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IntroductionBreast cancer (BC) is the leading cause of female cancer deaths in Africa, and in Zimbabwe, >80% present with advanced disease. A Needs Project (NP) was carried out to determine the key factors responsible for delayed diagnosis and poor BC outcomes and to investigate possible solutions in 6 rural and urban districts of Matabeleland South and Bulawayo Metropolitan Provinces.MethodsA mixed method approach was used to collect data in 2 phases. Phase 1: an exploration of key factors leading to poor BC outcomes with >50 professional stakeholders and patient representatives. Phase 2: (i) Quantitative arm; validated questionnaires recording breast cancer knowledge, demographic information and perceived barriers to care administered to women and their relatives (Group 1) and health professionals (HPs) (Group 2). (ii) Qualitative arm; 10 focus group discussions with medical specialists and interested lay representatives (Group 3). The Cochran sample size formulae technique was used to determine the quantitative sample size and data was aggregated and analysed using SPSS Version 23™. Purposive sampling for the qualitative study selected participants with an understanding of BC and the NP. Focus group discussions were recorded and a thematic analysis of the transcriptions was conducted using NVivo9™.ResultsQuantitative analysis of Group 1 data (n = 1107) confirmed that younger women (ConclusionThis study confirms that the reasons for poor BC outcomes in Zimbabwe are complex and multi-factorial. All stakeholders support better user and provider education, diagnostic service reconfiguration, targeted funding, and specialist training.

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Objective: This study aimed to identify the recurrence rate of genetic generalized epilepsy (GGE) and risk factors for recurrence after antiseizure medication (ASM) withdrawal in adolescent patients., Methods: We retrospectively reviewed medical records of patients with GGE who were included in the registry at the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital from 2000 through 2020. The eligibility criteria were as follows: onset of epileptic seizures at <15 years of age, treatment with an ASM, and attempted treatment withdrawal at 10-19 years of age. The rates of seizure recurrence after drug withdrawal were evaluated. Moreover, several variables were evaluated as predictors of recurrence., Results: In total, 77 patients with GGE (21, 13, and 43 patients with juvenile myoclonic epilepsy [JME], juvenile absence epilepsy [JAE], and epilepsy with generalized tonic-clonic seizures alone [EGTCSA], respectively) were included in this study. Recurrence was detected in 68% of patients with GGE (86%, 31%, and 70% of patients with JME, JAE, and EGTCSA, respectively). Recurrence rates for patients who developed epilepsy at ≥13 years of age, those who started dose reduction at ≥16 years of age, those who exhibited a seizure-free period of <36 months before withdrawal, and those who chose to discontinue treatment at their own discretion were significantly higher than those for their counterparts. Multivariate analysis revealed that initiation of dose reduction at ≥16 years of age was associated with increased recurrence risk. Meanwhile, a diagnosis of JAE was associated with decreased recurrence risk. All patients with JAE were treated with valproic acid., Significance: Antiseizure medication withdrawal at ≥16 years of age and a diagnosis other than JAE may be independent risk factors for seizure recurrence after drug withdrawal in adolescent patients., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures., Results: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses., Conclusion: This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Introduction: The appearance of spontaneous subdural hematoma (SSDH) is a rare phenomenon in chronic hemodialysis and is burdened with significant morbidity and mortality. It's prevalence remains low in Sub-Saharan Africa, is 0.43%. We report a case of SSDH in a young hemodialysis patient with favorable outcome after medico-surgical management., Clinical Observation: This is a 35-year-old patient who has been hemodialysed since June 2016 for chronic renal insufficiency of hypertensive origin. He was admitted on 18 July 2018 in the nephrology department of CHU Point G for intense headaches in a context of dysarthria. They associate themselves with speech disorders, photo-phonophobia, uncontrollable nausea and vomiting. It does not report any notion of head trauma. The physical examination noted dysarthria, a right pyramidal syndrome made of right Babinsky sign, right arm deficit at 4/5, and right hemicorporeal hyperkinesia. He weighed 62 kg for 165 cm, the blood pressure was 187 / 110 mmHg. The patient had clinical signs of extracellular dehydration. Non-injected cerebral CT showed an acute left sub-dural hematoma with peri-lesional cerebral hypodensity. Surgical evacuation of the hematoma through a trephine hole is performed under local anesthesia. The postoperative course was simple. His hemodialysis sessions were done without heparin from diagnosis until 23 days post operatively., Conclusion: Spontaneous subdural hematoma is multifactorial and rare in the dialysis patient. Despite high morbidity and mortality, hemodialysis should not refute surgical management of subdural hematoma., (Le comité de rédaction se réserve le droit de renvoyer aux auteurs avant toute soumission à l'avis des lecteurs les manuscrits qui ne seraient pas conformes à ces modalités de présentation. En outre il leur conseille de conserver un exemplaire du manuscrit, des figures et des tableaux.)

Objective: Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau-Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau-Kleffner syndrome., Methods: MEG data and the Wechsler intelligence scale for children-III scores at ECSWS diagnosis, and medical records, were reviewed. Multiple regression analysis was performed to examine the relationship of parameters of MEG spike dipole clusters, including anatomical location or laterality, with the Wechsler intelligence scale for children-III scores at ECSWS diagnosis., Results: Sixteen patients were included, all of whom were right-handed. Epilepsy onset (first unprovoked seizure) ranged from 31 to 110 months (mean, 68.5). The age at ECSWS diagnosis ranged from 72 to 156 months (mean, 108.9). The dipole clusters were estimated on the right Rolandic area (RA) in 4 patients (25%), right supramarginal gyrus (SMG) in 3 (19%), left RA in 2 (13%), left SMG in 2 (13%), bilateral RA in 3 (19%), multiple anatomical locations in 2 (13%). The age at epilepsy onset had the strongest prognostic effect, and full-scale intelligence quotient was relatively less-affected if the cluster was found on the SMG (β = 14.7, p = 0.031). Cases with only a right side cluster exhibited reduced impairment of perceptual organization compared with those with only a left side cluster or bilateral clusters (β = 17.48, p = 0.02). In 12 patients, long-term intellectual prognosis was evaluated, and was associated with intellectual level at the period of ECSWS diagnosis., Conclusion: In non-lesional ECSWS, the relationship between epileptic focus and cognitive deficits differs from that observed in adults. Rather, it is similar to epilepsies associated with congenital or early infantile brain insults, in that the left epileptic foci in right-handed patients were associated with lower non-verbal functions. Future studies are required to determine the role of plasticity of the immature brain in driving these differences., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Immune-mediated central nervous system manifestations of group A β -hemolytic Streptococcus (GABHS) infection include Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)-which includes tic and obsessive compulsive disorders-and a variety of neurobehavioral disorders. We report a case of Streptococcus dysgalactiae subspecies equisimilis (group G Streptococcus ) (GGS) infection associated with involuntary movements, complex tics, and emotional lability in an 11-year-old Japanese girl. Serum IgM and IgG antibodies to lysoganglioside were positive, and she responded rapidly to intravenous immunoglobulin treatment. Neuropsychiatric disorder associated with GGS infection was ultimately diagnosed. The present findings suggest that neuropsychiatric disorders can result from GGS infection and that the pathogenic mechanism is similar to that of GABHS infection. Future large-scale studies should examine the relation between GGS infection and onset of neuropsychiatric disorder.

Objective: α ( CAMK2A ) and β ( CAMK2B ) isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α - and β -CaMKII variants in neurodevelopmental disorders., Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis., Results: We identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII α . By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII α mutant in primary hippocampal neurons significantly increased A-type K + currents, which facilitated spike repolarization of single action potentials., Interpretation: Our data highlight the importance of CaMKII α and CaMKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K + currents as a possible pathophysiological basis.

Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.

Down syndrome (DS) is a genetic disorder caused by the presence of a third copy of chromosome 21. DS affects multiple organs, but it invariably results in altered brain development and diverse degrees of intellectual disability. A large body of evidence has shown that synaptic deficits and memory impairment are largely determined by altered GABAergic signaling in trisomic mouse models of DS. These alterations arise during brain development while extending into adulthood, and include genesis of GABAergic neurons, variation of the inhibitory drive and modifications in the control of neural-network excitability. Accordingly, different pharmacological interventions targeting GABAergic signaling have proven promising preclinical approaches to rescue cognitive impairment in DS mouse models. In this review, we will discuss recent data regarding the complex scenario of GABAergic dysfunctions in the trisomic brain of DS mice and patients, and we will evaluate the state of current clinical research targeting GABAergic signaling in individuals with DS.

Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Megalencephalic polymicrogyria syndromes include megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus. Recent genetic studies have identified that genes in the PI3K-AKT pathway are involved in the pathogenesis of these disorders. Herein, we report a patient who presented with developmental delay, epilepsy and peculiar neuroimaging findings of megalencephaly, polymicrogyria, and symmetrical band heterotopia in the periventricular region. The heterotopias exhibited inhomogeneous signals with undulatory mixtures of gray and white matter, resembling ribbon-like heterotopia, with a predominance in the temporal to occipital regions. These neuroradiological findings were not consistent with those in known megalencephalic polymicrogyria syndromes. No genetic abnormality was identified through whole-exome sequencing. The neuroimaging findings of this patient may represent a novel cortical malformation involving megalencephaly with polymicrogyria and ribbon-like band heterotopia., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders., Methods: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes., Results: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients., Conclusions: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We report a case of infantile refractory epilepsy associated with Turner syndrome (TS), showing very frequent, focal clonic seizures of the left upper extremity. Characteristically, in addition to spontaneous fits, her seizure was inducible by rubbing her left hand and forearm for a few seconds. Accordingly, she was diagnosed with a rare form of reflex epilepsy, "rub epilepsy". Neuroradiological investigation indicated the existence of cortical abnormalities, such as focal cortical dysplasia of the right parietal lobe. Patients with TS are reported to have neuroanatomical abnormalities, especially of the parietal lobe. Thus, our case may imply a causal relationship between potential cortical hyperexcitability of the parietal lobe and epilepsy in TS. This is the first reported infantile case of rub epilepsy, and more generally, reflex epilepsy associated with TS., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Modeling depression in animals is based on the observation of behaviors interpreted as analog to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field™ (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered exploratory behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests.

Background: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission., Methods: Behavioral tests included the forced swim test, memory tasks (passive avoidance, novel object recognition tests), and anxiety-related paradigms (novelty suppressed feeding, social interaction, light/dark box tests). Hippocampal protein levels were detected by Western blot. Hippocampal plasticity was studied by in slice field recording of CA3-CA1 long-term synaptic potentiation (LTP), and glutamatergic transmission by whole-cell patch clamp recording of excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons., Results: Clobenpropit, administered systemically or directly into the hippocampus, decreased immobility during the forced swim test; systemic injections reversed memory deficits and increased hippocampal GluN2A protein levels. FSL rats displayed anxiety-related behaviors not affected by clobenpropit treatment. Clobenpropit enhanced hippocampal plasticity, but did not affect EPSCs. H1R and H2R antagonists prevented the clobenpropit-induced increase in LTP and, injected locally into the hippocampus, blocked clobenpropit's effect in the forced swim test., Conclusions: Clobenpropit's antidepressant effects and the enhanced synaptic plasticity require hippocampal H1R and H2R activation, suggesting that clobenpropit acts through disinhibition of histamine release. Clobenpropit reverses memory deficits and increases hippocampal GluN2A expression without modifying anxiety-related phenotypes or EPSCs in CA1 pyramidal neurons., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Gómez-López-Hernández syndrome (GLHS) is a rare neurocutaneous syndrome characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, and bilateral parieto-occipital alopecia. We herein describe the first Japanese patient with GLHS characterized by the standard triad with typical craniofacial anomaly including hypertelorism, brachyturricephaly and midface retrusion, and a short stature. This female patient had also exhibited fever-induced convulsive seizures and psychomotor developmental delay since infancy. Brain magnetic resonance imaging showed severe rhombencephalosynapsis, supratentorial abnormalities (aplasia of the septum pellucidum, severe ventricular enlargement, and hypoplasia of the corpus callosum), and hippocampus atrophy. Bilateral ectopic cerebellums were also observed. This report describes the long-term clinical outcome of GLHS and a new neuroradiological finding regarding rhombencephalosynapsis., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. A novel de novo SCN1A mutation was identified by whole-exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A-associated epileptic encephalopathy. [Published with video sequences].

Mood disorders, such as major depressive disorder (MDD), bipolar disorder and generalized anxiety disorder usually comprise mood related as well as cognitive symptoms and the interaction between these symptoms is still not clear. Most antidepressant drugs have a positive effect on mood but do not treat the cognitive dysfunctions or even aggravate the symptoms. In this review we will evaluate the association between mood and cognition in the context of mood disorders. In the first section we will summarize the brain circuits at the intersection between cognition and emotion, highlighting the role of the hippocampus. In the second section, we will survey the contribution of the glutamate and GABA systems in the pathophysiology of mood disorders, making an effort to understand the link between emotions and cognition and how novel therapeutic approaches deal with them. In the third section we will explore the monoamine involvement in the emotion/cognition duality in the context of mood disorders. Finally we will underline the role of synaptic plasticity and neurogenesis in depression. We consider that a broader knowledge about the integrative mechanisms involved in specific aspects of mood disorders is crucial in the development of more powerful and effective antidepressant drugs. This article is part of a Special Issue entitled: Brain Integration., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Polyglutamine (polyQ) diseases are inherited neurodegenerative diseases characterized by the aggregation of proteins containing expanded polyQ tract. It has been shown that expanded polyQ tract-containing proteins impair the functions of other cellular proteins. However, quantitative changes of cellular proteins in cells expressing expanded polyQ tract-containing proteins have not been performed. Here, we performed proteomic analysis of cells expressing expanded polyQ tract-containing proteins, and showed that GRP78, the endoplasmic reticulum (ER) chaperone, was significantly decreased in the cells expressing enhanced green fluorescent protein with a pathological-length polyQ tract (EGFP-polyQ97), but not with a non-pathological-length polyQ tract (EGFP-polyQ24). In addition, we revealed that down-regulation of GRP78 expression resulted in increase of the aggregation of EGFP-polyQ97. Conversely, the aggregation of EGFP-polyQ97 was suppressed by the overexpression of GRP78 in the cells. Furthermore, it seemed that the decreased GRP78 expression in the cells expressing EGFP-polyQ97 was due to the enhanced protein degradation of GRP78 through the ubiquitin-proteasome pathway. These findings indicated that GRP78, which has an inhibitory effect on the aggregation of proteins containing expanded polyQ tract, may be an effective target for the treatment of polyQ diseases., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Antipsychotics are the mainstay of schizophrenia treatment. However, approximately one third of schizophrenic patients do not respond or respond poorly to antipsychotics. Therefore, there is a need for new approaches that can improve schizophrenia treatment significantly. Promising strategies arise from the modulation of glutamatergic system, according to its proposed involvement in schizophrenia pathogenesis. In this review, we critically updated preclinical and clinical data on the modulation of glutamate N-methyl-D-aspartate (NMDA) receptor activity by NMDA-Rs co-agonists, glycine transporters inhibitors, AMPAkines, mGluR5 agonists, NMDA-Rs partial agonists. We focused on: 1) preclinical results in animal models mimicking the pathophysiology of psychosis, mainly believed to be responsible of negative and cognitive symptoms, and predicting antipsychotic-like activity of these compounds; and 2) clinical efficacy in open-label and double-blind trials. Albeit promising preclinical findings for virtually all compounds, clinical efficacy has not been confirmed for D-cycloserine. Contrasting evidence has been reported for glycine and D-serine, that may however have a role as add-on agents. More promising results in humans have been found for glycine transporter inhibitors. AMPAkines appear to be beneficial as pro-cognitive agents, while positive allosteric modulators of mGluR5 have not been tested in humans. Memantine has been proposed in early stages of schizophrenia, as it may counteract the effects of glutamate excitotoxicity correlated to high glutamate levels, slowing the progression of negative symptoms associated to more advanced stages of the illness., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.

Objectives: The objective of this metallomics study is to investigate comprehensively some relationships between cancer risk and minerals, including essential and toxic metals., Methods: Twenty-four minerals including essential and toxic metals in scalp hair samples from 124 solid-cancer patients and 86 control subjects were measured with inductively coupled plasma mass spectrometry (ICP-MS), and the association of cancer with minerals was statistically analyzed with multiple logistic regression analysis., Results: Multiple logistic regression analysis demonstrated that several minerals are significantly correlated to cancer, positively or inversely. The most cancer-correlated mineral was iodine (I) with the highest correlation coefficient of r = 0.301, followed by arsenic (As; r = 0.267), zinc (Zn; r = 0.261), and sodium (Na; r = 0.190), with p < 0.01 for each case. In contrast, selenium (Se) was inversely correlated to cancer (r = -0.161, p < 0.05), followed by vanadium (V) (r = -0.128). Multiple linear regression value was highly significantly correlated with probability of cancer (R (2) = 0.437, p < 0.0001), and the area under the receiver-operating characteristic (ROC) curve was calculated to be 0.918. In addition, using contingency table analysis and the chi-square test, the precision of discrimination for cancer was estimated to be 0.871 (chi-square = 99.1, p < 0.0001)., Conclusions: These findings suggest that some minerals such as arsenic, selenium, and probably iodine, zinc, sodium, and vanadium contribute to regulation of cancer and also that metallomics study using multiple logistic regression analysis is a useful tool for estimating cancer risk.

Pseudohypoparathyroidism (PHP) type Ia is characterized by hypocalcemia due to PTH resistance and by features of Albright's hereditary osteodystrophy, including short stature, obesity, subcutaneous calcification and brachydactyly. A wide variety of clinical and biochemical manifestations have been reported. We report two cases of PHP type Ia in duozygotic twins with different phenotypes. The proband was a 10-yr-old girl. She showed subcutaneous ossification, shortening of the metacarpal bone, short stature, obesity and round face. She had normocalcemia (8.9 mg/dl), high-normal phosphate (5.0 mg/dl) and increased levels of serum intact PTH (152 pg/ml) and TSH (9.17 μIU/ml) levels. Her twin younger brother had atypical Albright's hereditary osteodystrophy with only mild obesity and subcutaneous calcifications, but he showed a low level of serum calcium (7.0 mg/dl) and high levels of serum phosphate (7.6 mg/dl), intact PTH (377 pg/ml) and TSH (6.9 μIU/ml). We diagnosed them as having PHP type Ia on the basis of clinical and biochemical findings, Ellsworth-Howard test and family history. There is considerable variability in clinical and biochemical features of PHP type Ia even among affected duozygotic twins. The differences of intrauterine environment and growth history cannot account for the variable phenotypes of PHP type Ia. Even if a patient shows no AHO features, examination of all family members should be undertaken.

Objectives: The purpose of this study was to evaluate the inhibitory effect of roxithromycin on the production of interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) in a murine tibial osteomyelitis model using Staphylococcus aureus., Methods: Cytokine levels in supernatants derived from bone homogenates were measured by enzyme-linked immunosorbent assay for 28 days, after oral administration of roxithromycin at 5 mg/kg/day., Results: There was no significant difference in IL-6 levels between a group receiving roxithromycin administration and a group not receiving roxithromycin. IL-1beta and TNF-alpha levels were significantly lower for the administration group after 7-14 days and after 21-28 days, respectively. However, a significant difference in bacterial counts in bone between the groups was not observed., Conclusion: These results indicate that roxithromycin suppresses the local expression of IL-1beta and TNF-alpha, and may exhibit an anti-inflammatory effect in this osteomyelitis model.

The purpose of this study is to evaluate local levels of interleukin-1 beta (IL-1 beta), -4 (IL-4), -6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha), in a model of murine osteomyelitis due to Staphylococcus aureus. Cytokine levels in supernatants derived from bone homogenates were determined by enzyme-linked immunosorbent assay, for 28 days following the direct implantation of murine tibiae with S.aureus. Levels of IL-1 beta and IL-6 in infected bone were elevated in the early post-infection period and then decreased. In contrast, TNF-alpha levels remained elevated 3 to 28 days post-infection, while IL-4 levels were elevated late in the course of infection. The histopathology of infected bone showed predominant infiltration of inflammatory cells and bone resorption 3 to 7 days after infection, and bone resorption and adjacent areas of formation 14 to 28 days after infection. These results suggest that the elevated IL-1 beta and IL-6 levels induced by infection may be related to bone damage mainly in the early phase of infection, and that TNF-alpha and IL-4 may at least in part be associated with histopathological changes, including both bone resorption and formation in the later phase of this osteomyelitis model.