bluuebunny/crossref_metadata_2025 huggingface dataset:
Cigarette smoke directly impairs skeletal muscle function through capillary regression and altered myofibre calcium kinetics in mice
Authors: Nogueira Leonardo , Trisko Breanna M. , Lima‐Rosa Frederico L. , Jackson Jason , Lund‐Palau Helena , Yamaguchi Masahiro , Breen Ellen C.
Published: May 2018

Key points

Cigarette smoke components directly alter muscle fatigue resistance and intracellular muscle fibre Ca2+ handling independent of a change in lung structure.

Changes in muscle vascular structure are associated with a depletion of satellite cells.

Sarcoplasmic reticulum Ca2+ uptake is substantially impaired in myofibres during fatiguing contractions in mice treated with cigarette smoke extract.

Cigarette smokers exhibit exercise intolerance before a decline in respiratory function. In the present study, the direct effects of cigarette smoke on limb muscle function were tested by comparing cigarette smoke delivered to mice by weekly injections of cigarette smoke extract (CSE), or nose‐only exposure (CS) 5 days each week, for 8 weeks. Cigarette smoke delivered by either route did not alter pulmonary airspace size. Muscle fatigue measured in situ was 50% lower in the CSE and CS groups than in control. This was accompanied by 34% and 22% decreases in soleus capillary‐to‐fibre ratio of the CSE and CS groups, respectively, and a trend for fewer skeletal muscle actin‐positive arterioles (P = 0.07). In addition, fewer quiescent satellite cells (Nes+Pax7+) were associated with soleus fibres in mice with skeletal myofibre VEGF gene deletion (decreased 47%) and CS exposed (decreased 73%) than with control fibres. Contractile properties of isolated extensor digitorum longus and soleus muscles were impaired. In flexor digitorum brevis myofibres isolated from CSE mice, fatigue resistance was diminished by 43% compared to control and CS myofibres, and this was accompanied by a pronounced slowing in relaxation, an increase in intracellular Ca2+ accumulation, and a slowing in sarcoplasmic reticulum Ca2+ uptake. These data suggest that cigarette smoke components may impair hindlimb muscle vascular structure, fatigue resistance and myofibre calcium handling, and these changes ultimately affect contractile efficiency of locomotor muscles independent of a change in lung function.
Multi-modal and short-range transmission loss in thin, ice-covered, near-shore Arctic waters
Authors: Penhale Miles B. , Barnard Andrew R. , Shuchman Robert
Published: May 2018

In the past century, extensive research has been done regarding the sound propagation in Arctic ice sheets. The majority of this research has focused on low-frequency propagation over long distances. Due to changing climate conditions in these environments, experimentation is warranted to determine sound propagation characteristics in, through, and under first-year, thin ice sheets, in shallow water, over short distances. In April 2016 several experiments were conducted approximately 2 km off the coast of Barrow, Alaska on shore-fast, first-year ice, approximately 1 m thick. To determine the propagation characteristics of various sound sources, frequency response functions were measured between a source location and several receiver locations at various distances from 1 m to 1 km. The primary sources used for this experiment were, an underwater speaker with various tonal outputs, an instrumented impact hammer on the ice, and a propane cannon that produced an acoustic blast wave in air. The transmission loss (TL) characteristics of the multipath propagation (air, ice, water) are investigated and reported. Data indicate that TL in frequency bands between 125 and 2000 Hz varied from approximately 3–6 dB per doubling of distance which is consistent with geometrical spreading losses, cylindrical and spherical, respectively.
Basic instincts
Authors: Hutson Matthew
Published: May 2018

Some say artificial intelligence needs to learn like a child.
Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells
Authors: Ma Chi , Han Miaojun , Heinrich Bernd , Fu Qiong , Zhang Qianfei , Sandhu Milan , Agdashian David , Terabe Masaki , Berzofsky Jay A. , Fako Valerie , Ritz Thomas , Longerich Thomas , Theriot Casey M. , McCulloch John A. , Roy Soumen , Yuan Wuxing , Thovarai Vishal , Sen Shurjo K. , Ruchirawat Mathuros , Korangy Firouzeh , Wang Xin Wei , Trinchieri Giorgio , Greten Tim F.
Published: May 2018

Bile acids and liver cancer

Liver cancer is a leading cause of cancer-related deaths in the United States. The composition of the gut microbiome influences many human diseases, including liver inflammatory disorders. Ma
et al.
found that commensal gut bacteria can recruit the immune system to control the growth of liver tumors in mice (see the Perspective by Hartmann and Kronenberg).
Clostridium
species modified bile acids to signal liver sinusoidal endothelial cells to produce the chemokine CXCL16. This recruited natural killer T (NKT) immune cells to perform antitumor surveillance of the liver. Growth of both primary and metastatic cancer was reduced by NKT cell–driven killing.

Science
, this issue p.
eaan5931
; see also p.
858
Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction
Authors: Friedfeld Max R. , Zhong Hongyu , Ruck Rebecca T. , Shevlin Michael , Chirik Paul J.
Published: May 2018

Reduction can make cobalt act precious

Enzymes rely on abundant metals such as iron and nickel to manipulate hydrogen. Chemists, on the other hand, have largely had to rely on precious metals such as platinum and rhodium for the task. Friedfeld
et al.
now report a simple trick to make cobalt act more like rhodium. Reduction of Co(II) to Co(I) by zinc reinforced binding of phosphine ligands to the metal to facilitate its use in asymmetric hydrogenation of alkenes. The cobalt catalysts tolerated alcohol solvents, unlike their rhodium congeners, and could be applied to a 200-gram-scale reduction at 0.08% loading.

Science
, this issue p.
888
Cancer immunity thwarted by the microbiome
Authors: Hartmann Nadine , Kronenberg Mitchell
Published: May 2018

Microbial bile acid metabolites promote liver metastasis
Structures of the fully assembled
Saccharomyces cerevisiae
spliceosome before activation
Authors: Bai Rui , Wan Ruixue , Yan Chuangye , Lei Jianlin , Shi Yigong
Published: May 2018

Structural basis for spliceosome assembly

The spliceosome removes noncoding sequences from precursor RNA and ligates coding sequences into useful mRNA. The pre-spliceosome (A complex) associates with a small nuclear ribonucleoprotein (snRNP) complex called U4/U6.U5 tri-snRNP to form the pre-B complex, which is converted into the precatalytic B complex. Bai
et al.
solved the cryo–electron microscopy structures of the pre-B and B complexes isolated from yeast. These structures show the U1 and U2 snRNPs and allow modeling of the A complex to reveal the early steps of spliceosome assembly and activation.

Science
, this issue p.
1423
Canada's call
Authors: Nemer Mona
Published: May 2018

Next month, Canada will host the Group of 7 (G7) summit in picturesque Charlevoix, Québec. As leaders from Canada, France, Germany, Italy, Japan, the United Kingdom, and the United States come together, along with European Union representatives, to discuss the progressive agenda, science will be on everyone's mind. With science and technology playing a prominent role in everyday life, access to science education and to science-based careers is ever more essential for inclusive growth and for women's empowerment.
Lipopeptide Paenipeptin Analogues Potentiate Clarithromycin and Rifampin against Carbapenem-Resistant Pathogens
Authors: Moon Sun Hee , Huang En
Published: May 2018

Two paenipeptin analogues at 4 μg/ml potentiated clarithromycin and rifampin against carbapenem-resistant
Acinetobacter baumannii
and
Klebsiella pneumoniae
strains. The combined treatment significantly increased their antibacterial efficacy in a microbiological medium and in human serum
in vitro
at therapeutically relevant concentrations. Moreover, these two paenipeptin analogues showed low cytotoxicity against a human kidney cell line. Therefore, combination therapy with paenipeptins may be an option for the treatment of antibiotic-resistant bacterial infections.
Involvement of β-Carbonic Anhydrase Genes in Bacterial Genomic Islands and Their Horizontal Transfer to Protists
Authors: Zolfaghari Emameh Reza , Barker Harlan R. , Hytönen Vesa P. , Parkkila Seppo
Published: May 2018

The evolutionary process is mediated by mobile genetic elements (MGEs), such as genomic islands (GIs). A gene or set of genes in the GIs is exchanged between and within various species through horizontal gene transfer (HGT). Based on the crucial role that GIs can play in bacterial survival and proliferation, they were introduced as environment- and pathogen-associated factors. Carbonic anhydrases (CAs) are involved in many critical biochemical pathways, such as the regulation of pH homeostasis and electrolyte transfer. Among the six evolutionary families of CAs, β-CA gene sequences are present in many bacterial species, which can be horizontally transferred to protists during evolution. This study shows the involvement of bacterial β-CA gene sequences in the GIs and suggests their horizontal transfer to protists during evolution.
Validation of prediction models for risk stratification of incidentally detected pulmonary subsolid nodules: a retrospective cohort study in a Korean tertiary medical centre
Authors: Kim Hyungjin , Park Chang Min , Jeon Sunkyung , Lee Jong Hyuk , Ahn Su Yeon , Yoo Roh-Eul , Lim Hyun-ju , Park Juil , Lim Woo Hyeon , Hwang Eui Jin , Lee Sang Min , Goo Jin Mo
Published: May 2018

Objectives

To validate the performances of two prediction models (Brock and Lee models) for the differentiation of minimally invasive adenocarcinoma (MIA) and invasive pulmonary adenocarcinoma (IPA) from preinvasive lesions among subsolid nodules (SSNs).

Design

A retrospective cohort study.

Setting

A tertiary university hospital in South Korea.

Participants

410 patients with 410 incidentally detected SSNs who underwent surgical resection for the pulmonary adenocarcinoma spectrum between 2011 and 2015.

Primary and secondary outcome measures

Using clinical and radiological variables, the predicted probability of MIA/IPA was calculated from pre-existing logistic models (Brock and Lee models). Areas under the receiver operating characteristic curve (AUCs) were calculated and compared between models. Performance metrics including sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were also obtained.

Results

For pure ground-glass nodules (n=101), the AUC of the Brock model in differentiating MIA/IPA (59/101) from preinvasive lesions (42/101) was 0.671. Sensitivity, specificity, accuracy, PPV and NPV based on the optimal cut-off value were 64.4%, 64.3%, 64.4%, 71.7% and 56.3%, respectively. Sensitivity, specificity, accuracy, PPV and NPV according to the Lee criteria were 76.3%, 42.9%, 62.4%, 65.2% and 56.3%, respectively. AUC was not obtained for the Lee model as a single cut-off of nodule size (≥10 mm) was suggested by this model for the assessment of pure ground-glass nodules. For part-solid nodules (n=309; 26 preinvasive lesions and 283 MIA/IPAs), the AUC was 0.746 for the Brock model and 0.771 for the Lee model (p=0.574). Sensitivity, specificity, accuracy, PPV and NPV were 82.3%, 53.8%, 79.9%, 95.1% and 21.9%, respectively, for the Brock model and 77.0%, 69.2%, 76.4%, 96.5% and 21.7%, respectively, for the Lee model.

Conclusions

The performance of prediction models for the incidentally detected SSNs in differentiating MIA/IPA from preinvasive lesions might be suboptimal. Thus, an alternative risk calculation model is required for the incidentally detected SSNs.
Is disability exclusion associated with psychological distress? Australian evidence from a national cross-sectional survey
Authors: Temple Jeromey B , Kelaher Margaret
Published: May 2018

Objective

To examine the association between disability exclusion and psychological distress.

Design

Cross-sectional study.

Setting

Population-based study of individuals living in households across Australia.

Participants

Respondents were persons aged 15 and over living with a disability.

Primary outcome measures

Reporting an experience of discrimination or avoidance behaviour due to a respondent’s disability. High or very high levels of psychological distress measured using the Kessler K10 instrument.

Methodology

Using the Survey of Disability, Ageing and Carers, we calculated the prevalence of persons with a disability experiencing psychological distress, disaggregated by experiences of disability exclusion, including discrimination and avoidance. Logistic regression models were fitted to examine the association between disability exclusion and psychological distress, once extensive controls and adjustments for survey design and presence of psychosocial disabilities were considered.

Results

About 62% of persons citing an experience of disability discrimination were in psychological distress, compared with 27% of those citing no discrimination. Furthermore, 53% of those who actively avoided social, familial or economic activities because of their disability experienced psychological distress, compared with 19% of those who did not avoid these situations. After controlling for demographic characteristics and disabling conditions, reporting an experience of disability discrimination or disability avoidance increased the odds of psychological distress by 2.2 (95% CI 1.74 to 2.26) and 2.6 (95% CI 2.28 to 2.97) times, respectively. Those who experienced both avoidance and discrimination were 3.7 (95% CI 2.95 to 4.72) times more likely to be in psychological distress than those experiencing neither. Avoidance and discrimination in healthcare settings were also found to be strongly associated with experiencing psychological distress.

Conclusions

Given new policy initiatives to improve disability care, coupled with the increasing speed of population ageing, the onus is on governments and its citizenry to address disability exclusion to offset potential mental health impacts.
Partly randomised, controlled study in children aged 6–10 years to investigate motor and cognitive effects of a 9-week coordination training intervention with concurrent mental tasks
Authors: Santner Antonia , Kopp Martin , Federolf Peter
Published: May 2018

Introduction

Physical training may play a prominent role in the development of preadolescent brains, but it is yet to be determined what type of exercise may generate higher cognitive effects, and if concurrent mental engagement provides further efficacy. The aim of this study is to investigate motor and cognitive effects of a 9-week exercise intervention in children aged 6–10 years. Trainings include the automatisation of challenging coordination exercises with concurrent mental tasks (intervention group) and multisport exercises with and without mental tasks (two control groups). It is hypothesised that all groups gain motor and cognitive effects, but highest benefits are expected for the combination of automatised coordination exercises with mental tasks.

Methods and analysis

Two elementary schools (∼500 students) take part in the study. Data are generated by using the German Motor Performance Test 6–18 (Deutscher Motorik-Test 6–18), TDS (Match 4 Point), d2-R test of attention and Kasel-Concentration-Task for Children Aged 3–8 Years; test-duration: 6–7 min. After pretesting in September 2017 and a 9-week training intervention, post-testing takes place in December 2017 and March 2018 (long-term effects). Training interventions consist of coordination exercises with concurrent mental tasks (intervention group) and multimotor exercises with and without concurrent mental tasks (control groups). Shapiro-Wilk test will be used to test for normal distribution and the Levene test for variance homogeneity. The appropriate multivariate statistical methods (multivariate analysis of variance or Kruskal-Wallis test) will be used for analysing differences among the groups and for comparing preintervention with postintervention performances.

Ethics and dissemination

All procedures have been approved by the board for ethical questions in science of the University of Innsbruck. Findings will be published in 2018 in international journals and presented at conferences. Schools will be informed of key results.
001 Ulnar neuropathy with abnormal non-localising electrophysiology: clinical, electrophysiological and ultrasound findings
Authors: Pelosi Luciana , Ming Yin Tse Dominic , Mulroy Eoin , Chancellor Andrew M , Boland Michael R
Published: May 2018

Introduction

Ulnar neuropathy with abnormal non-localising electrophysiology (NL-UN) is often associated with significant disability that is difficult to manage due to the absence of anatomically defining studies. We studied demographic, clinical and electrophysiological characteristics of NL-UN and used ultrasound in order to assist with classification and to examine the utility of ultrasound over and above the conventional electro-diagnostic approach.

Method

NL-UNs were identified from 113 consecutive referrals to a single neurophysiologist with suspected ulnar neuropathy. All received systematic electro-diagnostic tests and ulnar nerve ultrasound. NL-UN severity was graded using clinical and electrophysiological scales.

Results

In 64 of 113 referrals, an ulnar mononeuropathy was confirmed by electrophysiology. Sixteen of these 64 (25%) had NL-UN, predominantly males (14 out of 16 patients) with severe or moderately severe clinical and electrophysiological ratings in 81%. Ultrasound showed focal ulnar neuropathy at the elbow (UNE) in 13 out of 16, and diffuse ulnar nerve abnormality in three, and identified a likely or possible causative mechanism in 11 UNEs.

Conclusion

A quarter of ulnar neuropathies, as demonstrated by abnormal electrophysiology, were NL-UN, of heterogeneous aetiology; the majority were males with significant disability and axonal loss. Ultrasound had a significant role in localization and classification of NL-UN that facilitated management.
010 The melbourne mobile stroke unit substantially improves thrombolysis times and pre-hospital triage
Authors: Zhao Henry , Coote Skye , Pesavento Lauren , Langenberg Francesca , Desmond Patricia , Easton Damien , Bent Lindsay , Foster Shane , Stephenson Michael , Smith Karen , Bernard Stephen , Bladin Christopher , Cadilhac Dominique , Yan Bernard , Campbell Bruce CV , Parsons Mark , Donnan Geoffrey , Davis Stephen M
Published: May 2018

Introduction

The Melbourne mobile stroke unit (MSU) project is the first Australian pre-hospital stroke service that delivers on-scene imaging, treatment and triage. The MSU vehicle consists of a Mercedes Sprinter-5 chassis with on-board CereTom 8-slice portable CT scanner and telemedicine capabilities. On-board crew consists of a neurologist/telemedicine, nurse, radiographer and two paramedics (advanced-life-support and mobile-intensive-care). The MSU service is co-dispatched within 20 km of Royal Melbourne Hospital. We describe the service activity since project launch.

Methods

Data are sourced from the Melbourne MSU registry, an ongoing prospectively collected database of all MSU dispatched cases since November 2017.

Results

In the first 50 operational days, there were a total of n=255 dispatches (5.1/day), of which 47% of patients received on-scene attendance. On-scene CT was performed on 52% of all attendances. Of n=29 suspected ischaemic stroke cases<6 hours of symptom onset (24% of attended), n=10 (34%) received pre-hospital thrombolysis and n=6 (21%) were directed for endovascular thrombectomy. 30% of patients were thrombolysed within 90 min of symptom onset. A total of n=7 (14% of all stroke) patients were recommended to bypass the closest hospital to a specialist centre for endovascular, neurosurgical or other services. The median scene-to-thrombolysis time of 36.5 min was substantially better than Australian in-hospital averages and represented an estimated 30–45 min time saving compared to in-hospital treatment.

Discussion

The Melbourne MSU project shows that pre-hospital diagnosis and treatment of stroke patients is feasible and associated with substantial time saving in providing acute stroke treatment and triage. Future research will focus on optimising MSU dispatch and cost-effectiveness analysis.
101 Dispelling the curse: improvement of ventilatory drive in central alveolar hypoventilation syndrome after medullary infarction
Authors: Fedi Marco , Shen Shi Hong , Campbell Bruce , Dutschmann Mathias , O’brien Terrence , Anstey James , MacIsaac Christopher
Published: May 2018

Introduction

Central alveolar hypoventilation syndrome (CAHS) is a rare complication of stroke affecting the medullary respiratory centre. CAHS is characterised by impaired ventilatory response to CO2 leading to hypoventilation, hyper-capnoea and coma. Experimental studies have linked this syndrome to areas in the dorsal and ventrolateral medulla. CAHS is associated with long-term invasive ventilatory support, high mortality and morbidity. It is unclear whether sensitivity to CO2 can improve after the initial ischaemic medullary insult.

Case

A 78 year old woman presenting with CAHS secondary to a unilateral left posterior inferior cerebellar artery infarction. MRI images confirmed that dorsal and ventrolateral medullary areas were affected. The patient was intubated initially for hyper-capnoeic respiratory failure and required a tracheostomy for ongoing respiratory support. To assess progress of respiratory recovery, we measured the patient’s ventilatory response to PaCO2 at 5, 7, and 14 days of admission. Parameters recorded included PaO2, ETCO2, PaCO2, pH, respiratory rate, and minute ventilation. During this time the patient underwent progressive periods of unsupported ventilation with close monitoring. Statistical correlation between respiratory rate and CO2 was measured by Pearson’s correlation coefficient (R). Her RR initially did not increase with PaCO2 during spontaneous ventilation (R=0.2604 p=0.077). Apnoeic episodes were frequent up to 41 episodes per 30 min of observation lasting up to 30 s. On day 7(R=0.7203 p<0.05) and up to day 14 (R=0.6295 p<0.05), there was a progressive statistically significant improvement in positive correlation between PCO2 and respiratory rate. This was associated with a reduction in apnoeic episodes possibly reflecting a recovery in ventilatory drive.

Conclusion

This is the first detailed report demonstrating spontaneous recovery in CO2 responsiveness in the setting of CAHS secondary to unilateral medullary stroke. Plasticity of structures such as the retro-trapezoid nucleus are likely to play a role in recovery of CO2 sensitivity.

References

. Harper, et al. Functional neuroanatomy and sleep-disordered breathing: implications for autonomic regulation. Anatomical record2012;295(9):1385–95.

. Mishina, et al. Efficacy of tracheostomy for central alveolar hypoventilation syndrome caused by lateral medullary infarction. Journal of Nippon Medical School2014;81(4):276–84.
106 Post-traumatic neuromyelitis optica spectrum disorder
Authors: Gerbis Natasha , Parratt John , Liang Christina
Published: May 2018

Introduction

Neuromyelitis optica spectrum disorders (NMOSDs) are immune-mediated demyelinating disorders affecting the brain and spinal cord. There are case-series of post-traumatic multiple sclerosis, but only one case-report previously of post-traumatic neuromyelitis optica.

Case

A 57 year old man presented to hospital following a fall down two flights of stairs while intoxicated, and was found on CT to have small bi-frontal subdural haematomas, traumatic subarachnoid haemorrhage, bilateral occipital contusions, and non-displaced fractures through the right parietal bone and bilateral petrous temporal bones. While agitated, he developed subacute onset of visual loss and paraplegia at day 22. An MRI spine at day 12 showed only degenerative changes. However a repeat MRI brain and spine at day 26 revealed enhancing longitudinally extensive optic nerve lesions, indicative of optic neuritis and an extensive segment of intramedullary enhancement within the mid to lower thoracic cord, consistent with longitudinally extensive transverse myelitis. A CSF sample revealed raised protein (9.81 g/L), elevated lactate (3.54 mmol/L), 1 red cell, 41 monocytes. CSF oligoclonal bands, aquaporin 4 antibodies, MOG antibodies, anti-neuronal antibodies and ACE were negative. Serum anti-neuronal antibodies, HTLV-1 and 2 serology, ANA, ENA, ACE, MOG and aquaporin 4 antibodies were also negative. Treatment with iv methylprednisolone, plasma exchange and mycophenolate led to recovery of gait at 2 months and ability to drive by 1 year. Patient remains stable at 2 year follow-up.

Conclusion

We report a case of bilateral optic neuritis and longitudinally extensive thoracic transverse myelitis following a traumatic brain injury. The presentation was consistent with an NMOSD and the patient responded to immunomodulatory therapy. The hypothesis is that the traumatic brain injury led to a defect in the blood brain barrier, allowing autoantibodies to enter the CNS and incite inflammation.
109 Investigation of natural killer cell function and phenotypes in stable and active multiple sclerosis patients
Authors: Khalilidehkordi Elham , Cabanas Helene , Eaton Natalie , Broadley Simon , Balinas Cassandra , Preez Stanley Du , Maksoud Rebekah , Staines Donald , Marshall-Gradisnik Sonya
Published: May 2018

Introduction

Previous studies have reported that impaired cytotoxic activity of natural killer (NK) cells in peripheral blood is associated with multiple sclerosis (MS) activity. Furthermore, NK cell phenotype could be associated with new lesions on MRI. Cytotoxic activity of NK cells is determined by their phenotype and surface antigens. However, investigators are yet to comment on NK cell phenotype and cytotoxicity in MS patients with stable disease or recent disease activity compared to healthy controls (HC). This project investigates NK cell phenotype and cytotoxicity in MS patients with active and stable disease and in HC.

Methods

Seven patients with relapsing remitting MS who have been stable on alemtuzumab for at least 6 months, five patients with active MS not on any medication and five HCs were recruited in this study. Peripheral blood mononuclear cells were isolated by centrifugation over Ficoll-Paque density gradient medium. Then NK cells were isolated using immune-magnetic negative selection. Isolated NK cells were labelled with antibodies to determine CD56Dim and CD56Bright NK cells and cytotoxic function determined using target cells (K562) and flow cytometry.

Results

Our study showed that there is no significant difference between phenotype and cytotoxicity in three groups of stable RRMS, active RRMS and HC.

Conclusion

In previous studies, it has been suggested that CD56Bright NK cells are associated with stable disease and patients with large MRI lesions had reduced NK cell cytotoxicity. This finding raised the possibility of using NK cell as an indicator for disease activity. This study identified no significant difference between NK cell cytotoxicity or phenotypes between HC and MS patients with different disease activity. Given the small number of patients in this study, there remains a need for further studies on larger population to assess phenotype, cytotoxicity, cytokines and cell surface expression of NK cells.
021 Clinical implications of cortical dysfunction in motor neuron disease: a combined structural and functional approach
Authors: Dharmadasa Thanuja , Simon Neil G , Wang Chenyu , Vucic Steve , Kiernan Matthew C
Published: May 2018

Introduction

Motor neuron disease (MND) is characterised by progressive failure of upper (UMN) and lower motor neurons (LMN). UMN dysfunction remains difficult to detect clinically, and the influence of cortical change on disease progression and prognosis remains unclarified. This study quantitatively assessed cortical dysfunction in vivo using a novel combined structural and functional approach.

Methods

Forty-one newly diagnosed MND patients and 30 controls prospectively underwent 3T diffusion tensor magnetic resonance imaging (DTI) to assess cerebral white matter structural integrity. DTI measures including apparent diffusion coefficient (ADC) and functional anisotropy (FA) were analysed using statistical parametric mapping. Threshold tracking transcranial magnetic stimulation (TT-TMS) studies were additionally performed across all four limbs to concurrently assess the functional integrity of the motor cortex. All patients underwent detailed clinical and cognitive assessment.

Results

Cortical abnormalities were prominent, with FA significantly reduced (p<0.01) and ADC enhanced (p<0.03) along the primary motor tracts in all MND patients, suggestive of primary axonal degeneration. These changes correlated with clinical function and disease duration. TT-TMS revealed evidence of cortical hyper-excitability over the motor cortex corresponding with clinical site-of-onset (p<0.05). Structural (FA) and functional (cortical hyper-excitability) changes correlated across all extremities. Patients without clinical UMN signs also showed evidence of UMN dysfunction, identifying subclinical change. Subgroup analysis identified the greatest changes in bulbar-onset patients (p<0.03).

Conclusion

This multimodal technique identified UMN dysfunction in patients prior to clinically detectable change, which may contribute to earlier diagnosis. More significant cortical involvement in bulbar-onset patients aligns with their poorer survival, highlighting the cortically driven determination of clinical progression and prognosis. Further clinical translation of such patterns may therefore lend insight into pathophysiological disease mechanisms and may influence stratification for clinical trials. Overall, this can serve as a robust biomarker for earlier diagnosis, disease progression and prognosis.
035 Interferon beta induced thrombotic microangiopathy in multiple sclerosis: a clinical-pathological report
Authors: Yam Charmaine , Fok Anthony , McLean Catriona , Butler Ernest , Kempster Peter
Published: May 2018

Introduction

Thrombotic microangiopathy (TMA) has been described with long-term interferon-beta (IFN-β). We report a case of biopsy-proven TMA in a patient with multiple sclerosis (MS) who had been having IFN-β−1a injections for twenty years. These biopsy findings were similar to previously described lung histological changes in IFN β- induced pulmonary arterial hypertension (PAH).

Case

A 57 year old woman with relapsing-remitting multiple sclerosis had been administering IFN-β−1a injections for twenty years. Her BMI was 21 and she was on a dose of 44 mcg three times per week. She presented with acute pulmonary oedema, renal failure, malignant hypertension, micro-angiopathic haemolytic anaemia and thrombocytopenia after one week of increasing dyspnoea. A renal biopsy showed malignant hypertensive nephropathy and microangiopathy consistent with TMA. Alternative TMA syndromes including haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura were excluded. Renal function stabilised after the IFN was ceased but never returned to the baseline level.

Results

Her renal biopsy showed glomerular capillary thrombus deposition, endothelial reactivity, vessel necrosis and wall duplication with luminal thrombus. Fibromuscular proliferation, focal fibrinoid necrosis and luminal thrombus was also present within arterioles. These microvascular histopathological findings resemble vessel changes observed seen in lung biopsies in human IFN β mediated PAH, and those described in transgenic mouse models engineered to overproduce Type 1 IFN.1 2 Our patient was on treatment for twenty years at a dose exceeding 50 mcg per week. Both are postulated risk factors for the development of TMA.2

Conclusion

Our report highlights similarities between microvascular changes seen in IFN-induced TMA and those observed in pulmonary arterial hypertension associated with IFN therapy. This suggests a shared pathophysiological mechanism. Kavanagh et al had described a dose-dependent spectrum of renal microvascular disease in his mouse model.2 The duration and high dosage for weight of IFN Β supports a cumulative drug toxicity effect.

References

. Fok A, Williams T, McLean C, Butler E. Interferon beta- 1a long-term therapy related to pulmonary arterial hypertension in multiple sclerosis patients. Mult Scler2016Oct;22(11):1495–1498.

. Kavanagh D, McGlasson S, Jury A, et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood2016Aug;05–715987.
054 Disability improvement is observed in each functional system in alemtuzumab-treated patients with active RRMS: results from CARE-MS II extension
Authors: Macdonell Richard AL , Aburashed Rany A , Alroughani Raed , Dive Dominique , Izquierdo Guillermo , Kim Ho-Jin , Lycke Jan , Pozzilli Carlo , Sharrack Basil , Vermersch Patrick , Wiendl Heinz , Lysandropoulos Andreas , Chung Luke , Daizadeh Nadia , Hunter Samuel F ,   on behalf of the CARE-MS II and CAMMS03409 Investigators
Published: May 2018

Introduction

In CARE-MS II (NCT00548405), alemtuzumab (12 mg/day, baseline: 5 days; 12 months later: 3 days) significantly improved clinical/MRI outcomes versus subcutaneous interferon beta-1a over 2 years in relapsing-remitting MS patients with inadequate response to prior therapy; significantly greater percentage of alemtuzumab-treated patients achieved 6 month confirmed disability improvement (CDI). Efficacy remained durable in a 4 year extension (NCT00930553). Here we assess alemtuzumab efficacy on disability at the level of functional systems (FS) scores of the Expanded Disability Status Scale (EDSS) over 6 years.

Methods

EDSS and individual FS scores were recorded at baseline and quarterly; CDI (≥1.0 point EDSS decrease confirmed over 6 months) was assessed in patients with baseline EDSS score ≥2.0.

Results

Of the 393 patients who entered the extension, 338 (86%) remained on study through Year 6; 50% received neither alemtuzumab retreatment nor other disease-modifying therapy after the initial 2 courses. Through Years 3–6, 76%–80% of patients showed stable (≤0.5 point change) or improved (≥1.0 point decrease) EDSS scores versus core study mean (SD) baseline score of 2.7 (1.2);≥75% were stable/improved in each FS. Through Year 6, 43% achieved 6 month CDI and 96% of patients with CDI had an EDSS score <4. 71% of patients with CDI achieved improvements in >1 FS. Improvements were observed in each FS, most frequently occurring in the sensory (48%), pyramidal (44%), and cerebellar (44%) systems; 21%–25% showed improvements in the brainstem, cerebral, visual, and bowel/bladder FS.

Conclusion

Most (86%) CARE-MS II patients who entered the extension remained on the study through Year 6;≥75% of alemtuzumab-treated patients had improved/stable scores across all FS over 6 years. Improvements were seen for each FS in patients with 6 month CDI, with 71% showing improvements in >1 FS, indicating a broad treatment effect with alemtuzumab on multiple aspects of disability improvements.

Study support

Sanofi and Bayer HealthCare Pharmaceuticals.
062 Cadasil presenting with focal and generalised epilepsy due to a novel NOTCH3 mutation
Authors: Chen Benson S , Cleland James C , King Richard I , Anderson Neil E
Published: May 2018

Introduction

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the NOTCH3 gene. Clinical manifestations include migraine, recurrent ischaemic strokes, and cognitive decline. Seizures are an uncommon early symptom and usually occur after the onset of stroke. We report a CADASIL family with epilepsy as an early clinical symptom due to a novel NOTCH3 mutation.

Methods

The clinical histories of three family members from two generations are reported, alongside para-clinical details including results of magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic testing.

Results

The proband developed focal and generalised seizures at age 51. She had a preceding history of cognitive impairment and migraines. The proband’s son developed focal seizures at age 25 involving his left arm and then generalised seizures. He experienced intermittent headaches, without history of stroke or cognitive impairment. His sister (the proband’s daughter) had epilepsy from age 12, characterised by blank spells and generalised seizures. Cognitive decline was noted from age 38, without history of stroke. There was no family history of epilepsy in those without CADASIL. MRI in all three family members showed multifocal T2 FLAIR hyperintensities within the supratentorial white matter, particularly the temporal lobes. EEG was abnormal only in the proband’s son, with paroxysmal bursts of poorly organised 3–4 Hz spike-wave activity. Genetic testing in all three family members found a novel NOTCH3 mutation, c.1337G>A p.(Cys446Tyr).

Conclusion

We have identified a novel NOTCH3 mutation in a kindred with epilepsy as an early manifestation of CADASIL without prior history of strokes. The association with epilepsy is unlikely to be coincidental given the strong segregation of epilepsy and CADASIL in this kindred and the clear focal seizure semiology noted in all family members. Whether this mutation represents a distinct new phenotype requires further investigation.
065 A pilot time and motion study for treatments of relapsing remitting multiple sclerosis (RRMS) in australia
Authors: Lechner-Scott Jeanette , Davey Ryan , Davey Peter , Bogeski Goce , Cheah Esther
Published: May 2018

Introduction

The time burden of managing relapsing remitting multiple sclerosis (RRMS) for patients and healthcare staff is not well quantified despite its importance in treatment choice. Of interest were three higher efficacy RRMS therapies, cladribine tablets, alemtuzumab, and fingolimod because of their different modes of administration. Time and motion (T and M) surveys have previously been used to quantify time burden by asking respondents about duration of treatment administration. The objective is to determine the time taken by patients, nurses, neurologist and other specialists to treat RRMS with cladribine tablets, alemtuzumab and fingolimod using purposely developed T and M surveys.

Methods

We created two T and M surveys, one for neurologists and nurses, and another for patients. Surveys were informed by product information documents, validated by an MS nurse, and completed by telephone with patients (n=3), neurologists (n=3), and nurses (n=8) from eight MS clinics.

Results

The overall mean time spent on treatment with cladribine tablets, fingolimod, and alemtuzumab extrapolated over 4 years was 25±3, 62±6, and 189±18 hours (p<0.0001, 1-way ANOVA, repeated measures). Neurologists’ overall time spent also favoured cladribine tablets (2.3±0.7 hours) over alemtuzumab (9.5±1.8 hours) and fingolimod (2.9±0.7 hours), (overall p=0.001). Similar results were found for nurses and patients, with the largest difference between therapies (favouring cladribine tablets) recorded for patients.

Conclusion

Cladribine tablets were associated with a significantly lower overall time taken to treat RRMS compared to fingolimod and alemtuzumab. This warrants further research to determine if cladribine tablets could (a) increase productivity for doctors and nurses, and (b) improve patient quality of life by reducing the burden of managing their disease.
070 Baseline characteristics and safety profile of patients with relapsing-remitting multiple sclerosis (RRMS) in the first interim analysis of the peginterferon BETA-1A treatment in the phase 4 plegridy observational program (POP)
Authors: Salvetti Marco , Yun Jang , Appiah-Badu David , Sabatella Guido , Naylor Maria L
Published: May 2018

Introduction

The 5 year, observational, phase 4 POP study explores the long-term safety and effectiveness of peginterferon beta-1a 125 mcg every 2 weeks in RRMS patients treated in real-world settings. This analysis presents interim data from POP on baseline characteristics, adverse events (AEs), and clinical effectiveness.

Methods

POP is ongoing in >150 sites in 14 countries. Patients who initiated peginterferon beta-1a treatment either ≤31 days pre-enrolment (naive subgroup, ‘PegNaive’) or >31 days pre-enrolment (experienced subgroup, ‘PegExperienced’) will be followed for ≤5 years.

Results

At the time of this analysis, 467 patients were included, 411 (88%) of whom were followed for ≥12 months. A total of 153 patients (33%) discontinued treatment, primarily due to AEs (55%) or lack of efficacy (13%). At baseline, mean age was 44.9 years, 76% of patients were female, and mean Expanded Disability Status Scale score was 1.9. Of the 371 patients (79%) with prior disease-modifying therapy use, 217 (58%) had been treated with intramuscular interferon beta-1a. More patients were PegNaive than PegExperienced (60% vs 40%). AEs were more common in PegNaive patients than in PegExperienced patients (35% vs 20%), as were AEs leading to treatment discontinuation (29% vs 15%). The most commonly reported AEs leading to treatment discontinuation in both groups were injection-site erythema and influenza-like illness. Serious AEs were reported in 5% of PegNaive and 9% of PegExperienced patients. A high proportion of patients in both groups were relapse free (PegNaive, 84.4%; PegExperienced, 81.5%).

Conclusion

In this first interim analysis of the POP study, the safety profile was consistent with that observed in the phase 3 trial of peginterferon beta-1a. No new safety signals were observed. PegNaive patients were more likely than PegExperienced patients to experience AEs and discontinue treatment due to injection-site reactions and flu-like symptoms, highlighting a need for prophylactic mitigation strategies.

Study support

Biogen
073 Alemtuzumab induced allergic inflammatory syndrome (ALIAS) with eosinophilic acalculous cholecystitis: a report of two cases
Authors: Fontes-Villalba Ariadna , Parratt John DE
Published: May 2018

Introduction

Alemtuzumab, a humanised monoclonal antibody directed at CD52, is a highly active treatment for multiple sclerosis (MS) that induces rapid depetion of circulating lymphocytes. Infusion-associated reactions and autoimmune disorders are established adverse effects. We describe two cases of alemtuzumab associated allergic inflammatory syndrome involving the lungs and gallbladder in two young patients after their first course of Alemtuzumab.

Case 1 A 26 year old female with relapsing-remitting MS (RRMS) received her first course of alemtuzumab. On the fourth day of treatment, she developed bronchospasm, chest pain and an interstitial infiltrate in the right lower lobe on chest X-ray. She had right upper quadrant pain and a positive Murphy’s sign and ‘gallbladder sludge’ on ultrasound. Blood tests showed lymphopenia and eosinophilia. The patient was diagnosed with acalculous cholecystitis. Antibiotic therapy was initiated but laparoscopic cholecystectomy was required. The pathology demonstrated eosinophilic cholecystitis.

Case 2 A 29 year old man with RRMS was switched to alemtuzumab due to positive JCV antibody status. He had an episode of hemoptysis on the fifth day of the infusion. Two days later, haemoptysis was accompanied by chest tightness. Physical examination revealed a palpable liver and positive Murphy sign. Blood tests were remarkable for abnormal liver enzymes. Signs of interstitial changes in the right lower lobe were observed on a chest X-ray. The patient was diagnosed with acalculous cholecystitis and antibiotic therapy was initiated. The infiltrate resolved and the clinical signs quickly improved.

Conclusion

The characteristics of this condition are acute onset (within days of alemtuzumab) and non-infective inflammation of the lung (right lower lobe in these cases) and gallbladder. The pathology in one case indicates this is likely to be a drug related, allergic phenomenon with extensive eosinophilic infiltration of the gallbladder.
082 Real world experience of treating multiple sclerosis with alemtuzumab
Authors: Khalili Ellie , Venning Brent , Boggild Mike , Broadley Simon A
Published: May 2018

Introduction

Alemtuzumab is a highly effective therapy for multiple sclerosis that has a significant, but well-defined adverse event profile. We report cases treated since the commercial release of alemtuzumab at two centres in Queensland with the aim of comparing real-world experience with trial data.

Methods

This was a retrospective case note review of patients treated with alemtuzumab for multiple sclerosis since becoming commercially available in Australia. The two sites were the Gold Coast University Hospital and the Townsville Hospital. Demographic, clinical and MRI data were systematically collected from the available records at each site. De-identified aggregated data were analysed using descriptive statistics (mean (±SD), median (range)) and compared with phase III clinical trial data.

Results

104 cases treated with alemtuzumab were identified at the two sites. The median age at first treatment was 3817–55 years, slightly older than the trial populations (33 and 35 years) and two-thirds were female. The mean disease duration was 8.4 (±7.0) years, which is longer that seen in the trials (2.1 and 4.5 years). The median number of prior relapses was 31–12 with 1 (0–3) in the prior 2 years. The median number of prior treatments for MS was 1.5. The median follow up was 201–35 months. The median EDSS at time of first treatment was 2 (0–7) and at last follow up was 1.5 (0–7). At last follow up, 24/104 (23%) had improved, 61/104 (58%) were stable and 9/104 (9%) had worsened. Autoimmune adverse events were seen in 18/104 (17%) with autoimmune thyroid disease being the most common (13/104 (13%).

Conclusion

Alemtuzumab is an effective therapy for MS. Clinical outcomes in a real world setting were similar to those seen in phase III clinical trials. Autoimmune diseases occurred in a similar proportion to those seen in clinical trials.

References

. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet2012;380(9856):1819–28.

. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet2012;380(9856):1829–39.