IJMS, Vol. 18, Pages 2251: Antifungal Effect of Polygodial on Botrytis cinerea, a Fungal Pathogen Affecting Table Grapes

IJMS, Vol. 18, Pages 2251: Antifungal Effect of Polygodial on Botrytis cinerea, a Fungal Pathogen Affecting Table Grapes

International Journal of Molecular Sciences doi: 10.3390/ijms18112251

Authors: Héctor Carrasco Christian Robles-Kelly Julia Rubio Andrés Olea Rolando Martínez Evelyn Silva-Moreno

The antifungal activity of polygodial, a secondary metabolite extracted from Canelo, on mycelial growth of different Botrytis cinerea isolates has been evaluated. The results show that polygodial affects growth of normal and resistant isolates of B. cinerea with EC50 values ranging between 117 and 175 ppm. In addition, polygodial markedly decreases the germination of B. cinerea, i.e., after six hours of incubation the percentage of germination decreases from 92% (control) to 25% and 5% in the presence of 20 ppm and 80 ppm of polygodial, respectively. Morphological studies indicate that conidia treated with polygodial are smaller, with irregular membrane border, and a lot of cell debris, as compared to conidia in the control. The existence of polygodial-induced membrane damage was confirmed by SYTOX® Green uptake assay. Gene expression studies confirm that the effect of polygodial on B. cinerea is mainly attributed to inhibition of germination and appears at early stages of B. cinerea development. On the other hand, drimenol, a drimane with chemical structure quite similar to polygodial, inhibits the mycelial growth efficiently. Thus, both compounds inhibit mycelial growth by different mechanisms. The different antifungal activities of these compounds are discussed in terms of the electronic density on the double bond.

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When targets miss the mark

Warnings of a looming winter crisis in the NHS are coming thicker and faster, with another just last week (doi:10.1136/bmj.j4885). It's appropriate, then, that our latest Head to Head debate...

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Diagnosis and management of cystic fibrosis: summary of NICE guidance

What you need to knowSome people with cystic fibrosis (including adults) are undiagnosed because they missed the newborn screening process; they carry less common cystic fibrosis mutations; or have...

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Northern Ireland trainees are well supported and supervised, GMC finds

Trainee doctors in Northern Ireland feel well supported and well supervised and enjoy their clinical training placements, the General Medical Council has found.Between February and April this year...

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Upper limb cortical maps in amputees with targeted muscle and sensory reinnervation

Abstract

Neuroprosthetics research in amputee patients aims at developing new prostheses that move and feel like real limbs. Targeted muscle and sensory reinnervation (TMSR) is such an approach and consists of rerouting motor and sensory nerves from the residual limb towards intact muscles and skin regions. Movement of the myoelectric prosthesis is enabled via decoded electromyography activity from reinnervated muscles and touch sensation on the missing limb is enabled by stimulation of the reinnervated skin areas. Here we ask whether and how motor control and redirected somatosensory stimulation provided via TMSR affected the maps of the upper limb in primary motor (M1) and primary somatosensory (S1) cortex, as well as their functional connections. To this aim, we tested three TMSR patients and investigated the extent, strength, and topographical organization of the missing limb and several control body regions in M1 and S1 at ultra high-field (7 T) functional magnetic resonance imaging. Additionally, we analysed the functional connectivity between M1 and S1 and of both these regions with fronto-parietal regions, known to be important for multisensory upper limb processing. These data were compared with those of control amputee patients (n = 6) and healthy controls (n = 12). We found that M1 maps of the amputated limb in TMSR patients were similar in terms of extent, strength, and topography to healthy controls and different from non-TMSR patients. S1 maps of TMSR patients were also more similar to normal conditions in terms of topographical organization and extent, as compared to non-targeted muscle and sensory reinnervation patients, but weaker in activation strength compared to healthy controls. Functional connectivity in TMSR patients between upper limb maps in M1 and S1 was comparable with healthy controls, while being reduced in non-TMSR patients. However, connectivity was reduced between S1 and fronto-parietal regions, in both the TMSR and non-TMSR patients with respect to healthy controls. This was associated with the absence of a well-established multisensory effect (visual enhancement of touch) in TMSR patients. Collectively, these results show how M1 and S1 process signals related to movement and touch are enabled by targeted muscle and sensory reinnervation. Moreover, they suggest that TMSR may counteract maladaptive cortical plasticity typically found after limb loss, in M1, partially in S1, and in their mutual connectivity. The lack of multisensory interaction in the present data suggests that further engineering advances are necessary (e.g. the integration of somatosensory feedback into current prostheses) to enable prostheses that move and feel as real limbs.

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Entangled cerebral networks in Parkinson’s disease

This scientific commentary refers to 'Abnormal intrinsic brain functional network dynamics in Parkinson's disease', by Kim et al. (doi:10.1093/brain/awx233).

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Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization

Abstract

The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.

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Editorial

One of the more enjoyable roles of the editor is to choose a cover for each issue of Brain. Cover images are mostly, although not invariably, drawn from suggestions submitted by authors of papers appearing in the same issue. They often go through several iterations before being sent for production. Some covers are composed in the Editorial Office drawing on original artwork, or archives held by libraries and museums. For authors contemplating cover suggestions in the future, here are some guidelines. The image should be striking and invite the casual viewer to open the journal or to click on the link that describes it. It should, ideally, tell a story, or at least have some conceptual link to the message of the paper to which it relates. Although figures taken directly from the article are unlikely to work, they can sometimes be adapted to create a visual narrative. Authors are invited to suggest ideas based on sketches before involving a professional designer. However, because of the relatively short delay from finalizing the contents of an issue and printing it, any third party must be prepared to work to strict deadlines. Histology images rarely work on their own, and graphs, DNA sequences, wordy flow charts, biochemical pathways, clinical brain scans, and portraits of long-deceased bearded neurologists are unlikely to be selected.

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Reduced neural ‘effort’ after naming treatment in anomia

This scientific commentary refers to 'Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients', by Nardo et al. (doi:10.1093/brain/awx234).

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Presence of tau pathology within foetal neural allografts in patients with Huntington’s and Parkinson’s disease

Abstract

Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative diseases, but also that tau pathology can manifest in healthy neural tissue transplanted into the brains of patients with two distinct neurodegenerative disorders.

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A little man of some importance

Eighty years ago, Penfield and Boldrey introduced the homunculus in a paper published in Brain. In a reappraisal of the iconic aide-mémoire, Marco Catani reanalyses the original data, and argues that through its extended network the homunculus holds the key to the precise coding that results in coordinated activation of peripheral muscles.

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The multiple faces of TOR1A: different inheritance, different phenotype

This scientific commentary refers to 'TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor', by Kariminejad et al. (doi:10.1093/brain/awx230).

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In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis

Abstract

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T₁/T₂-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T₂*-weighted imaging for cortical lesion segmentation and 3 T T₁/T₂-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

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Beta burst dynamics in Parkinson’s disease OFF and ON dopaminergic medication

Abstract

Exaggerated basal ganglia beta activity (13–35 Hz) is commonly found in patients with Parkinson's disease and can be suppressed by dopaminergic medication, with the degree of suppression being correlated with the improvement in motor symptoms. Importantly, beta activity is not continuously elevated, but fluctuates to give beta bursts. The percentage number of longer beta bursts in a given interval is positively correlated with clinical impairment in Parkinson's disease patients. Here we determine whether the characteristics of beta bursts are dependent on dopaminergic state. Local field potentials were recorded from the subthalamic nucleus of eight Parkinson's disease patients during temporary lead externalization during surgery for deep brain stimulation. The recordings took place with the patient quietly seated following overnight withdrawal of levodopa and after administration of levodopa. Beta bursts were defined by applying a common amplitude threshold and burst characteristics were compared between the two drug conditions. The amplitude of beta bursts, indicative of the degree of local neural synchronization, progressively increased with burst duration. Treatment with levodopa limited this evolution leading to a relative increase of shorter, lower amplitude bursts. Synchronization, however, was not limited to local neural populations during bursts, but also, when such bursts were cotemporaneous across the hemispheres, was evidenced by bilateral phase synchronization. The probability of beta bursts and the proportion of cotemporaneous bursts were reduced by levodopa. The percentage number of longer beta bursts in a given interval was positively related to motor impairment, while the opposite was true for the percentage number of short duration beta bursts. Importantly, the decrease in burst duration was also correlated with the motor improvement. In conclusion, we demonstrate that long duration beta bursts are associated with an increase in local and interhemispheric synchronization. This may compromise information coding capacity and thereby motor processing. Dopaminergic activity limits this uncontrolled beta synchronization by terminating long duration beta bursts, with positive consequences on network state and motor symptoms.

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MRI findings of visual system alterations in Parkinson’s disease

Sir,

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Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice

Abstract

Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease—with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

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Reply: MRI findings of visual system alterations in Parkinson’s disease

Sir,

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Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

Abstract

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABA_A receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α₃-subunit of the GABA_A receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH₂-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α₃-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.

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Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

Abstract

The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.

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Reply: Genotype-phenotype correlation in ATAD3A deletions: not just of scientific relevance

Sir,

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Genotype-phenotype correlation in ATAD3A deletions: not just of scientific relevance

Sir,

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Abnormal intrinsic brain functional network dynamics in Parkinson’s disease

Abstract

See Nieuwhof and Helmich (doi:10.1093/brain/awx267) for a scientific commentary on this article.Parkinson's disease is a neurodegenerative disorder characterized by nigrostriatal dopamine depletion. Previous studies measuring spontaneous brain activity using resting state functional magnetic resonance imaging have reported abnormal changes in broadly distributed whole-brain networks. Although resting state functional connectivity, estimating temporal correlations between brain regions, is measured with the assumption that intrinsic fluctuations throughout the scan are stable, dynamic changes of functional connectivity have recently been suggested to reflect aspects of functional capacity of neural systems, and thus may serve as biomarkers of disease. The present work is the first study to investigate the dynamic functional connectivity in patients with Parkinson's disease, with a focus on the temporal properties of functional connectivity states as well as the variability of network topological organization using resting state functional magnetic resonance imaging. Thirty-one Parkinson's disease patients and 23 healthy controls were studied using group spatial independent component analysis, a sliding windows approach, and graph-theory methods. The dynamic functional connectivity analyses suggested two discrete connectivity configurations: a more frequent, sparsely connected within-network state (State I) and a less frequent, more strongly interconnected between-network state (State II). In patients with Parkinson's disease, the occurrence of the sparsely connected State I dropped by 12.62%, while the expression of the more strongly interconnected State II increased by the same amount. This was consistent with the altered temporal properties of the dynamic functional connectivity characterized by a shortening of the dwell time of State I and by a proportional increase of the dwell time pattern in State II. These changes are suggestive of a reduction in functional segregation among networks and are correlated with the clinical severity of Parkinson's disease symptoms. Additionally, there was a higher variability in the network global efficiency, suggesting an abnormal global integration of the brain networks. The altered functional segregation and abnormal global integration in brain networks confirmed the vulnerability of functional connectivity networks in Parkinson's disease.

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Pharmacological targeting of apelin impairs glioblastoma growth

Abstract

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

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Ubiquitin carboxyl-terminal hydrolases: involvement in cancer progression and clinical implications

Abstract

Protein ubiquitination and deubiquitination participate in a number of biological processes, including cell growth, differentiation, transcriptional regulation, and oncogenesis. Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), includes four members: UCH-L1/PGP9.5 (protein gene product 9.5), UCH-L3, UCHL5/UCH37, and BRCA1-associated protein-1 (BAP1). Recently, more attention has been paid to the relationship between the UCH family and malignancies, which play different roles in the progression of different tumors. It remains controversial whether UCHL1 is a tumor promoter or suppressor. UCHL3 and UCH37 are considered to be tumor promoters, while BAP1 is considered to be a tumor suppressor. Studies have showed that UCH enzymes influence several signaling pathways that play crucial roles in oncogenesis, tumor invasion, and migration. In addition, UCH families are associated with tumor cell sensitivity to therapeutic modalities. Here, we reviewed the roles of UCH enzymes in the development of tumors, highlighting the potential consideration of UCH enzymes as new interesting targets for the development of anticancer drugs.

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Reflection

British Dental Journal 223, 549 (2017). doi:10.1038/sj.bdj.2017.894

Author: Stephen Hancocks

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Paediatric dentistry: A multidisciplinary approach

British Dental Journal 223, 551 (2017). doi:10.1038/sj.bdj.2017.895

Author: V. Argent

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Stress and burnout research project

British Dental Journal 223, 559 (2017). doi:10.1038/sj.bdj.2017.912

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Dental notation: Mental gymnastics

British Dental Journal 223, 551 (2017). doi:10.1038/sj.bdj.2017.896

Author: M. J. Trenouth

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Fracture resistance of zirconia-based all-ceramic crowns after bur adjustment

British Dental Journal 223, 587 (2017). doi:10.1038/sj.bdj.2017.918

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Dental education: A gentle touch

British Dental Journal 223, 552 (2017). doi:10.1038/sj.bdj.2017.898

Author: R. Bettles

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Patient benefits: Incorrect advice

British Dental Journal 223, 552 (2017). doi:10.1038/sj.bdj.2017.899

Author: J. Ballard

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Oral surgery II: Part 3. Cysts of the mouth and jaws and their management

British Dental Journal 223, 573 (2017). doi:10.1038/sj.bdj.2017.916

Authors: C. M. Hill & T. Renton

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From the archive: Sydney turns 100

British Dental Journal 223, 552 (2017). doi:10.1038/sj.bdj.2017.900

Author: P. Grennan

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An estimated carbon footprint of NHS primary dental care within England. How can dentistry be more environmentally sustainable?

British Dental Journal 223, 589 (2017). doi:10.1038/sj.bdj.2017.839

Authors: B. Duane, M. Berners Lee, S. White, R. Stancliffe & I. Steinbach

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Primary dental care: You're not serious

British Dental Journal 223, 552 (2017). doi:10.1038/sj.bdj.2017.901

Author: K. F. Marshall

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Eavesdroppers and nosey neighbours required

British Dental Journal 223, 558 (2017). doi:10.1038/sj.bdj.2017.909

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Alternative sugars: Syrup

British Dental Journal 223, 555 (2017). doi:10.1038/sj.bdj.2017.902

Elaine Gardner, British Dietetic Association (BDA) Spokesperson, discusses the sugar content in syrup and provides related oral health advice.

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Is it time to digitally enable dentistry with the rest of healthcare?

British Dental Journal 223, 559 (2017). doi:10.1038/sj.bdj.2017.911

Author: Tashfeen Kholasi

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Spreading the word about a devastating disease

British Dental Journal 223, 555 (2017). doi:10.1038/sj.bdj.2017.903

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BDA AGM

British Dental Journal 223, 559 (2017). doi:10.1038/sj.bdj.2017.913

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Biochemical and structural characterization of Marinomonas mediterranea D-mannose isomerase Marme_2490 phylogenetically distant from known enzymes

Publication date: Available online 26 October 2017
Source:Biochimie
Author(s): Wataru Saburi, Nongluck Jaito, Koji Kato, Yuka Tanaka, Min Yao, Haruhide Mori
d-Mannose isomerase (MI) reversibly isomerizes d-mannose to d-fructose, and is attractive for producing d-mannose from inexpensive d-fructose. It belongs to the N-acylglucosamine 2-epimerase (AGE) superfamily along with AGE, cellobiose 2-epimerase (CE), and aldose-ketose isomerase (AKI). In this study, Marinomonas mediterranea Marme_2490, showing low sequence identity with any known enzymes, was found to isomerize d-mannose as its primary substrate. Marme_2490 also isomerized d-lyxose and 4-OH d-mannose derivatives (d-talose and 4-O-monosaccharyl-d-mannose). Its activity for d-lyxose is known in other d-mannose isomerizing enzymes, such as MI and AKI, but we identified, for the first time, its activity for 4-OH d-mannose derivatives. Marme_2490 did not isomerize d-glucose, as known MIs do not, while AKI isomerizes both d-mannose and d-glucose. Thus, Marme_2490 was concluded to be an MI.The initial and equilibrium reaction products were analyzed by NMR to illuminate mechanistic information regarding the Marme_2490 reaction. The analysis of the initial reaction product revealed that β-d-mannose was formed. In the analysis of the equilibrated reaction products in D2O, signals of 2-H of d-mannose and 1-H of d-fructose were clearly detected. This indicates that these protons are not substituted with deuterium from D2O and Marme_2490 catalyzes the intramolecular proton transfer between 1-C and 2-C.The crystal structure of Marme_2490 in a ligand-free form was determined and found that Marme_2490 is formed by an (α/α)6-barrel, which is commonly observed in AGE superfamily enzymes. Despite diverse reaction specificities, the orientations of residues involved in catalysis and substrate binding by Marme_2490 were similar to those in both AKI (Salmonella enterica AKI) and epimerase (Rhodothermus marinus CE). The Marme_2490 structure suggested that the α7→α8 and α11→α12 loops of the catalytic domain participated in the formation of an open substrate-binding site to provide sufficient space to bind 4-OH d-mannose derivatives.



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A rational approach to enhancing antibody Fc homodimer formation for robust production of antibody mixture in a single cell line [Immunology]

Combinations of different antibodies have been shown to be more effective for managing certain diseases than monotherapy. Co-expression of the antibody mixture in a single cell line is key to reducing complexity during antibody development and manufacturing. However, co-transfection of multiple light and heavy chains into cells often leads to production of mismatched, heterodimeric by-products that are inactive, making the development of co-expression systems that robustly and efficiently produce highly active antibody mixtures a high priority. In this study, we modified the CH3 domain interface of the antibody fragment crystallizable (Fc) region by changing several charge pairs to create electrostatic interactions favoring Fc homodimer formation and disfavoring Fc heterodimer formation. When co-expressed, these modified antibodies with altered charge polarity across the Fc dimer interface preferentially formed homodimers that fully preserved the functions of each component, rather than inactive heterodimers whose formation was reduced because of rationally designed repulsive interactions. We designed eight different combinations and experimentally screened the best one, which enabled us to produce a binary antibody mixture against the EGF receptor with a minimal heterodimer contaminant. We further determined the crystal structure of a triple-mutated Fc variant in the best combination, and we elucidated the molecular interactions favoring Fc homodimer over heterodimer formation, which provided a structural basis for further optimization. The approach presented here demonstrates the feasibility of rational antibody modification for efficient and consistent production of monoclonal antibody mixtures in a single cell line and thus broadens our options for manufacturing more effective antibody-based therapeutic agents.

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Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes [Immunology]

Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro. In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo. We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 weeks to female nonobese diabetic (NOD) mice, beginning at 3 weeks of age, followed by twice-weekly injections until age 25 weeks, protects the animals from diabetes. The preservation of β-cells was because of a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro. All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing additional evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased numbers of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.

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The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription [Gene Regulation]

2,3,7,8-Tetrachlorodibenzo-p-dioxin and related compounds are extraordinarily potent environmental toxic pollutants. Most of the 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicities are mediated by aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor belonging to the basic helix-loop-helix (bHLH) Per-ARNT-Sim (PAS) family. Upon ligand binding, AhR forms a heterodimer with AhR nuclear translocator (ARNT) and induces the expression of genes involved in various biological responses. One of the genes induced by AhR encodes AhR repressor (AhRR), which also forms a heterodimer with ARNT and represses the activation of AhR-dependent transcription. The control of AhR activation is critical for managing AhR-mediated diseases, but the mechanisms by which AhRR represses AhR activation remain poorly understood, because of the lack of structural information. Here, we determined the structure of the AhRR–ARNT heterodimer by X-ray crystallography, which revealed an asymmetric intertwined domain organization presenting structural features that are both conserved and distinct among bHLH-PAS family members. The structures of AhRR–ARNT and AhR–ARNT were similar in the bHLH-PAS-A region, whereas the PAS-B of ARNT in the AhRR–ARNT complex exhibited a different domain arrangement in this family reported so far. The structure clearly disclosed that AhRR competitively represses AhR binding to ARNT and target DNA and further suggested the existence of an AhRR–ARNT-specific repression mechanism. This study provides a structural basis for understanding the mechanism by which AhRR represses AhR-mediated gene transcription.

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SOCS1 is an inducible negative regulator of interferon {lambda} (IFN-{lambda})-induced gene expression in vivo [Signal Transduction]

Type I (α and β) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis. Type I IFN signaling is controlled by the inducible negative regulators suppressor of cytokine signaling 1 (SOCS1), SOCS3, and ubiquitin-specific peptidase 18 (USP18). The physiological role of these proteins in IFN-γ signaling has not been clarified. Here we used knockout cell lines and mice to show that IFN-λ signaling is regulated by SOCS1 but not by SOCS3 or USP18. These differences were the basis for the distinct kinetic properties of type I and III IFNs. We found that IFN-α signaling is transient and becomes refractory after hours, whereas IFN-λ provides a long-lasting IFN-stimulated gene induction.

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Switch I-dependent allosteric signaling in a G-protein chaperone-B12 enzyme complex [Enzymology]

G-proteins regulate various processes ranging from DNA replication and protein synthesis to cytoskeletal dynamics and cofactor assimilation and serve as models for uncovering strategies deployed for allosteric signal transduction. MeaB is a multifunctional G-protein chaperone, which gates loading of the active 5′-deoxyadenosylcobalamin cofactor onto methylmalonyl-CoA mutase (MCM) and precludes loading of inactive cofactor forms. MeaB also safeguards MCM, which uses radical chemistry, against inactivation and rescues MCM inactivated during catalytic turnover by using the GTP-binding energy to offload inactive cofactor. The conserved switch I and II signaling motifs used by G-proteins are predicted to mediate allosteric regulation in response to nucleotide binding and hydrolysis in MeaB. Herein, we targeted conserved residues in the MeaB switch I motif to interrogate the function of this loop. Unexpectedly, the switch I mutations had only modest effects on GTP binding and on GTPase activity and did not perturb stability of the MCM–MeaB complex. However, these mutations disrupted multiple MeaB chaperone functions, including cofactor editing, loading, and offloading. Hence, although residues in the switch I motif are not essential for catalysis, they are important for allosteric regulation. Furthermore, single-particle EM analysis revealed, for the first time, the overall architecture of the MCM–MeaB complex, which exhibits a 2:1 stoichiometry. These EM studies also demonstrate that the complex exhibits considerable conformational flexibility. In conclusion, the switch I element does not significantly stabilize the MCM–MeaB complex or influence the affinity of MeaB for GTP but is required for transducing signals between MeaB and MCM.

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{beta}-Catenin directs the transformation of testis Sertoli cells to ovarian granulosa-like cells by inducing Foxl2 expression [Gene Regulation]

Sertoli and granulosa cells are two major types of somatic cells in male and female gonads, respectively. Previous studies have shown that Sertoli and granulosa cells are derived from common progenitor cells and that differentiation of these two cell types is regulated by sex differentiation genes. The signaling pathway including the adhesion and transcription factor Ctnnb1 (cadherin-associated protein, β1, also known as β-catenin) regulates differentiation of granulosa cells in the absence of the transcription factor Sry, and overactivation of β-catenin in the presence of Sry leads to granulosa prior to sex determination. Surprisingly, our previous study found that β-catenin overactivation in Sertoli cells after sex determination can also cause disruption of the testicular cord and aberrant testis development. However, the underlying molecular mechanism was unclear. In this study, we found that constitutive activation of Ctnnb1 in Sertoli cells led to ectopic expression of the granulosa cell-specific marker FOXL2 in testes. Co-staining experiments revealed that FOXL2-positive cells were derived from Sertoli cells, and Sertoli cells were transformed into granulosa-like cells after Ctnnb1 overactivation. Further studies demonstrated that CTNNB1 induced Foxl2 expression by directly binding to transcription factor Tcf/Lef-binding sites in the FOXL2 promoter region. We also found that direct overexpression of Foxl2 decreased the expression of Sertoli cell-specific genes in primary Sertoli cells. Taken together, these results demonstrate that repression of β-catenin (CTNNB1) signaling is required for lineage maintenance of Sertoli cells. Our study provides a new mechanism for Sertoli cell lineage maintenance during gonad development.

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Structural analyses of the Haemophilus influenzae peptidoglycan synthase activator LpoA suggest multiple conformations in solution [Microbiology]

In many Gram-negative bacteria, the peptidoglycan synthase PBP1A requires the outer membrane lipoprotein LpoA for constructing a functional peptidoglycan required for bacterial viability. Previously, we have shown that the C-terminal domain of Haemophilus influenzae LpoA (HiLpoA) has a highly conserved, putative substrate-binding cleft between two α/β lobes. Here, we report a 2.0 Å resolution crystal structure of the HiLpoA N-terminal domain. Two subdomains contain tetratricopeptide-like motifs that form a concave groove, but their relative orientation differs by ∼45° from that observed in an NMR structure of the Escherichia coli LpoA N domain. We also determined three 2.0–2.8 Å resolution crystal structures containing four independent full-length HiLpoA molecules. In contrast to an elongated model previously suggested for E. coli LpoA, each HiLpoA formed a U-shaped structure with a different C-domain orientation. This resulted from both N-domain twisting and rotation of the C domain (up to 30°) at the end of the relatively immobile interdomain linker. Moreover, a previously predicted hinge between the lobes of the LpoA C domain exhibited variations of up to 12°. Small-angle X-ray scattering data revealed excellent agreement with a model calculated by normal mode analysis from one of the full-length HiLpoA molecules but even better agreement with an ensemble of this molecule and two of the partially extended normal mode analysis-predicted models. The different LpoA structures helped explain how an outer membrane-anchored LpoA can either withdraw from or extend toward the inner membrane-bound PBP1A through peptidoglycan gaps and hence regulate the synthesis of peptidoglycan necessary for bacterial viability.

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Compositional and expression analyses of the glideosome during the Plasmodium life cycle reveal an additional myosin light chain required for maximum motility [Microbiology]

Myosin A (MyoA) is a Class XIV myosin implicated in gliding motility and host cell and tissue invasion by malaria parasites. MyoA is part of a membrane-associated protein complex called the glideosome, which is essential for parasite motility and includes the MyoA light chain myosin tail domain–interacting protein (MTIP) and several glideosome-associated proteins (GAPs). However, most studies of MyoA have focused on single stages of the parasite life cycle. We examined MyoA expression throughout the Plasmodium berghei life cycle in both mammalian and insect hosts. In extracellular ookinetes, sporozoites, and merozoites, MyoA was located at the parasite periphery. In the sexual stages, zygote formation and initial ookinete differentiation precede MyoA synthesis and deposition, which occurred only in the developing protuberance. In developing intracellular asexual blood stages, MyoA was synthesized in mature schizonts and was located at the periphery of segmenting merozoites, where it remained throughout maturation, merozoite egress, and host cell invasion. Besides the known GAPs in the malaria parasite, the complex included GAP40, an additional myosin light chain designated essential light chain (ELC), and several other candidate components. This ELC bound the MyoA neck region adjacent to the MTIP-binding site, and both myosin light chains co-located to the glideosome. Co-expression of MyoA with its two light chains revealed that the presence of both light chains enhances MyoA-dependent actin motility. In conclusion, we have established a system to study the interplay and function of the three glideosome components, enabling the assessment of inhibitors that target this motor complex to block host cell invasion.

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A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding [Molecular Biophysics]

N-terminal histone tails are subject to many posttranslational modifications that are recognized by and interact with designated reader domains in histone-binding proteins. BROMO domain adjacent to zinc finger 2B (BAZ2B) is a multidomain histone-binding protein that contains two histone reader modules, a plant homeodomain (PHD) and a bromodomain (BRD), linked by a largely disordered linker. Although previous studies have reported specificity of the PHD domain for the unmodified N terminus of histone H3 and of the BRD domain for H3 acetylated at Lys14 (H3K14ac), the exact mode of H3 binding by BAZ2B and its regulation are underexplored. Here, using isothermal titration calorimetry and NMR spectroscopy, we report that acidic residues in the BAZ2B PHD domain are essential for H3 binding and that BAZ2B PHD–BRD establishes a polyvalent interaction with H3K14ac. Furthermore, we provide evidence that the disordered interdomain linker modulates the histone-binding affinity by interacting with the PHD domain. In particular, lysine-rich stretches in the linker, which resemble the positively charged N terminus of histone H3, reduce the binding affinity of the PHD finger toward the histone substrate. Phosphorylation, acetylation, or poly(ADP-ribosyl)ation of the linker residues may therefore act as a cellular mechanism to transiently tune BAZ2B histone-binding affinity. Our findings further support the concept of interdomain linkers serving a dual role in substrate binding by appropriately positioning the adjacent domains and by electrostatically modulating substrate binding. Moreover, inhibition of histone binding by a histone-mimicking interdomain linker represents another example of regulation of protein–protein interactions by intramolecular mimicry.

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Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment-maintaining phosphoprotein (CAMP) [DNA and Chromosomes]

Mitotic arrest deficient 2–like protein 2 (MAD2L2), also termed MAD2B or REV7, is involved in multiple cellular functions including translesion DNA synthesis (TLS), signal transduction, transcription, and mitotic events. MAD2L2 interacts with chromosome alignment–maintaining phosphoprotein (CAMP), a kinetochore-microtubule attachment protein in mitotic cells, presumably through a novel "WK" motif in CAMP. Structures of MAD2L2 in complex with binding regions of the TLS proteins REV3 and REV1 have revealed that MAD2L2 has two faces for protein–protein interactions that are regulated by its C-terminal region; however, the mechanisms underlying the MAD2L2–CAMP interaction and the mitotic role of MAD2L2 remain unknown. Here we have determined the structures of human MAD2L2 in complex with a CAMP fragment in two crystal forms. The overall structure of the MAD2L2–CAMP complex in both crystal forms was essentially similar to that of the MAD2L2–REV3 complex. However, the residue interactions between MAD2L2 and CAMP were strikingly different from those in the MAD2L2–REV3 complex. Furthermore, structure-based interaction analyses revealed an unprecedented mechanism involving CAMP's WK motif. Surprisingly, in one of the crystal forms, the MAD2L2–CAMP complex formed a dimeric structure in which the C-terminal region of MAD2L2 was swapped and adopted an immature structure. The structure provides direct evidence for the dynamic nature of MAD2L2 structure, which in turn may have implications for the protein–protein interaction mechanism and the multiple functions of this protein. This work is the first structural study of MAD2L2 aside from its role in TLS and might pave the way to clarify MAD2L2's function in mitosis.

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Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation [Bioenergetics]

Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. Moreover, METTL12 was strongly inhibited by the reaction product S-adenosylhomocysteine (AdoHcy). In summary, we have uncovered a novel human mitochondrial KMT that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues. Based on the established naming nomenclature for similar enzymes, we suggest that METTL12 be renamed CS-KMT (gene name CSKMT).

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The Rho ADP-ribosylating C3 exoenzyme binds cells via an Arg-Gly-Asp motif [Membrane Biology]

The Rho ADP-ribosylating C3 exoenzyme (C3bot) is a bacterial protein toxin devoid of a cell-binding or -translocation domain. Nevertheless, C3 can efficiently enter intact cells, including neurons, but the mechanism of C3 binding and uptake is not yet understood. Previously, we identified the intermediate filament vimentin as an extracellular membranous interaction partner of C3. However, uptake of C3 into cells still occurs (although reduced) in the absence of vimentin, indicating involvement of an additional host cell receptor. C3 harbors an Arg–Gly–Asp (RGD) motif, which is the major integrin-binding site, present in a variety of integrin ligands. To check whether the RGD motif of C3 is involved in binding to cells, we performed a competition assay with C3 and RGD peptide or with a monoclonal antibody binding to β1-integrin subunit and binding assays in different cell lines, primary neurons, and synaptosomes with C3-RGD mutants. Here, we report that preincubation of cells with the GRGDNP peptide strongly reduced C3 binding to cells. Moreover, mutation of the RGD motif reduced C3 binding to intact cells and also to recombinant vimentin. Anti-integrin antibodies also lowered the C3 binding to cells. Our results indicate that the RGD motif of C3 is at least one essential C3 motif for binding to host cells and that integrin is an additional receptor for C3 besides vimentin.

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Specialized function of yeast Isa1 and Isa2 proteins in the maturation of mitochondrial [4Fe-4S] proteins. [Additions and Corrections]

VOLUME 286 (2011) PAGES 41205–41216There were several errors in this article. In Fig. 2E, the Rip1 immunoblots from Gal-ISA1 and Gal-ISU1 cells were unintentionally duplicated. In Fig. 3E, the Lys4-HA immunoblots were inadvertently mixed up. Additionally, the wrong Isa2 immunoblot for Gal-ISA2 cells was used. In Fig. 7B, the top portion showed the wrong immunoblot for the porin loading control. Both the porin and Isa1 immunoblots were replaced from a replicate experiment. In the lower portion of Fig. 7B, the two immunoblots were accidentally flipped horizontally. These errors have now been corrected and do not affect the results or conclusions of the work.jbc;292/43/17979/FU1F1FU1jbc;292/43/17979/FU2F2FU2jbc;292/43/17979/FU3F3FU3

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The transcription factor HOXB7 regulates ERK kinase activity and thereby stimulates the motility and invasiveness of pancreatic cancer cells [Signal Transduction]

HOX genes encode transcription factors that function as sequence-specific transcription factors that are involved in cellular proliferation, differentiation, and death. The aim of this study was to investigate the role of a HOX family protein, HOXB7, in the motility and invasiveness of pancreatic cancer cells. We previously identified a HOXB7 transcript that is one of a number of transcripts that are preferentially translated in membrane protrusions in pancreatic cancer cells. Immunocytochemistry showed that HOXB7 was localized to the cell protrusions of migrating pancreatic cancer cells. Knockdown of HOXB7 by transfection with HOXB7-specific siRNA decreased these protrusions and inhibited the motility and invasiveness of the cells. Transfection of a HOXB7-rescue construct into the HOXB7-knockdown cells restored peripheral actin structures in cell protrusions and abrogated the HOXB7 knockdown–induced decrease in cell protrusions. It is generally accepted that the Rho family of GTPases regulate the organization of actin filaments and contribute to the formation of cell protrusions. The levels of the active Rho GTPases were not influenced by HOXB7 in the cells; however, HOXB7 knockdown decreased the level of phosphorylated ERK1/2. This inactivation of ERK1/2 decreased cell protrusions, thereby inhibiting the invasiveness of pancreatic cancer cells. Further investigation showed that HOXB7/ERK1/2 signaling selectively stimulated JNK and HSP27 phosphorylation and thereby increased the motility and invasiveness of pancreatic cancer cells. These results suggested that HOXB7 stimulates ERK1/2 phosphorylation and provided evidence that HOXB7, besides its role in transcriptional regulation, also promotes cell motility and invasiveness.

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PI3K/Akt/mTOR pathway involvement in regulating growth hormone secretion in a rat pituitary adenoma cell line

Abstract

Purpose

Insulin-like growth factor 1 (IGF1) controls growth hormone (GH) secretion via a negative feed-back loop that may disclose novel mechanisms possibly useful to control GH hyper-secretion. Our aim was to understand whether PI3K/Akt/mTOR pathway is involved in IGF1 negative feedback on GH secretion.

Methods

Cell viability, GH secretion, Akt, and Erk 1/2 phosphorylation levels in the rat GH3 cell line were assessed under treatment with IGF1 and/or everolimus, an mTOR inhitior.

Results

We found that IGF1 improves rat GH3 somatotroph cell viability via the PI3K/Akt/mTOR pathway and confirmed that IGF1 exerts a negative feedback on GH secretion by a transcriptional mechanism. We demonstrated that the negative IGF1 loop on GH secretion requires Akt activation that seems to play a pivotal role in the control of GH secretion. Furthermore, Akt activation is independent of PI3K and probably mediated by mTORC2. In addition, we found that Erk 1/2 is not involved in GH3 cell viability regulation, but may have a role in controlling GH secretion, independently of IGF1.

Conclusion

Our data confirm that mTOR inhibitors may be useful to reduce pituitary adenoma cell viability, while Erk 1/2 pathway may be considered as a useful therapeutic target to control GH secretion. Our results open the field for further studies searching for effective drugs to control GH hyper-secretion.

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Corrigendum

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SOCIETY NEWS

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Issue Information

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Achieving a 'top-down change agenda by driving and supporting a collaborative 'bottom-up process: case study of a large-scale enhanced recovery programme

There is increasing recognition that organisations need to look beyond their boundaries for new innovations. However, the introduction and implementation of best practice that has been developed externally may need different processes of implementation if a successful change process is going to be achieved. Using an enhanced recovery programme as an example, we report a case study that combines the best of a top-down approach with the principles of bottom-up collaborative working to successfully embed a large-scale quality improvement programme that was commissioned to improve the adoption of enhanced recovery in elective surgery. We describe a large-scale change programme that was established, coordinated and driven from within a central 'top' organisation but delivered and owned locally by individual organisations working collaboratively across southeast region of England. We discuss why we believe our methodology of implementing this programme was successful, the important triggers for success and the lessons we learned from the programme.

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Effectiveness of a multi-component quality improvement intervention on rates of hyperglycaemia

Purpose

To evaluate the effectiveness of a multifaceted, hospital-wide glycaemic control quality improvement programme.

Methods

The quality improvement intervention comprised three components, derived through root cause analysis: standardising and simplifying care (including evidence-based order sets), increasing visibility (through provider access to clinical data and direct feedback) and educational outreach (directed at the entire institution). Effectiveness was determined at a single urban acute care hospital through time-series analysis with statistical process control charts. Primary outcomes included rate of hyperglycaemia and rate of hypoglycaemia.

Results

The study included 70 992 hospital admissions for 50 404 patients, with 3 35 645 patient days. The hyperglycaemia ratio decreased 25.2% from 14.1% to 10.5% (95% CI 3.3 to 3.9 percentage points, p<0.001). The ratio of patient days with highly elevated blood glucose (>299 mg/dL) decreased 31.8% from 4.8% to 3.3% (95% CI 1.4 to 1.7 percentage points, p<0.001). Hypoglycaemia ratio decreased from 5.2% to 4.6% (95% CI 0.27 to 0.89 percentage points, p<0.001) in patients with diabetes, but increased in patients without diabetes from 1.2% to 1.7% (95% CI 0.46 to 0.70 percentage points, p<0.001).

Conclusions

We demonstrate improved hospital-wide glycaemic control after a multifaceted quality improvement intervention in the context of strong institutional commitment, national mentorship and Lean management

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Improving handover between triage and locality wards in a large mental health trust

Background

South London and Maudsley NHS Foundation Trust is the largest mental health trust in the UK, serving four boroughs in South East London. In 2014, the 'triage ward' system was introduced in three boroughs. Similar to an acute medical admission unit, the triage ward would rapidly assess and treat all new admissions. The patients would either be discharged or admitted to a 'locality ward' for further treatment.

Problem

The unforeseen consequences of the 'triage ward' system were duplications and omissions of medical tasks on receiving wards, which affected efficiency and quality of care. This was due to a lack of formal medical handover. We aimed to improve efficiency and patient safety by formalising the junior doctor handover between triage and locality wards, ensuring every patient transferred had a documented handover in their electronic notes.

Method

We consulted our colleagues with a survey, ascertaining their views on the current system, the need for a more formalised system and what form that system should take. Using their feedback, we devised a handover template, to be completed for all patients transferred to locality wards. We then rolled the project out to the other two boroughs using the same methodology.

Results

A follow-up survey showed improvement in our baseline results and that the majority of transferred patients were formally handed over. Serious incident data showed a decrease in incident rates pre-intervention and post-intervention. The intervention was sustained a year later. The transfer of the intervention to other sites was problematic.

Discussion

The project showed the lack of handover was a concern shared by colleagues, and they considered our template a useful way of addressing this. The results suggested that the intervention was sustainable despite frequent rotations of staff. The difficulties in transferring an intervention to new sites are discussed.

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Reducing medical-surgical inpatient falls and injuries with videos, icons and alarms

Background

Inpatient falls and subsequent injuries are among the most common hospital-acquired conditions with few effective prevention methods.

Objective

To evaluate the effectiveness of patient education videos and fall prevention visual signalling icons when added to bed exit alarms in improving acutely hospitalised medical-surgical inpatient fall and injury rates.

Design

Performance improvement study with historic control.

Setting

Four medical-surgical units in one US public acute care hospital.

Study participants

Adult medical-surgical inpatients units.

Interventions

A 4 min video was shown to patients by trained volunteers. Icons of individual patient risk factors and interventions were placed at patients' bedsides. Beds with integrated three-mode sensitivity exit alarms were activated for confused patients at risk of falling.

Main outcome measures

The main outcome measure is the incident rate per 1000 patient days (PDs) for patient falls, falls with any injury and falls with serious injury. The incident rate ratio (IRR) for each measure compared January 2009–September 2010 (baseline) with the follow-up period of January 2015–December 2015 (intervention).

Results

Falls decreased 20% from 4.78 to 3.80 per 1000 PDs (IRR 0.80, 95% CI 0.66 to 0.96); falls with any injury decreased 40% from 1.01 to 0.61 per 1000 PDs (IRR 0.60, 95% CI 0.38 to 0.94); and falls with serious injury 85% from 0.159 to 0.023 per 1000 PDs (IRR 0.15, 95% CI 0.01 to 0.85). Icons were not fully implemented.

Conclusion

The first known significant reduction of falls, falls with injury and falls with serious injury among medical-surgical inpatients was achieved. Patient education and continued use of bed exit alarms were associated with large decreases in injury. Icons require further testing. Multicentre randomised controlled trials are needed to confirm the effectiveness of icons and video interventions and exit alarms.

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Liver-related morbidity and mortality in patients with chronic hepatitis C and cirrhosis with and without sustained virologic response

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The Impact of Intraoperative Magnetic Resonance Imaging on Patient Safety Management During Awake Craniotomy.

Background: Awake craniotomy paired with intraoperative magnetic resonance imaging (iMRI) is now the established technique for maximizing surgical resection, while preserving neurological function. However, leaving an unsecured airway patient in the iMRI gantry represents considerable risk. Our study aimed at identifying the incidence of critical adverse events in unsecured airway patients during iMRI as part of awake craniotomy. Materials and Methods: We conducted a clinical chart review of consecutive awake craniotomies performed between November 1999 and December 2015. Sequences of iMRI performed without invasive airway management were selected for assessment and the incidence of critical adverse events, including general convulsive seizure, respiratory arrest, nausea/vomiting and agitation, was identified. Results: Critical adverse events occurred in 21 of 356 unsecured airway patients within 24 of the 579 iMRI sequences. In cases using the low-field strength open MRI scanner, emergency termination of scans due to patient decline was recorded in only 4 cases: no cases of cardiac arrest, accidental death, or thermal injury were recorded. Compared with cardiovascular monitoring, patient respiratory status was poorly recorded. Conclusions: In terms of anesthesia, concurrent use of iMRI for awake craniotomy is clinically acceptable providing potential intraoperative complications can be controlled. Further, the configuration of the iMRI scanner as well as the reduced exposure from the lower magnetic field strength was found to impact patient safety management. Therefore when a conscious patient is left in the gantry without airway support, it is advisable that levels of oxygenation and ventilation should be monitored at all times. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Pneumothorax Following Rib Graft: An Atypical Presentation.

No abstract available

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Intraoperative Spinal Cord Pulsations: A Good Sign or a Disaster Waiting to Happen?.

No abstract available

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Radiographic Predictors of Difficult Laryngoscopy in Acromegaly Patients.

Background: Patients with acromegaly have a high risk of difficult laryngoscopy. However, clinical predictors, such as upper lip bite test or modified Mallampati class, show limited predictive performance for difficult laryngoscopy in such patients. In this retrospective study, we evaluated radiographic indices obtained from skull lateral x-ray and ostiomeatal unit computed tomography images to predict difficult laryngoscopy in acromegaly patients. Materials and Methods: Data on demographics, preoperative serum levels of pituitary hormones, and radiographic indices were collected from 90 acromegaly patients that underwent transsphenoidal removal for pituitary tumor from January 2010 to December 2016. Difficult laryngoscopy was defined as Cormack-Lehane grade >=III. Results: Difficult laryngoscopy occurred in 21 (23%) patients. In univariate analysis, age and radiographic indices indicating tongue size, such as tongue area (TA) on ostiomeatal unit computed tomography, linear distance from the alveolar line of the mandible to the hyoid bone, and linear distance from the interior border of the mandible to the hyoid bone on skull lateral x-ray, were associated with difficult laryngoscopy. In multivariate analysis, age (odds ratio [95% confidence interval], 1.084 [1.037-1.190]; P=0.002) and TA (1.002 [1.000-1.003], P=0.014) were independent risk factors for difficult laryngoscopy. The area under the curve of the combined model of age and TA was 0.80. Conclusions: Old age and radiographic predictors indicating large tongue size (large TA, long alveolar line of the mandible to the hyoid bone and mandible to the hyoid bone) were associated with an increased rate of difficult laryngoscopy in acromegaly patients. Preoperative radiographic measurements of tongue size can be helpful for safe airway management in such patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Patient feedback for acupuncture practice improvement: A survey from Mayo Clinic

Abstract

Objective

To understand patient satisfaction with acupuncture appointment duration for the first and subsequent appointments in the plan of care, time spent with the acupuncture provider, willingness to pay for longer duration appointments, and lack of insurance coverage.

Methods

Patients who were referred for an acupuncture consult to the Center for Integrative Medicine at Mayo Clinic were asked to participate in the survey in August 2014. Patients were given paper survey at time of appointment check-in and entered into Research Electronic Data Capture Survey database tool to reveal patient-reported outcomes.

Results

In total, 104 of 329 patients receiving acupuncture treatment responded to the survey with a 32% response rate. Insight and recommended changes to the duration of the initial and subsequent appointments were obtained. Most patients reported that time spent with the provider (76 cases, 74%) and appointment length (74 cases, 68%) were "just right". Seventy cases (70%) of respondents indicated that they wanted longer treatment. Patients reported return appointments with duration of 30 min was not enough. Fifty-three patients (62%) were willing to pay for additional costs not covered by insurance.

Conclusions

We used patient feedback to assess the acupuncture practice in a complementary and integrative medicine program. Most patients referred for the acupuncture consult appeared to be satisfied with the current level of practice. These findings were used to establish a quality improvement plan that may be implemented to improve patient satisfaction with the acupuncture practice.

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Pivotal factors concerned in design of acupuncture clinical research: From two articles in JAMA

Abstract

Two randomized controlled trials of acupuncture concerning polycystic ovary syndrome (PCOS) and stress urinary incontinence (SUI) were published simultaneously in the 24th issue, 2017 of The Journal of the American Medical Association (JAMA). A trial involving PCOS indicated that active acupuncture did not increase live birth compared with sham acupuncture; meanwhile, another trial referring to SUI showed that electroacupuncture resulted in less urine leakage compared with sham electroacupuncture. With an eye to the negative and positive results of acupuncture, three pivotal factors should be contemplated: (1) proper illness for acupuncture, that is, a problem need to be solved in current medical science, and acupuncture may really work for it; (2) proper pre-studied primary outcome, which is better be objective and repeatedly measurable to reveal the therapeutic effect of acupuncture truly and objectively; (3) proper sham control, which can blind the patients to the upmost extent with minimal biological effects. Through the publication of clinical trials of acupuncture in high-impact journals in recent years, researchers should have confidence in their clinical trials by pondering over these three pivotal factors.

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Nitric oxide signaling molecules in acupoints: Toward mechanisms of acupuncture

Abstract

Recent clinical trial studies have demonstrated that the effects of acupuncture on pain improvement are small and no difference between acupoints and non-points. Whether acupuncture needles must be inserted in specific points depends on whether acupoint specificity exists that is still not resolved, and is now urgent. Previous anatomical studies have demonstrated that acupoints exist higher number of nerve fibers/trunks, blood vessels, hair follicles, and sweat glands as well as density of the gap junction. Recent evidence shows that nitric oxide (NO) level is elevated in the acupoints/ meridians and is associated with an enhanced expression of NO synthase endowed with transient receptor potential vanilloid type-1. There is growing evidence from international groups showing that acupuncture induces NO-mediated vasodilatation, which increases local blood flow and allows for a flush of algesic or sensitizing substances, leading to pain relief. Previous studies, using a novel biocapture system, have demonstrated that NOx^– (total nitrite and nitrate) and cyclic guanosine monophosphate (cGMP) concentrations are consistently increased over skin acupoints compared to non-meridian control regions (NMCR) in humans. Dermal microdialysis in humans showed that NO-cGMP releases in the subcutaneous tissue of acupoint are higher than those in NMCR and increased by electroacupuncture (EA). Recent studies have demonstrated that low-frequency electrical stimulation and manual acupuncture with low stimulating force and rate produce an elevation of NO release predominantly over acupoints. In contrast, NO levels over the areas of the skin regions are moderately reduced by high-frequency EA stimulation. The results from anatomical and biochemical studies consistently show that acupoints exist higher levels of NO signaling molecules, and stimulus-evoked NO release is also with a higher level at acupoints. Results suggest that NO signaling molecules contribute to the specificity of acupoints, and selecting well-trained acupuncturetists for using correct acupoints and appropriate parameters should improve acupuncture clinical trial studies.

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To be, or not to be: The calculated politics of acupuncture in JAMA

Abstract

Ten acupuncture-related articles were published in The Journal of the American Medical Association (JAMA) between 1998 and 2017. Five studies showed positive results in terms of the effectiveness of acupuncture/Chinese medicine (CM); five studies showed negative results. This article summarizes the acupuncturerelated clinical trials published over the last 20 years in JAMA, and addresses what seems to be a fundamental ambivalence in Western medical journals regarding the scientific validity of acupuncture/CM. As yet there has been no consensus on the role of acupuncture in healthcare in Western countries. This is hardly surprising, considering the conflicting evidence found in published studies. Skepticism regarding acupuncture/CM is largely grounded in the fact that an accurate model for assessing the true clinical effects of acupuncture has yet to be created. This article discusses some of the pitfalls which result from applying Western-based scientific principles to CM, and suggests that in many cases, "negative" studies have been misinterpreted. The clinical experience of acupuncture practitioners is often in direct conflict with many of the negative conclusions published in journals. We are in need of an accurate model for sham and placebo treatments, and must analyze all published studies for design flaws and faulty conclusions.

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Acupuncture treatment for idiopathic trigeminal neuralgia: A longitudinal case-control double blinded study

Abstract

Objective

To evaluate the treatment effect of acupuncture on patients with idiopathic trigeminal neuralgia (ITN) by case-control longitudinal blinded study.

Methods

Sixty ITN patients and 30 healthy subjects were included. The ITN patients were randomly assigned to acupuncture group (15 cases), sham-acupuncture group (15 cases) and carbamazepine group (30 cases), respectively. Clinical orofacial evaluation (including pain intensity and medication doses), research diagnostic criteria for temporomandibular disorders (RDC/TMD) and Helkimo indexes (for functional evaluation of the masticatory system), and quantitative sensory testing for sensory thresholds (gustative, olfactory, cold, warm, touch, vibration and superficial and deep pain) were evaluated before treatment, immediately after treatment, and 6 months after treatment.

Results

The mean pain intensity by the Visual Analogue Scale only decreased in the acupuncture group at the last evaluation (P=0.012). Patients in the sham-acupuncture group had an increase in carbamazepine doses according to the prescriptions (P<0.01). There was a reduction in secondary myofascial pain and mandibular limitations at the acupuncture and sham-acupuncture groups, however only the acupuncture group kept the changes after 6 months (P<0.01, P=0.023). There was a decrease in mechanical thresholds in the acupuncture group (tactile, P<0.01; vibration, P=0.027) and an increase in deep pain thresholds in both acupuncture and sham-acupuncture groups (P=0.013).

Conclusions

Acupuncture can be an option in the treatment of ITN due to its analgesic effect in both ITN and secondary myofascial pain associated with it.

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Who Receives Nalmefene and How Does It Work in the Real World? A Single-Arm, Phase IV Study of Nalmefene in Alcohol Dependent Outpatients: Baseline and 1-Month Results

Abstract

Background

Alcohol dependence remains a major health problem from both a public health and clinical perspective. Harm reduction strategies have been increasingly recognized as suitable treatment goals. Nalmefene has been recently approved for this precise therapeutic indication after completion of phase III trials. However, more data from routine practice settings are needed in order to obtain evidence with high external validity. The aim of this study was to conduct a single-arm, phase IV study with alcohol-dependent outpatients starting nalmefene for the first time.

Methods

An observational, multisite, single-arm, phase IV study was conducted among adult alcohol-dependent outpatients who received nalmefene for the first time. The study consisted of four visits: baseline, 4 weeks (referred to as 1 month hereafter), 6 and 12 months. At each visit, drinking variables were obtained from the Timeline Followback regarding the previous month. Satisfaction with medication was also assessed for both patients and professionals, with the Medication Satisfaction Questionnaire. A repeated measures mixed model was performed for effectiveness analysis regarding drinking outcomes (reduction in total alcohol consumption and number of heavy drinking days). Regression analyses were performed in order to find predictors of response to nalmefene.

Results

A total of 110 patients were included, with 88 reporting data at the 1-month visit. On average, patients took nalmefene 68% of the days. The number of heavy drinking days decreased from 13.5 to 6.8 days/month, and total alcohol consumption decreased from 169 to 79 units. For both outcomes, significant reductions at 1 month were found, with no other significant variables reaching significance. Thirty-seven patients were considered medication responders, but given the high presence of low-risk drinkers in our sample, no significant predictors could be found. Satisfaction was globally high for both professionals and patients, and overall nalmefene was well tolerated, with no serious adverse events reported.

Conclusion

The data provided by this phase IV study suggest nalmefene is an effective, well-tolerated treatment for alcohol dependence in real-world, clinical settings.

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Introductory Head and Neck Imaging (1st Edition) provides housestaff with a worthwhile introductory text,...

Introductory Head and Neck Imaging (1st Edition) provides housestaff with a worthwhile introductory text, helpful for shelf exams, board review, or as a pocket refernce. This well-written and succinct neuroradiology textbook highlights the imaging intracacies of head and neck anatomy for medical students, residents, fellows, and attendings seeking to expand their knowledge base and interpretative skills.

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Editorial Board

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Table of Contents

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Editorial Board

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Prognostic role of neutrophil-to-lymphocyte ratio in head and neck cancer: A meta-analysis

Abstract

Background

Neutrophils play substantial roles in cancer progression. Previous reports demonstrated the prognostic impact of the pretreatment neutrophil-to-lymphocyte ratio (NLR) in various types of solid cancers. The purpose of this study was to quantify the prognostic impact of NLR on head and neck squamous cell carcinoma (HNSCC).

Methods

We systematically searched electronic databases, identified articles regarding NLR and HNSCC mortality, and extracted hazard ratios (HRs) and 95% confidence intervals (CIs). Pooled HRs for overall survival (OS) and disease-specific survival (DSS) were estimated using random effect models.

Results

Nineteen studies enrolling 3770 patients were included in the analyses. Overall, NLR greater than the cutoff value was associated with poorer OS and DSS (HR 1.69; 95% CI 1.47-1.93; P < .001 and HR 1.88; 95% CI 1.20-2.95; P = .006, respectively).

Conclusion

Elevated NLR predicts worse outcomes in patients with HNSCC.

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Heterotopic thyroid autotransplantation: A preliminary clinical study

Abstract

Background

Thyroid autotransplantation offers an attractive alternative to subtotal thyroidectomy and replacement therapy. However, it has not been sufficiently clinically investigated.

Methods

Total thyroidectomy was performed for 20 patients with benign thyroid disorders, and at least 10 g of thyroid tissue were implanted intramuscularly. Graft monitoring was achieved through ^99mTc scan at 2 months, free triiodothyronine (FT3), FT4, and thyroid-stimulating hormone (TSH) measurements at 1, 2, 4, 6, 8, 10, and 12 months postoperatively, and clinical examination.

Results

Grafts survived and gradually functioned in all patients to a variable extent after a latent period (mean ^99mTc uptake = 1.28 ± 0.37%). Mean values for FT3, FT4, TSH at 12 months were 1.75 ± 0.48 pg/mL, 1.06 ± 0.26 ng/dL, and 28.08 ± 34.01 μIU/mL respectively.

Conclusion

Thyroid autotransplantation restored euthyroid status in 33.3% of patients after 12 months. A role of age, operative time, and ^99mTc-uptake in determining the final graft outcome is possible.

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AHNS Series: Do you know your guidelines? Review of current knowledge on laryngeal cancer

Abstract

The following article is part of a series in an initiative by the American Head and Neck Society's Education Committee and will review clinical practice guidelines for head and neck oncology. The primary goal is to increase awareness of current best practices pertaining to head and neck surgery and oncology. This manuscript is a review of current knowledge in laryngeal cancer with a focus on anatomy, epidemiology, diagnosis, evaluation, and treatment.

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Prognostic role of neutrophil-to-lymphocyte ratio in head and neck cancer: A meta-analysis

Abstract

Background

Neutrophils play substantial roles in cancer progression. Previous reports demonstrated the prognostic impact of the pretreatment neutrophil-to-lymphocyte ratio (NLR) in various types of solid cancers. The purpose of this study was to quantify the prognostic impact of NLR on head and neck squamous cell carcinoma (HNSCC).

Methods

We systematically searched electronic databases, identified articles regarding NLR and HNSCC mortality, and extracted hazard ratios (HRs) and 95% confidence intervals (CIs). Pooled HRs for overall survival (OS) and disease-specific survival (DSS) were estimated using random effect models.

Results

Nineteen studies enrolling 3770 patients were included in the analyses. Overall, NLR greater than the cutoff value was associated with poorer OS and DSS (HR 1.69; 95% CI 1.47-1.93; P < .001 and HR 1.88; 95% CI 1.20-2.95; P = .006, respectively).

Conclusion

Elevated NLR predicts worse outcomes in patients with HNSCC.

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Heterotopic thyroid autotransplantation: A preliminary clinical study

Abstract

Background

Thyroid autotransplantation offers an attractive alternative to subtotal thyroidectomy and replacement therapy. However, it has not been sufficiently clinically investigated.

Methods

Total thyroidectomy was performed for 20 patients with benign thyroid disorders, and at least 10 g of thyroid tissue were implanted intramuscularly. Graft monitoring was achieved through ^99mTc scan at 2 months, free triiodothyronine (FT3), FT4, and thyroid-stimulating hormone (TSH) measurements at 1, 2, 4, 6, 8, 10, and 12 months postoperatively, and clinical examination.

Results

Grafts survived and gradually functioned in all patients to a variable extent after a latent period (mean ^99mTc uptake = 1.28 ± 0.37%). Mean values for FT3, FT4, TSH at 12 months were 1.75 ± 0.48 pg/mL, 1.06 ± 0.26 ng/dL, and 28.08 ± 34.01 μIU/mL respectively.

Conclusion

Thyroid autotransplantation restored euthyroid status in 33.3% of patients after 12 months. A role of age, operative time, and ^99mTc-uptake in determining the final graft outcome is possible.

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AHNS Series: Do you know your guidelines? Review of current knowledge on laryngeal cancer

Abstract

The following article is part of a series in an initiative by the American Head and Neck Society's Education Committee and will review clinical practice guidelines for head and neck oncology. The primary goal is to increase awareness of current best practices pertaining to head and neck surgery and oncology. This manuscript is a review of current knowledge in laryngeal cancer with a focus on anatomy, epidemiology, diagnosis, evaluation, and treatment.

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