Hypoxia and nicotine effects on Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor 1 (PAC1) in the developing piglet brainstem

Pituitary adenylate cyclase activating polypeptide (PACAP) and its cognate receptor 1 (PAC1), have been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Two main risk factors for SIDS are prone sleeping and cigarette smoke exposure. Using piglet models of these risk factors, intermittent hypercapnic hypoxia (IHH-mimicking rebreathing in prone position) and nicotine (main reinforcing element of cigarettes), this study aimed to determine their effects on PACAP and PAC1 protein expression in the medulla. IHH was delivered for 1 (n = 7), 2 (n = 6), 3 (n = 6) and 4 (n = 7) days prior to euthanasia at 13–14 days of age, while nicotine (n = 7) was continuous for the first 14 days of life. An additional group of combined nicotine and 1 day IHH (1DIHH) was studied to determine the combined effects of the risk factors. Changes in expression were seen after the acute 1DIHH exposure (none after repeated daily exposures) and included a decrease in PACAP in the dorsal motor nucleus of vagus (DMNV; p = 0.024), nucleus of the solitary tract (NTS; p = 0.024) and the gracile nucleus (GRAC; p = 0.001), and a decrease in PAC1 in the NTS (p = 0.01). No PACAP change was noted in the nicotine-exposed piglets, however, a decrease in PAC1 was found in the DMNV (p = 0.02). IHH exposure in piglets with pre-exposure to nicotine led to a significant decrease in PACAP in the Grac (p = 0.04) but had no effect on PAC1. These findings show for the first time, the vulnerability of PACAP in the brainstem during early development to an acute hypercapnic hypoxic exposure and that those effects are greater than from nicotine exposure.     

Prenatal cigarette smoke exposure effects on apoptotic and nicotinic acetylcholine receptor expression in the infant mouse brainstem

Infants exposed to cigarette smoked during pregnancy into infancy have increased respiratory and cardiac abnormalities. Nicotine, the major neurotoxic component of cigarette smoke, induces its actions by binding to nicotinic acetylcholine receptors (nAChR), with one downstream effect being increased apoptosis. Using a pre- into post- natal cigarette smoke exposure mouse model (SE), we studied the immunohistochemical expression of nAChR subunits α2, α3, α4, α5, α7, α9, β1 and β2 and two markers of apoptosis, active caspase-3 and TUNEL, in seven nuclei of the medulla and facial nucleus of the pons in male mice. Pups of dams exposed to two cigarettes (nicotine ≤1.2 mg, CO ≤15 mg) twice daily for six weeks prior to mating, during gestation and lactation (n = 5; SE), were compared to pups exposed to air under the same condition (n = 5; SHAM) at P20. Results showed that the hypoglossal nucleus had increased α3, α4, α7, α9, Casp-3 and TUNEL, dorsal motor nucleus of the vagus had increased α3, α5, α7, β1 and Casp-3, nucleus of the solitary tract had increased α3 but decreased α4, α5, β1 and apoptosis, cuneate nucleus had increased α3, β2 and Casp- 3, but decreased α5, nucleus of the spinal trigeminal tract had increased α3, α7, β1, lateral reticular nucleus had decreased β1, inferior olivary nucleus had increased β1 but decreased apoptosis, and the facial had increased α2, α3 and α7. This is the first study to demonstrate that nAChR subunits are affected following pre- into post-natal SE and that they simultaneously coincided with changes in apoptotic expression.     

GABAA receptor expression and white matter disruption in intrauterine growth restricted piglets

Intrauterine growth restriction (IUGR) is one of the most common causes of perinatal mortality and morbidity. White matter and neuronal injury are major pathophysiological features of the IUGR neonatal brain. GABA_A (γ-aminobutyric acid type A) receptors have been shown to play a role in oligodendrocyte differentiation and proliferation in the neonatal brain and may be a key factor in white matter injury and myelination in IUGR neonates. Whether there are impairments to the GABAergic system and neuronal cytoskeleton in IUGR brain has yet to be elucidated. This study aims to examine GABA_A receptor α₁ and α₃ subunit protein expression and distribution in parietal cortex and hippocampus of the IUGR piglet at four different ages (term = 115 d – days gestational age), 100 d, 104 d, birth (postnatal day 0–P0) and P7 and to examine neuronal and myelination patterns. Significant alterations to GABA_A receptor α₁ and α₃ protein expression levels were observed in the IUGR piglet brain of P7 IUGR piglets with significantly greater α₃ expression compared to α₁ expression in the hippocampus while there was virtually no difference between the two subunits in the parietal cortex. However a significantly lower α₁/α₃ ratio was evident in P7 IUGR cortex when compared with P7 NG cortex. Neuronal somatodendrites studied using MAP2 immunohistochemistry showed reduced and disrupted somatodendrites while MBP immunolabelling showed loss of axonal fibres from gestational day 104 d through to P7. These findings provide insights into the effects of IUGR on the development of the GABA system, altered developmental maturation of GABA_A receptor subunit expression in the IUGR brain may influence myelination and may partly explain the cognitive disabilities observed in IUGR. Understanding the mechanisms behind grey and white matter injury in the IUGR infant is essential to identifying targets for treatments to improve long-term outcomes for IUGR infants.     

Changes in orexinergic immunoreactivity of the piglet hypothalamus and pons after exposure to chronic postnatal nicotine and intermittent hypercapnic hypoxia

We recently showed that orexin expression in sudden infant death syndrome (SIDS) infants was reduced by 21% in the hypothalamus and by 40–50% in the pons as compared with controls. Orexin maintains wakefulness/sleeping states, arousal, and rapid eye movement sleep, abnormalities of which have been reported in SIDS. This study examined the effects of two prominent risk factors for SIDS, intermittent hypercapnic hypoxia (IHH) (prone‐sleeping) and chronic nicotine exposure (cigarette‐smoking), on orexin A (OxA) and orexin B (OxB) expression in piglets. Piglets were randomly assigned to five groups: saline control (n = 7), air control (n = 7), nicotine [2 mg/kg per day (14 days)] (n = 7), IHH (6 min of 7% O₂/8% CO₂ alternating with 6‐min periods of breathing air, for four cycles) (n = 7), and the combination of nicotine and IHH (N + IHH) (n = 7). OxA/OxB expression was quantified in the central tuberal hypothalamus [dorsal medial hypothalamus (DMH), perifornical area (PeF), and lateral hypothalamus], and the dorsal raphe, locus coeruleus of the pons. Nicotine and N + IHH exposures significantly increased: (i) orexin expression in the hypothalamus and pons; and (ii) the total number of neurons in the DMH and PeF. IHH decreased orexin expression in the hypothalamus and pons without changing neuronal numbers. Linear relationships existed between the percentage of orexin‐positive neurons and the area of pontine orexin immunoreactivity of control and exposure piglets. These results demonstrate that postnatal nicotine exposure increases the proportion of orexin‐positive neurons in the hypothalamus and fibre expression in the pons, and that IHH exposure does not prevent the nicotine‐induced increase. Thus, although both nicotine and IHH are risk factors for SIDS, it appears they have opposing effects on OxA and OxB expression, with the IHH exposure closely mimicking what we recently found in SIDS.     

Litter and sex effects on maternal behavior and DNA methylation of the Nr3c1 exon 17 promoter gene in hippocampus and cerebellum

Early life events can alter gene expression through DNA methylation. The methylation status of the exon 1₇ promoter of the glucocorticoid receptor (Nr3c1 gene) in hippocampus associates with frequency of pup licking. Much of this work was conducted with male rats. Because dams more frequently lick male pups, this may contribute to sex differences in phenotypes through DNA methylation. Modifying litter gender composition (LGC), in which offspring of single-sex litters are compared to mixed-sex litters, alters maternal behavior. Previously, we demonstrated that LGC and sex affected pup licking times as well as anxiety and hippocampal DNA methylation of the Nr3c1 exon 1₇ promoter gene in adolescence. Now, we expand upon this work by examining effects in cerebellum and measuring mRNA levels. We also re-assessed DNA methylation in hippocampus using pyrosequencing and re-analyzed pup licking with the more commonly used frequency measure. Litters, culled to 8 pups on postnatal day 1 (PN1), were assigned to one of three conditions: all male (n = 10), all female (n = 12), or half of each sex (n = 20). Licking was rated on PN4, 7, and 10. On PN35, hippocampal and cerebellar samples were obtained. Single-sex males were licked the least and mixed-sex males, the most. Hippocampal Nr3c1 mRNA levels were lowest in mixed females with no LGC or Sex effects in DNA methylation. Cerebellar DNA methylation levels were lowest in mixed males with no effect on mRNA levels. Maternal pup licking associated with DNA methylation of the Nr3c1 exon 1₇ promoter gene in cerebellum and with hippocampal mRNA.     

Arrêt et réduction du tabac chez le patient souffrant de schizophrénie

ObjectivesThis systematic review of the literature looked at data on pharmacological and non-pharmacological strategies of smoking cessation and reduction of consumption in patients with schizophrenia.MethodThe research was conducted on Medline for the period 1980–2018. We included randomized controlled trials, including preliminary studies of stable schizophrenic patients with no other severe psychiatric disorder and no other substance use than tobacco, treated with antipsychotic medications. Individual or group smoking cessation programs with or without pharmacological treatment, including a validation of abstinence, were included.ResultsPharmacotherapies for nicotine dependence—nicotine replacement therapy (n = 3), bupropion (n = 6), varenicline (n = 8), association of medications (n = 4)—were used in 23 studies combined with behavioral support. Compared to the placebo, bupropion and varenicline at the end of treatment were found to be the most effective pharmacotherapies to stop or reduce smoking and control craving. All the medications were well tolerated and did not lead to aggravation of psychosis or changes in symptoms. Non-pharmacological interventions: behavioral and cognitive therapies (n = 5) combined with pharmacological treatment facilitated the management of smoking risk situations and improved adherence to antipsychotics; other psychosocial interventions (n = 7) allowed the development of social skills; contigency management strategies with financial reinforcement can be used (n = 4); the practice of physical activity and the use of an electronic cigarette allowed reduction of tobacco consumption. The results of transcranial electromagnetic stimulation studies (n = 6) were discordant. Atypical antipsychotics appear to be associated with a better success of attempts to stop smoking.ConclusionSmoking cessation strategies for patients with schizophrenia appear to be effective and should combine (1) smoking cessation medications with sufficient duration, (2) diversified psychosocial approaches and (3) physical activity practice.     

Flattening plasma corticosterone levels increases the prevalence of serotonergic dorsal raphe neurons inhibitory responses to nicotine in adrenalectomised rats

Major depression is characterized by a diminished activity of the brain serotonergic system as well as by the flattening of plasma cortisol levels. Nicotine improves mood in patients with major depression and in experimentally depressed animals by increasing brain serotonin (5-HT), noradrenaline and dopamine levels. The present study was directed to determine if flattening plasma glucocorticoid levels changes nicotine's stimulatory effects upon 5-HT DRN neurons. The experiments were performed in brain slices obtained from rats previously (14 days) adrenalectomised and implanted subcutaneously with one pellet containing 75 mg of corticosterone (Adx + CSR rats). Whole cell voltage and current clamp techniques were used to study the activity of immunocitochemically identified 5-HT DRN neurons. Administration of nicotine (1 μM) in sham-operated animals produced stimulatory effects in all 5-HT DRN neurons studied. In Adx + CSR rats however, nicotine inhibited 75% of 5-HT DRN neurons and increased the potassium-dependent inward rectifying current. The inhibitory effect of nicotine upon 5-HT DRN neurons was dependent on serotonin release inside the DRN, since it was converted into a stimulatory response by the selective antagonist of 5-HT_1A receptors N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY100635, 25 nM). Adx + CSR rats also presented an increased function of 5-HT_1A autoreceptors, since, in these rats, serotonin (1–10 μM) produced a higher increase in the potassium dependent inward rectifying current in comparison with sham-operated animals. Serotonin release inside DRN was mediated by α4β2 nicotinic acetylcholine receptors since the selective antagonist of these receptors dihydro-β-erytroidine hydrobromide (DHβE, 100 nM) blocked the inhibitory effects of nicotine 5-HT DRN neurons. These data indicate that, in the experimental model of adrenalectomised rats implanted with corticosterone pellets, nicotine increases the function of 5-HT_1A receptors of 5-HT DRN neurons.     

Efficacy and safety of eslicarbazepine acetate monotherapy for partial-onset seizures: Experience from a multicenter,observational study

Eslicarbazepine acetate (ESL, Aptiom™) is a once-daily anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). Historical-controlled trials investigating the use of ESL as monotherapy have demonstrated a favorable efficacy and tolerability profile in patients with POS. This prospective, non-interventional study recruited POS patients in 17 hospitals in Spain. After a 3-month baseline period, ESL therapy was initiated as 400 mg QD and up-titrated to an optimal maintenance dose based on clinical response and tolerance. The incidence of seizures was assessed via seizure calendars and the nature and severity of adverse events (AEs) were also recorded. A total of 117 patients (aged 9–87 years) enrolled in the study and were treated with ESL at either 400 mg/day (3.4% patients), 800 mg/day (61% patients), 1200 mg/day (27.1% patients) or 1600 mg/day (8.5% patients). At 3 months, 82.0% (n = 72) of patients achieved a ≥ 50% reduction in seizure frequency, compared to 79.7% (n = 67) of patients at 6 months and 83.0% (n = 49) at 12 months. Patients who suffered secondary generalized tonic-clonic (SGTC) seizures had seizure-free rates of 71% (n = 27), 69.6% (n = 29), and 72.7% (n = 16) at 3, 6, and 12 months, respectively. Overall, 18 patients (15.3%) reported AEs of instability and dizziness (n = 9), somnolence (n = 3), mild hyponatremia (n = 3), headache (n = 1), hypertriglyceridemia (n = 1), and allergic reaction (n = 1), which caused ESL discontinuation of ESL treatment. ESL is effective and well tolerated as monotherapy for patients with POS, which supports previous findings. Early use is supported by its frequent use as monotherapy in this study and lack of severe side effects.     

Upregulation of α-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways

PurposeNeuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinson’s. The symptoms in Parkinson’s including fatigue are thought to be related to α-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT).Patients and methodsSixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19–21, D21), completion (days 38–42, D42), and four weeks post-EBRT (days 68–72, D72). Gene expression profiling using microarray analysis was performed from peripheral blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach.ResultsMicroarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95-fold change at D21from baseline. SNCA expression was confirmed by qPCR (p < 0.001) and ELISA (p < 0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r = 0.55, p < 0.05) and plasma α-synuclein concentrations on D42 of EBRT (r = 0.54, p = 0.04).ConclusionFatigue experienced during EBRT may be mediated by α-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population.     

Manganese-enhanced MR imaging (MEMRI) combined with electrophysiology in the study of cross-modal plasticity in binocularly blind rats

Our study aimed to determine and verify the establishment of visual to auditory cross-modal plasticity using manganese-enhanced MR imaging (MEMRI) combined with examinations of the visual evoked potential (VEP), auditory brainstem response (ABR) and bilateral visual cortex response to a bilateral auditory stimulus (AVR). Fourteen healthy male Sprague-Dawley newborn rats were randomly divided into 2 groups (n = 7 per group). Optic nerve transection was performed in the 7 rats of Group A three weeks after birth to obtain binocularly blind models, and the 7 rats of Group B were maintained as the control group. The VEP was measured to ensure complete binocular blindness. Four months after the operation, MnCl₂ was injected into the left inner ear perilymph of all rats, and an MRI examination was performed 24 h after injection. Then, ABR and AVR were measured to detect the generation of auditory compensatory function. The results of the VEP have confirmed complete binocular blindness. The normalized signal intensity of the bilateral medial geniculate nucleus, auditory cortex, visual center (including the lateral geniculate nucleus, superior colliculus and visual cortex) and right hippocampus in binocularly blind rats was significantly increased compared with that in normal rats (P ≤ 0.005), which was confirmed by measurement of the ABR and AVR. Our results suggested that MEMRI combined with electrophysiology can show changes in the auditory and visual pathways of binocularly blind rats and demonstrate the generation of an auditory compensatory pathway.     

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder

ObjectiveTo determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder.MethodsThe clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria.Results172 cases were identified, of whom 143 (83%) were men. The mean ± SD age of onset in years for the core features were as follows – RBD, 62 ± 14 (range, 20–93), cognitive impairment (n = 147); 69 ± 10 (range, 22–90), parkinsonism (n = 151); 68 ± 9 (range, 20–92), and autonomic dysfunction (n = 42); 62 ± 12 (range, 23–81). Death age was 75 ± 9 years (range, 24–96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10 ± 12 (range, 1–61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n = 97), Parkinson’s disease with or without mild cognitive impairment or dementia (n = 32), multiple system atrophy (MSA) (n = 19), Alzheimer’s disease (AD)(n = 9) and other various disorders including secondary narcolepsy (n = 2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD)(n = 77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n = 59), MSA (n = 19), AD (n = 6), progressive supranulear palsy (PSP) (n = 2), other mixed neurodegenerative pathologies (n = 6), NBIA-1/LBD/tauopathy (n = 1), and hypothalamic structural lesions (n = 2). Among the neurodegenerative disorders associated with RBD (n = 170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features.ConclusionsIn this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.     

Experimental colitis triggers the release of substance P and calcitonin gene-related peptide in the urinary bladder via TRPV1 signaling pathways

Clinical data provide evidence of high level of co-morbidity among genitourinary and gastrointestinal disorders characterized by chronic pelvic pain. The objective of this study was to test the hypothesis that colonic inflammation can impact the function of the urinary bladder via activation of TRPV1 signaling pathways followed by alterations in gene and protein expression of substance P (SP) and calcitonin gene-related peptide (CGRP) in sensory neurons and in the bladder. Inflammation was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS, 12.5 mg/kg), and desensitization of TRPV1 receptors was evoked by intracolonic resiniferatoxin (RTX, 10^?7 M). mRNA and protein concentrations of CGRP and SP were measured at 3, 5 and 30 days. RTX instillation in the colon caused 3-fold up-regulation of SP mRNA in the urinary bladder at day 5 (n = 7, p ≤ 0.05) followed by 35-fold increase at day 30 (n = 5, p ≤ 0.05). Likewise, TNBS colitis triggered 15.8-fold up-regulation of SP mRNA 1 month after TNBS (n = 5, p ≤ 0.05). Desensitization of colonic TRPV1 receptors prior to TNBS abolished SP increase in the urinary bladder. RTX led to 4.3-fold increase of CGRP mRNA at day 5 (n = 7, p ≤ 0.05 to control) in the bladder followed by 28-fold increase at day 30 post-RTX (n = 4, p ≤ 0.05). Colitis did not alter CGRP concentration during acute phase; however, at day 30 mRNA level was increased by 17.8 ± 6.9-fold (n = 5, p ≤ 0.05) in parallel with 4-fold increase in CGRP protein (n = 5, p ≤ 0.01) in the detrusor. Protein concentration of CGRP in the spinal cord was diminished by 45–65% (p ≤ 0.05) during colitis. RTX pretreatment did not affect CGRP concentration in the urinary bladder; however, it caused a reduction in CGRP release from lumbosacral DRG neurons during acute phase (3 and 5 days post-TNBS). Our results clearly demonstrate that colonic inflammation triggers the release of pro-inflammatory neuropeptides SP and CGRP in the urinary bladder via activation of TRPV1 signaling mechanisms enunciating the neurogenic nature of pelvic organ cross-sensitization.     

Clinico-radiological spectrum in enterovirus 71 infection involving the central nervous system in children

Enterovirus 71 infection causes hand, foot and mouth disease in children, and can produce diverse neurologic complications. Epidemics occurring in Korea between 2009 and 2012 resulted in the death of some patients. The present study aimed to clarify the correlation between clinical features and MRI findings in patients presenting with acute neurologic manifestations related to enterovirus 71 infection. Based on their clinical features, the patients were classified into four clinical groups: (1) brainstem encephalitis (n = 17), characterized by myoclonus, tremor, ataxia, and autonomic dysregulation such as pulmonary hemorrhage; (2) aseptic meningitis (n = 2); (3) encephalitis (n = 2), characterized by decreased consciousness, seizure, and fever without myoclonus, tremor, ataxia, and autonomic dysregulation; and (4) acute flaccid paralysis (n = 1). Thirteen of the 17 patients with brainstem encephalitis showed characteristic lesions in the dorsal brainstem and bilateral cerebellar dentate nuclei on brain MRI, whereas three had no abnormality. One of the two patients with meningitis had a small lesion in the left dorsal pons. Two patients with encephalitis had no apparent MRI abnormality. One patient with acute flaccid paralysis of the right leg had contrast-enhancement of the bilateral ventral nerve roots at the lumbar spine level on MRI. Five of 13 patients with lesions in the bilateral dentate nuclei of the cerebellum exhibited no cerebellar symptoms, while two with no cerebellar lesions developed ataxia. Although most patients presenting with neurologic manifestations of enterovirus 71 infection had characteristic clinical features together with typical MRI findings, the clinical features were not necessarily consistent with MRI findings.     

Non-Wilsonian hepatolenticular degeneration: Clinical and MRI observations in four families from south India

Non-Wilsonian hepatolenticular degeneration (NWHD) is a heterogeneous neurological disorder occurring secondary to chronic acquired liver disease. Genetically determined familial NWHD is rare, poorly understood, and often mistaken for Wilson’s disease (WD). We analysed clinical and MRI profiles of NWHD patients who did not have obvious cause for acquired liver disease, such as alcohol intake or hepatitis. Six patients from four families (four males, two females, mean age: 17.0 ± standard deviation 7.9 years), presenting with chronic extrapyramidal disorder resembling WD and imaging (abdominal ultrasound/MRI) evidence of cirrhosis were studied. They lacked Kayser–Fleischer rings or biochemical and/or genetic evidence of WD. Clinical features included dystonia (n = 6), parkinsonism (n = 3), tremor (n = 1), cerebellar ataxia (n = 3), orofacial dyskinesia (n = 1), behavioural abnormalities (n = 3), and cognitive decline (n = 1). Brain MRI revealed T1-weighted hyperintensity in the pallidum (n = 6), crus cerebri (n = 4), putamen (n = 1), caudate (n = 1), thalamus (n = 1), and red nucleus (n = 1) with T2-weighted shortening in some of these regions. Additional findings included giant cisterna magna (n = 1), face of giant panda sign (n = 1) and thin corpus callosum (n = 1). Areas of “blooming” on susceptibility weighted images were noted in two patients in the caudate (n = 2) and putamen (n = 1). The finding of T1 shortening is distinct from that of WD where the majority of lesions are T1-hypointense and T2-hyperintense. Extrapallidal T1-hyperintensity is also an exceptional observation in NWHD. The MRI appearance of intense T1 shortening coupled with the lack of increased susceptibility changes suggests that the most likely mineral deposited is manganese. The association of this neurological disorder and cirrhosis of the liver in the absence of an acquired liver disease is a distinct disease entity. This syndrome may represent a disorder of manganese metabolism resulting in its toxic deposition.     

Does successful smoking cessation reduce anxious arousal among treatment-seeking smokers?

IntroductionThere is limited work that has examined the effect of quitting smoking on anxious arousal, an underlying dimension of anxiety symptoms and psychopathology.MethodSmokers (n = 185, 54.1% female) enrolled in a smoking cessation treatment trial were monitored post-cessation in terms of abstinence status (biochemically verified; at Weeks 1, 2, and Month 1 post-quit) and severity of panic-relevant symptoms (self-reported; at Month 1 and 3 post-quit). Structural equation models were conducted, adjusting for participant sex, age, treatment condition, and pre-cessation nicotine dependence, presence of depressive/anxiety disorders, anxious arousal, and anxiety sensitivity.ResultsAfter adjusting for covariates, participants who remained abstinent for one month (n = 80; 43.2%) relative to those who did not (n = 105; 56.8%) demonstrated significant reductions in anxious arousal at Month 1 (β = −.26, p = .04) and Month 3 post-quit (β = −.36, p = .006); abstinence status had a non-significant effect on anxious arousal severity at Month 3 after controlling for Month 1 anxious arousal (β = −.18, p = .09).DiscussionFindings align with theoretical models of smoking-anxiety interplay and suggest that smoking cessation can result in reductions in anxious arousal.     

Clinicoradiological presentation,management options and a review of sellar and suprasellar tuberculomas

Clinicoradiological presentation and management of patients with sellar and suprasellar tuberculomas (SST) were reviewed. The SSTs of eight patients were divided into five radiological subgroups: a sellar–suprasellar mass (n = 3); multiple coalescing ring enhancing granulomas (n = 2); an intrasellar abscess (n = 1); pachymeningitis with suprasellar extension (n = 1); and skull-base lesion involving the sella (n = 1). The predominant endocrinopathies were hypogonadism, hypothyroidism and diabetes insipidus. The management options included surgery utilizing the frontotemporal, transylvian approach (n = 4) or the transsphenoidal approach (n = 1), stereotactic biopsy and ventriculoperitoneal shunt (n = 1); endoscopic transsphenoidal biopsy (n = 1); and antituberculous therapy (ATT) without surgery (n = 1). All patients received ATT for 15–18 months. Patients with rapid visual deterioration (n = 2) or with associated intramedullary tuberculoma (n = 2) also received steroids for 2 weeks. At follow-up (range 10 months to 5.5 years; mean 3.2 years), the radiological response to ATT was evaluated. MRI after ATT showed resolution of SST in all except two patients with solid lesions. However, these lesions were smaller and had reduced contrast enhancement on imaging. Thus, SST may present with five radiological subtypes. Surgery is useful in obtaining histology. Short-term steroid therapy with ATT may reduce edema and adhesions around the optic nerve when rapid visual deterioration occurs and relieve symptoms of raised intracranial pressure. The often-associated hypopituitarism indicates the requirement for preoperative hormonal evaluation.     

Syndrome de Susac : étude de cinq cas

IntroductionSusac syndrome is a rare microangiopathy, responsible for small cerebral, retinal and cochlear infarcts. The classic clinical triad includes multiple neurologic signs (from headaches to coma), retinal branch occlusions and sensorineural hearing loss.MethodsWe report a series of five patients with Susac syndrome followed in our department from 1997 to 2007.ResultsThere were four women and one man (mean age at onset: 35.2 years). Clinical symptoms at onset were neurological (n = 1), ophthalmological (n = 1), auditory (n = 1) and clinical triad (n = 2). Neurologic symptoms included encephalopathy (n = 2), headache (n = 5), transient ischemic attacks (n = 1). Brain MRI showed T2 lesions in the white and grey matter, corpus callosum and gadolinium-enhanced punctiform lesions. Cerebrospinal fluid contained an elevated protein level in three cases. Immunologic treatments (steroids [n = 4], cylophosphamid [n = 3], intravenous immunoglobulins [n = 5]) associated with aspirin and/or oral anticoagulants, despite early relapses (n = 2), led to dramatic clinical improvement (n = 5).ConclusionDue to its polymorphism the SS is difficult to diagnose when the clinical triad is lacking. In the absence of clinical trial and consensus treatment is empiric and based on supposed pathogenesis.     

BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas

BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and ganglioglioma’s clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem ganglioglioma’s clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation. The volume of tumours was calculated accurately by using 3D Slicer software. The clinical data of these patients were retrospectively analysed. In tumours with BRAF V600E mutations, the tumour regrowth rate was significantly faster than that of the wild type group (p = 0.001). Moreover, the BRAF V600E mutant group had shorter progression-free survival (PFS) compared with wild type (p = 0.012). On multivariate analysis, no factor was found to be an independent prognostic factor; however, tumours with faster regrowth rates had a strong trend towards an increased risk for shorter PFS (HR = 1.027, p = 0.056). No statistical analysis could be performed to evaluate factors affecting overall survival (OS). These data suggest that BRAF V600E can predict the regrowth rate of brainstem gangliogliomas after microsurgery, and a BRAF V600E-targeted therapeutic may be a promising early intervention measure for patients who harbour BRAF V600E mutation after microsurgery.     

Involvement of GABAergic transmission in the midbrain ventral tegmental area in the regulation of hippocampal theta rhythm

Previously we indicated that the ventral tegmental area (VTA) may belong to the system regulating hippocampal theta rhythm. In the present study, we aimed at assessing the role of the GABAergic system of the VTA in regulation of hippocampal electric activity. Male Wistar rats received unilateral intra-VTA microinjection of either bicuculline (50 ng/0.5 μl, n = 9), muscimol (100 ng/0.5 μl, n = 10) or phaclofen (500 ng/0.5 μl, n = 9). 1-min tail pinch stimulations were applied at 10-min intervals to evoke theta rhythm episodes in hippocampus. We analysed peak power (P_max) and corresponding frequency (F_max) of EEG signal at delta and theta bands. Bicuculline induced theta rhythm in both hippocampi with 0 latency, continuous for ca. 33 min. Phaclofen also induced theta but in this group it appeared with latency (17.45 ± 3.16 min on average), lasted for ca. 33.6 min and during this time was interrupted by periods of irregular activity of variable length. Tail pinch was not applied in these groups. Muscimol induced an opposite effect: depression of theta P_max with simultaneous increase in delta P_max and a decrease in F_max delta during episodes of tail pinch-evoked theta. This effect had variable latency and no return to the control EEG could be observed. We propose that GABA activity in the VTA is of tonic character, so that abolition of this mechanism produces immediate effect, i.e. theta induction (strong by GABA_A and weak by GABA_B receptors blockade), whereas enhancing the already present GABAergic inhibition causes delayed, prolonged changes expressed as gradual loss of theta synchronisation.