Cognitive outcome and its neural correlates after cardiorespiratory arrest in childhood.

Hypoxia-ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia-ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life. Here, we studied the long-term outcome of 28 children who suffered early CA (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, sex and socio-economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by academic attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter. In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum. We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities. RESEARCH HIGHLIGHTS: Our data shed light on the long-term outcome and associated neural mechanisms after paediatric hypoxia-ischaemia as a result of cardiorespiratory arrest. Patients had impaired scores on memory, language and academic attainment. Memory impairments were associated with smaller hippocampi, thalami, and striatum. Lower academic attainment correlated with reduced fractional anisotropy of the superior cerebellar peduncle.

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy.

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

Is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children the same condition as in adults?

This case series describes three children with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), an inflammatory condition characterized by a relapsing-remitting disease course responsive to steroids. The patients (two males, age 3y and 13y; one female, age 14y) presented with ataxia, dysarthria, and multiple cranial neuropathies. All patients demonstrated bilateral nodular lesions with contrast enhancement in the brainstem and cerebellum on magnetic resonance imaging, and perivascular lymphocytes and macrophages infiltrates on brain biopsies. Despite an initially good response to corticosteroids, all patients eventually became steroid-dependent or -resistant, with frequent relapses on maintenance immunosuppressive therapy. Natalizumab and intravenous immunoglobulin stopped neurological disease progression in Patient 1 but he died at 17 years from respiratory complications. Patient 2 went into remission on infliximab and intravenous methylprednisolone for several months but was then diagnosed with Epstein-Barr virus driven B-cell lymphoma 3 years after symptom onset. Patient 3 failed to respond to treatment and died 4 years after diagnosis. CLIPPERS disease in children is aggressive, with poor response to immunotherapy. Earlier use of newer immunotherapeutic agents such as natalizumab may be beneficial. Potential side effects need to be considered carefully. WHAT THIS PAPER ADDS: Paediatric chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) appears a more severe condition than previously reported in adults. Aggressive treatment before neuroaxonal loss may be required for a better outcome.

¿ES LA INFLAMACIÓN LINFOCÍTICA CRÓNICA CON REALCE PERIVASCULAR PONTINO SENSIBLE A LOS ESTEROIDES (CLIPPERS) EN LOS NIÑOS CON LA MISMA CONDICIÓN QUE EN LOS ADULTOS?: Esta serie de casos describe a tres niños con inflamación linfocítica crónica con realce pontinal perivascular sensible a esteroides (CLIPPERS), una enfermedad inflamatoria caracterizada por un curso de enfermedad recurrente-remitente sensible a los esteroides. Los pacientes (dos varones, edad 3 y 13 años, una mujer, edad 14 años) presentaron ataxia, disartria y neuropatías craneales múltiples. Todos los pacientes demostraron lesiones nodulares bilaterales con realce de contraste en el tallo cerebral y el cerebelo en imágenes de resonancia magnética y linfocitos perivasculares y infiltrados de macrófagos en biopsias cerebrales. A pesar de una respuesta inicialmente buena a los corticosteroides, todos los pacientes finalmente se volvieron dependientes de esteroides o resistentes, con recaídas frecuentes en la terapia inmunosupresora de mantenimiento. El natalizumab y la inmunoglobulina intravenosa suspendieron la progresión de la enfermedad neurológica en el paciente 1, pero falleció a los 17 años por complicaciones respiratorias. El paciente 2 entró en remisión con infliximab y metilprednisolona por vía intravenosa durante varios meses, pero luego se le diagnosticó linfoma de células B dirigido por el virus de Epstein-Barr, 3 años después del inicio de los síntomas. El paciente 3 no respondió al tratamiento y murió 4 años después del diagnóstico. La enfermedad de CLIPPERS en los niños es agresiva, con una respuesta deficiente a la inmunoterapia. El uso previo de agentes inmunoterápicos más nuevos como natalizumab puede ser beneficioso. Los posibles efectos secundarios deben considerarse cuidadosamente.

A INFLAMAÇÃO LINFOCÍTICA CRÔNICA COM REALCE PERIVASCULAR PONTINO RESPONSIVA A ESTERÓIDES (CLIPPERS) É A MESMA CONDIÇÃO EM CRIANÇAS E ADULTOS?: Esta série de casos descreve três crianças com inflamação linfocítica crônica com realce perivascular pontino responsiva a esteróides (CLIPPERS), uma condição inflamatória caracterizada por uma doença com curso remissivo-recidivante responsive a esteróides. Os pacientes (dois meninos, idades 3 e 13 anos; uma menina, idade 14 anos) apresentaram ataxia, disartria, e múltiplas neuropatias craniais. Todos os pacientes demonstraram lesões nodulares bilaterais com realce no tronco cerebral e cerebelo ao exame ne ressonância magnética, e infiltrados perivasculares de linfócitos e macrófagos nas biópsias cerebrais. Apesar de uma resposta inicialmente boa aos corticoesteróides, todos os pacientes eventualmente se tornaram esteróide-dependentes ou resistentes, com frequentes recidivas com manutenção de imunoterapia supressora. Natalizumab e imunoglobulina intravenosa interromperam a progressão neurológica da doença no Paciente 1, mas ele veio a óbito na idade de 17 anos devido a complicações respiratórias. O Paciente 2 entrou em remissão com infliximab e metilprednosolona intravenosa por vários meses, mas foi então diagnosticado com linfoma de células B causado por virus Epstein-Barr 3 anos após o início dos sintomas. O Paciente 3 não respondeu ao tratamento e veio a óbito 4 anos após o diagnóstico. Patient 2 went into remission on infliximab and intravenous methylprednisolone for several months but was then diagnosed with Epstein-Barr virus driven B-cell lymphoma 3 years after symptom onset. Patient 3 failed to respond to treatment and died 4 years after diagnosis. INTERPRETAÇÃO: A doença CLIPPERS em crianças é agressiva, com pouca resposta à imunoterapia. O uso precoce de agentes imunoterapêuticos mais novos como natalizumab pode ser benéfico. Potenciais efeitos colaterais devem ser considerados com cautela.

Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis.

Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuVJL5) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuVJL5 associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis was only possible by deep sequencing of the brain biopsy. Sequence comparison of the vaccine batch to the MuVJL5 isolated from brain identified biased hypermutation, particularly in the matrix gene, similar to those found in measles from cases of SSPE. The findings provide unique insights into the pathogenesis of paramyxovirus brain infections.

Melanoma in congenital melanocytic naevi.

Congenital melanocytic naevi (CMN) are a known risk factor for melanoma, with the greatest risk currently thought to be in childhood. There has been controversy over the years about the incidence of melanoma, and therefore over the clinical management of CMN, due partly to the difficulties of histological diagnosis and partly to publishing bias towards cases of malignancy. Large cohort studies have demonstrated that melanoma risk in childhood is related to the severity of the congenital phenotype. New understanding of the genetics of CMN offers the possibility of improvement in diagnosis of melanoma, identification of those at highest risk, and new treatment options. We review the world literature and our centre's experience over the last 25 years, including the molecular characteristics of melanoma in these patients and new melanoma incidence and outcome data from our prospective cohort. Management strategies are proposed for presentation of suspected melanoma of the skin and the central nervous system in patients with CMN, including use of oral mitogen-activated protein kinase kinase inhibitors in NRAS-mutated tumours.

Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus MRI.

OBJECTIVES: To compare the diagnostic yield of whole-body post-mortem computed tomography (PMCT) imaging to post-mortem magnetic resonance (PMMR) imaging in a prospective study of fetuses and children. METHODS: We compared PMCT and PMMR to conventional autopsy as the gold standard for the detection of (a) major pathological abnormalities related to the cause of death and (b) all diagnostic findings in five different body organ systems. RESULTS: Eighty two cases (53 fetuses and 29 children) underwent PMCT and PMMR prior to autopsy, at which 55 major abnormalities were identified. Significantly more PMCT than PMMR examinations were non-diagnostic (18/82 vs. 4/82; 21.9 % vs. 4.9 %, diff 17.1 % (95 % CI 6.7, 27.6; p < 0.05)). PMMR gave an accurate diagnosis in 24/55 (43.64 %; 95 % CI 31.37, 56.73 %) compared to 18/55 PMCT (32.73 %; 95 % CI 21.81, 45.90). PMCT was particularly poor in fetuses <24 weeks, with 28.6 % (8.1, 46.4 %) more non-diagnostic scans. Where both PMCT and PMMR were diagnostic, PMMR gave slightly higher diagnostic accuracy than PMCT (62.8 % vs. 59.4 %). CONCLUSION: Unenhanced PMCT has limited value in detection of major pathology primarily because of poor-quality, non-diagnostic fetal images. On this basis, PMMR should be the modality of choice for non-invasive PM imaging in fetuses and children. KEY POINTS: • Overall 17.1 % more PMCT examinations than PMMR were non-diagnostic • 28.6 % more PMCT were non-diagnostic than PMMR in fetuses <24 weeks • PMMR detected almost a third more pathological abnormalities than PMCT • PMMR gave slightly higher diagnostic accuracy when both were diagnostic.

Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man.

Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.

Classification of neurological abnormalities in children with congenital melanocytic naevus syndrome identifies magnetic resonance imaging as the best predictor of clinical outcome.

BACKGROUND: The spectrum of central nervous system (CNS) abnormalities described in association with congenital melanocytic naevi (CMN) includes congenital, acquired, melanotic and nonmelanotic pathology. Historically, symptomatic CNS abnormalities were considered to carry a poor prognosis, although studies from large centres have suggested a much wider variation in outcome. OBJECTIVES: To establish whether routine MRI of the CNS is a clinically relevant investigation in children with multiple CMN (more than one at birth), and to subclassify radiological abnormalities. METHODS: Of 376 patients seen between 1991 and 2013, 289 fulfilled our criterion for a single screening CNS MRI, which since 2008 has been more than one CMN at birth, independent of size and site of the largest naevus. Cutaneous phenotyping and radiological variables were combined in a multiple regression model of long-term outcome measures (abnormal neurodevelopment, seizures, requirement for neurosurgery). RESULTS: Twenty-one per cent of children with multiple CMN had an abnormal MRI. Abnormal MRI was the most significant predictor of all outcome measures. Abnormalities were subclassified into group 1 'intraparenchymal melanosis alone' (n = 28) and group 2 'all other pathology' (n = 18). Group 1 was not associated with malignancy or death during the study period, even when symptomatic with seizures or developmental delay, whereas group 2 showed a much more complex picture, requiring individual assessment. CONCLUSIONS: For screening for congenital neurological lesions a single MRI in multiple CMN is a clinically relevant strategy. Any child with a stepwise change in neurological/developmental symptoms or signs should have an MRI with contrast of the brain and spine to look for new CNS melanoma.

Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses and children.

AIM: To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. MATERIALS AND METHODS: Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort (n = 400) of fetuses (n = 277; 185 ≤ 24 weeks and 92 > 24 weeks gestation) and children <16 years (n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. RESULTS: Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. CONCLUSIONS: PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic-ischaemic brain injury, and may not detect rarer disorders not encountered in this study.

PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease.

Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy' is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.

New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk.

BACKGROUND: Facial port-wine stains (PWSs) are usually isolated findings; however, when associated with cerebral and ocular vascular malformations they form part of the classical triad of Sturge-Weber syndrome (SWS). OBJECTIVES: To evaluate the associations between the phenotype of facial PWS and the diagnosis of SWS in a cohort with a high rate of SWS. METHODS: Records were reviewed of all 192 children with a facial PWS seen in 2011-13. Adverse outcome measures were clinical (seizures, abnormal neurodevelopment, glaucoma) and radiological [abnormal magnetic resonance imaging (MRI)], modelled by multivariate logistic regression. RESULTS: The best predictor of adverse outcomes was a PWS involving any part of the forehead, delineated at its inferior border by a line joining the outer canthus of the eye to the top of the ear, and including the upper eyelid. This involves all three divisions of the trigeminal nerve, but corresponds well to the embryonic vascular development of the face. Bilateral distribution was not an independently significant phenotypic feature. Abnormal MRI was a better predictor of all clinical adverse outcome measures than PWS distribution; however, for practical reasons guidelines based on clinical phenotype are proposed. CONCLUSIONS: Facial PWS distribution appears to follow the embryonic vasculature of the face, rather than the trigeminal nerve. We propose that children with a PWS on any part of the 'forehead' should have an urgent ophthalmology review and a brain MRI. A prospective study has been established to test the validity of these guidelines.

COL4A1 mutations should not be a contraindication for epilepsy surgery.

PURPOSE: We describe the first case in the literature of complication-free epilepsy surgery in a paediatric patient with collagen type IV alpha 1 (COL4A1) mutation. METHODS: This is a case report. RESULTS: COL4A1 mutations disrupt the integrity of vascular basement membranes, so predisposing to a broad spectrum of disorders including periventricular leucomalacia, haemorrhagic stroke, aneurysm formation, epilepsy and developmental delay. Intracranial haemorrhage is reported and may be recurrent or associated with trauma and anticoagulant therapy. Children have an increased risk of stroke with general anaesthesia. A 6-year-old girl, COL4A1 mutation positive, had drug-resistant epilepsy, cerebral palsy and developmental delay. Following presurgical evaluation, she was a candidate for corpus callosotomy. Previous general anaesthesia had been uncomplicated. Preoperative full blood count and coagulation studies were normal. Perioperatively, normotension was maintained, and anticoagulation was avoided. A complete corpus callosotomy was performed with no intracranial haemorrhage or other perioperative complications. CONCLUSION: Although there is an increased risk of intracranial haemorrhages in COL4A1 patients, this is not clearly quantifiable. There are minimal data in the literature on the subject. COL4A1 mutations should not be a contraindication for presurgical evaluation. Each patient should be individually evaluated and assessed, risks and benefits were carefully weighed, and informed decisions were reached after thorough discussions with patients and families.

Anatomo-functional changes in neural substrates of cognitive memory in developmental amnesia: Insights from automated and manual MRI examinations.

Despite bilateral hippocampal damage dating to perinatal or early-childhood period, and severely-impaired episodic memory that unfolds in later childhood, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganise to rescue aspects of these critical cognitive memory processes after early injury. We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40% while the atrophy of the uncus was moderate (-23%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions, such that the greater the damage, the more likely it is that surrounding cortical areas will be recruited to rescue the putative functions of the damaged subregions. Our findings document for the first time not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.

Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder.

BACKGROUND: The first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the SLC30A10 gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia. METHODS: We present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in SLC30A10. RESULTS: The patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging. CONCLUSIONS: We wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. © 2012 Movement Disorder Society.

A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs.

The IOP lowering effects of NCX 139, a new chemical entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the respective des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan(®)) and the prostaglandin agonist, latanoprost (Xalatan(®)) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC(50)=0.70±0.06 µM; E(max)=80.6±2.9%). Like bimatoprost (IC(50)=3.07±1.3 µM) or latanoprost (IC(50)=0.48±0.15 µM), NCX 139 displaced (3)H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77±0.13 µM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent reduction of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ(max)=-12.8±2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro derivative (Δ(max)=-4.6±1.0 and -2.7±1.3 mmHg, respectively for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compound targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.

Neocortical and hippocampal volume loss in a human ciliopathy: A quantitative MRI study in Bardet-Biedl syndrome.

Cilia are ubiquitous cell surface organelles with diverse roles from embryogenesis to adult life. The neurodevelopmental functions of the cilium are currently under investigation in animal systems, but relevance to human brain development remains uncertain. We present the first systematic investigation of structural neuroanatomy in a ciliopathy-Bardet-Biedl syndrome (BBS). Qualitative and quantitative aspects of brain structure were evaluated via magnetic resonance imaging in 10 patients with BBS (ages 14-28 years). In comparison to age and gender-matched healthy controls, BBS patients had significantly reduced total gray matter (GM) volume but no total white matter (WM) or cerebrospinal fluid volume changes. Voxel-based morphometric analysis indicated regional GM volume loss bilaterally in the anterior temporal lobes and in the medial orbitofrontal cortex, and WM volume loss in the right inferior longitudinal fasciculus. Region-of-interest measurements revealed reduced volume of the hippocampus. Two patients were found to have ventriculomegaly. Global GM reduction and regional volume reductions in the temporal lobe may underlie the learning disabilities and behavioral problems experienced by some patients with BBS. These findings are consistent with previous observations in mouse models of BBS, and further implicate the cilium in neurodevelopmental processes relevant to human cognitive function.