory's reference reagent (Siemens' Thromborel S). For linearity, ...the average master curve for PT and five nominal prothrombin concentrations was obtained from five calibration curves. Within-assay precision (repeatability) was calculated after measuring 20 successive tests of normal and pathological controls. For correlation, 581 routine clinical citrated plasma samples were assessed with both reagents. The BCS XP hemostasis analyzer was used. Linearity of the DG-PT L Rec was good (P < 0.001). The coefficient of variation met the desirable imprecision of less than 2% (normal controls: 1.7%; pathological controls: 0.9%). Correlation between DG-PT L Rec and Thromborel S was high (r = 0.9795; PT in %). In subgroups of anticoagulated, low fibrinogen, lipemic, jaundice, and hemolyzed samples the correlation was more than 0.95. Performance of DG-PT L Rec was high and comparable to the reference reagent.
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