Novel OCTN2 mutations: No genotype–phenotype correlations: Early carnitine therapy prevents cardiomyopathy

Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile‐onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L ‐carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high‐affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 μM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11‐bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype. © 2002 Wiley‐Liss, Inc.     

Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain

Recent postmortem studies have been suggesting that a defect of GABAergic neurotransmission might occur in the corticolimbic system of subjects with schizophrenia and bipolar disorder. To explore this possibility, a method for immunolocalizing the 65 kdalton isoform of glutamate decarboxylase (GAD₆₅) has been developed and applied to the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of 12 normal controls (CONs), 12 schizophrenics (SZs) and 5 manic depressive (MDs) subjects. A computer-assisted technique was employed under strictly blind conditions to determine the density of GAD₆₅-IR terminals in apposition with pyramidal (PNs) and nonpyramidal (NPs) neurons and in neuropil (NPL) of layers II, III, V and VI of each cortical region. For SZs, no difference in the numerical density of GAD₆₅-IR terminals in contact with either PNs or NPs or in NPL of layers II–VI in ACCx or PFCx was detected. There were also no differences in the size of either PNs and NPs that could have influenced the nature of these findings. Using a pixel count analysis, the size of IR terminals was, however, found to be increased in layers II (10.3%) and III (15.8%) of SZs, but only in subjects treated with neuroleptic drugs. For MDs, the density of GAD₆₅-IR terminals was significantly reduced in all four layers of ACCx, but these differences were most significant in layers II (27.8%) and III (37.2%), whether or not the subjected were treated with neuroleptics. In PFCx, the MDs showed similar differences in terminal density for PNs and NPs but not neuropil in the four laminae examined. The MD group showed no differences in either the size of cell bodies or IR terminals. Age and PMI did not account for any of the differences between the CONs vs SZs and MDs. Overall, the results of this study, though preliminary, suggest that there may be complex changes in GABAergic terminals in SZ and MD, ones that may vary with respect to primary diagnosis and neuroleptic exposure.     

Gaucher disease: diagnosis and treatment

Gaucher's disease is the most common lysosomal storage disorder. It was identified in 1882 by Phillipe Gaucher, a French dermatologist. However, it was not until 1965 that Gaucher disease was found to be due to a deficiency in the enzyme glucocerebrosidase (EC 3.2.1.45) which breaks down glucocerebroside, a cell membrane component. The deficiency in this enzyme leads to an accumulation of glucocerebroside within the lysosomes of macrophages throughout the body. Gaucher's disease is classified into three types: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Of the three, type 1 is the most common, affecting one in 40,000-200,000 people and having a high prevalence among Ashkenazi Jews, affecting one in 450-1500. The signs and symptoms of type 1 disease demonstrate marked heterogeneity, from asymptomatic or mildly symptomatic, to severe disability with disfigurement and even death. Hepatosplenomegaly and thrombocytopenia are well documented. Less well-recognized are often insidious skeletal complications which affect the majority of type 1 patients and which are its most debilitating feature. In addition to clinical suspicion, some morphologic, hematologic and biochemical indicators can help establish the diagnosis. However, definitive diagnosis is only made by determining the catalytic activity of the lysosomal enzyme glucocerebrosidase. Confirmation of heterozygosity requires the use of molecular biotechnology methods. About 150 mutations of the glucocerebrosidase gene have been identified in patients with Gaucher's disease, some of which are predictive of phenotype. The history of treatment of Gaucher disease started with splenectomy and continued with bone marrow transplantation, before the recent introduction of safe and effective enzyme replacement therapy. In Croatia, nine patients with type 1 Gaucher's disease have been identified so far. Seven patients are on enzyme replacement therapy, and past results demonstrated significant improvement in all clinical symptoms, without development of any side effects. However, new treatments, such as substrate balance therapy and gene therapy, may become available within the next few years. The place, if any, that such therapies will have in the treatment of patients with Gaucher's disease will be dependent on the results of clinical studies currently in progress.     

Early Isolated Subarachnoid Hemorrhage Versus Hemorrhagic Infarction in Cerebral Venous Thrombosis

BackgroundCerebral venous thrombosis (CVT) is a rare cerebral vascular disease, the presentation of which is highly variable clinically and radiologically. A recent study demonstrated that isolated subarachnoid hemorrhage (iSAH) in CVT is not as rare as thought previously and may have a good prognostic significance. Hemorrhagic venous infarction, however, is an indicator of an unfavorable outcome. We therefore hypothesized that patients who initially suffered iSAH would have a better clinical outcome than those who suffered hemorrhagic cerebral infarction.Patients and methodsWe selected patients hospitalized due to CVT, who presented either with isolated SAH or cerebral hemorrhagic infarction at admission or during the following 24 hours: 23 (10 men) aged 22–73 years. The data were extracted from hospital admission records, our computer data system, and the hospital radiological database.ResultsThe iSAH group consisted of 8 (6 men) aged 49.3 ± 16.2 and the hemorrhagic infarction group included 15 (4 men) aged 47.9 ± 16.8. Despite having a significantly greater number of thrombosed venous sinuses/deep veins (Mann-Whitney Rank Sum Test, p = 0.002), the isolated SAH group had a significantly better outcome on its modified Rankin Score (mRs) than the hemorrhagic infarction group (Mann-Whitney Rank Sum Test, p = 0.026). Additional variables of significant impact were edema formation (p = 0.004) and sulcal obliteration (p = 0.014).ConclusionsThe patients who suffer iSAH initially had a significantly better outcome prognosis than the hemorrhagic infarction patients, despite the greater number of thrombosed sinuses/veins in the iSAH group. A possible explanation might include patent superficial cerebral communicating veins.Key words: cerebral venous thrombosis, subarachnoid hemorrhage, hemorrhagic brain infarction, superficial communicating veins     

Theta oscillatory dynamics of inhibitory control,error processing,and post-error adjustments: Neural underpinnings and alcohol-induced dysregulation in social drinkers

Background

Alcohol intoxication impairs inhibitory control, resulting in disinhibited, impulsive behavior. The anterior cingulate cortex (ACC) plays an essential role in a range of executive functions and is sensitive to the effects of alcohol, which contributes to the top-down cognitive dysregulation. This study used a multimodal approach to examine the acute effects of alcohol on the neural underpinnings of inhibitory control, inhibition failures, and neurobehavioral optimization as reflected in trial-to-trial dynamics of post-error adjustments.

Methods

Adult social drinkers served as their own controls by participating in the Go/NoGo task during acute alcohol and placebo conditions in a multi-session, counterbalanced design. Distributed source modeling of the magnetoencephalographic signal was combined with structural magnetic resonance imaging to characterize the spatio-temporal dynamics of inhibitory control in the time-frequency domain.

Results

Successful response inhibition (NoGo) elicited right-lateralized event-related theta power (4 to 7 Hz). Errors elicited a short-latency increase in theta power in the dorsal (dACC), followed by activity in the rostral (rACC), which may underlie an affective “oh, no!” orienting response to errors. Error-related theta in the dACC was associated with subsequent activity of the motor areas on the first post-error trial, suggesting the occurrence of post-error output adjustments. Importantly, a gradual increase of the dACC theta across post-error trials closely tracked improvements in accuracy under placebo, which may reflect cognitive control engagement to optimize response accuracy. In contrast, alcohol increased NoGo commission errors, dysregulated theta during correct NoGo withholding, and abolished the post-error theta enhancement of cognitive control.

Conclusions

Confirming the sensitivity of frontal theta to inhibitory control and error monitoring, the results support functional and temporal dissociation along the dorso-rostral axis of the ACC and the deleterious effects of alcohol on the frontal circuitry subserving top-down regulation. Over time, alcohol-induced disinhibition may give rise to compulsive drinking and contribute to alcohol misuse.     

Modafinil in the treatment of idiopathic hypersomnia without long sleep time—a randomized,double‐blind,placebo‐controlled study

In 2010 the European Medicines Agency withdrew the indication of modafinil for the treatment of obstructive sleep apnea, shift work sleep disorder and for idiopathic hypersomnia (IH). In uncontrolled studies, modafinil has been reported to be efficacious in the treatment of sleep disorders. We therefore performed a randomized, placebo‐controlled study with the aim of proving the efficacy of modafinil treatment in these patients. Drug‐free IH patients without long sleep according to ICSD2 criteria, age >18 years and disease duration >2 years were included. After a washout phase, patients at baseline received placebo or 100 mg modafinil in the morning and at noon over 3 weeks, followed by 1 week without medication. At each visit the Epworth Sleepiness Scale (ESS) and Clinical Global Impression (CGI) rating scale were performed. At baseline and on days 8 and 21 four Maintenance of Wakefulness Tests (MWTs)/day or per day were performed. Patients kept a sleep–wake diary throughout the study. Between 2009 and 2011 three sleep centres recruited 33 participants. Compared to placebo, modafinil decreased sleepiness significantly and improved mean sleep latency in the MWT non‐significantly. The CGI improved significantly from baseline to the last visit on treatment. The most frequent adverse events were headaches and gastrointestinal disorders; skin and psychiatric reactions were not reported. The number of reported naps and duration of daytime sleepiness decreased significantly. Total sleep time of nocturnal sleep was slightly reduced. The sleep diaries showed increases in feeling refreshed in the morning; the diurnal diaries showed significant improvement of performance and of exhaustion. Modafinil is an effective and safe medication in the treatment of IH. Adverse events are mild to moderate.     

Antitumor activity of novel <Emphasis Type="Italic">N</Emphasis>-sulfonylpyrimidine derivatives on the growth of anaplastic mammary carcinoma in vivo

Purpose: The purpose of this study was to investigate in vivo antitumor activity of newly synthesized N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)cytosine (4H), 1-(p-toluenesulfonyl)cytosine hydrochloride (4H×HCl) and zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K). Materials and methods: In order to do that we have used mouse anaplastic mammary carcinoma (AMCa). Tumor cells (10⁶) in a volume of 0.02 ml were transplanted into the thigh of the right hind leg of CBA mice. All compounds were dissolved in distilled water immediately before injecting to animals. Results: Antitumor effect of these compounds depends on drug doses and time interval between tumor transplantation and drug application. Further the efficacy of these compounds depends on number of drug injections, i. e. whether drug was given in single or in multiple doses. Multiple doses of 400 mg/kg of 1-(p-toluenesulfonyl)cytosine (4H) showed good antitumor effect when applied on day 1, 3, 5, 7 and 9 after tumor transplantation. Still good but slightly lower antitumor effect was also achieved when that compound was given in a single dose (1,200 mg/kg) on day 1 after tumor transplantation. The longest period of tumor growth time was obtained after application of 1-(p-toluenesulfonyl)cytosine hydrochloride (4H×HCl) given as a single dose (300 mg/kg) on day 1 or on day 6 after tumor implantation. However, antitumor effect of zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K) was very strong when 300 mg/kg was given on day 1 or day 6, while this effect was slightly lower when drug (200 mg/kg/inj) was given on day 1, 3, 5, 7 and 9 or on day 6, 8, 10, 12 and 14. Conclusion: In this work it has been found that N-1-sulfonylcytosine derivatives have strong antitumor activity against mouse mammary carcinoma which is a good reason for further research of these compounds both in experimental and preclinical studies.