Use of intravenous immunoglobulin for the treatment of autoimmune encephalitis: audit of the NHS experience.

OBJECTIVES: The treatments of limbic and other autoimmune encephalitis include immunosuppression, symptomatic treatment, and in the case of paraneoplastic syndromes, appropriate therapy for underlying neoplasms. When immunotherapy is considered, intravenous immunoglobulin is one option for treatment, either alone or in combination with corticosteroids. To date, however, evidence for the use of intravenous immunoglobulin in this context comes from case series/expert reviews as no controlled trials have been performed. We aimed to analyse the NHS England Database of intravenous immunoglobulin usage, which was designed to log use and guide procurement, to explore usage and therapeutic effect of intravenous immunoglobulin in autoimmune encephalitis in England. DESIGN: We conducted a retrospective audit and review of the NHS England Database on intravenous immunoglobulin use. SETTING: NHS England Database of intravenous immunoglobulin use which covers secondary and tertiary care prescribing and use of intravenous immunoglobulin for all patients in hospitals in England. PARTICIPANTS: Hospital in-patients with confirmed or suspected autoimmune/limbic encephalitis between September 2010 and January 2017. RESULTS: A total of 625 patients who were 18 years of age or older were treated with intravenous immunoglobulin for autoimmune encephalitis, of whom 398 were determined as having 'highly likely' or 'definite' autoimmune/limbic encephalitis. Ninety-six percent were treated with a single course of intravenous immunoglobulin. The availability and accuracy of reporting of outcomes was very poor, with complete data only available in 27% of all cases. CONCLUSIONS: This is the first review of data from this unique national database. Whilst there was evidence for clinical improvement in many cases of patients treated with intravenous immunoglobulin, the quality of outcome data was generally inadequate. Methods to improve quality, accuracy and completeness of reporting are crucial to maximise the potential value of this resource as an auditing tool.

The haemtrack home therapy reporting system: Design, implementation, strengths and weaknesses: A report from UK Haemophilia Centre Doctors Organisation.

INTRODUCTION: Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. METHODS: The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones. Haemtrack interfaces with the UK Haemophilia Centre Information System and the National Haemophilia Database (NHD). Data are validated locally by Haemophilia Centres and centrally by NHD. Data collected include as follows: treatment brand, dose and batch number, time/date of bleed onset and drug administration, reasons for treatment (prophylaxis, bleed, follow-up), bleed site, severity, pain-score and outcome. RESULTS: Haemtrack was used by 90% of haemophilia treatment centres (HTCs) in 2015, registering 2683 patients using home therapy of whom 1923 used Haemtrack, entering >17 000 treatments per month. This included 68% of all UK patients with severe haemophilia A. Reporting compliance varied and 55% of patients reported ≥75% of potential usage. Centres had a median 78% compliance overall. A strategy for progressively improving compliance is in place. Age distribution and treatment intensity were similar in Haemtrack users/non-users with severe haemophilia treated prophylactically. CONCLUSION: The Haemtrack system is a valuable tool that may improve treatment compliance and optimize treatment regimen. Analysis of national treatment trends and large-scale longitudinal, within-patient analysis of changes in regimen and/or product will provide valuable insights that will guide future clinical practice.

Survey of distribution of seasonal influenza vaccine doses in 201 countries (2004-2015): The 2003 World Health Assembly resolution on seasonal influenza vaccination coverage and the 2009 influenza pandemic have had very little impact on improving influenza control and pandemic preparedness.

There is no global monitoring system for influenza vaccination coverage, making it difficult to assess progress towards the 2003 World Health Assembly (WHA) vaccination coverage target. In 2008, the IFPMA Influenza Vaccine Supply International Task Force (IVS) developed a survey method to assess the global distribution of influenza vaccine doses as a proxy for vaccination coverage rates. The latest dose distribution data for 2014 and 2015 was used to update previous analyses. Data were confidentially collected and aggregated by the IFPMA Secretariat, and combined with previous IFPMA IVS survey data (2004-2013). Data were available from 201 countries over the 2004-2015 period. A "hurdle" rate was defined as the number of doses required to reach 15.9% of the population in 2008. Overall, the number of distributed doses progressively increased between 2004 and 2011, driven by a 150% increase in AMRO, then plateaued. One percent fewer doses were distributed in 2015 than in 2011. Twenty-three countries were above the hurdle rate in 2015, compared to 15 in 2004, but distribution was highly uneven in and across all WHO regions. Three WHO regions (AMRO, EURO and WPRO) accounted for about 95% of doses distributed. But in EURO and WPRO, distribution rates in 2015 were only marginally higher than in 2004, and in EURO there was an overall downward trend in dose distribution. The vast majority of countries cannot meet the 2003WHA coverage targets and are inadequately prepared for a global influenza pandemic. With only 5% of influenza vaccine doses being distributed to 50% of the world's population, there is urgency to redress the gross inequities in disease prevention and in pandemic preparedness. The 2003WHA resolution must be reviewed and revised and a call issued for the renewed commitment of Member States to influenza vaccination coverage targets.

Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies.

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.

A review of percutaneous transhepatic biliary drainage at a tertiary referral centre.

AIM: To review percutaneous biliary drainage (PBD) procedures performed in Beaumont Hospital, Dublin, Ireland, over a 6-year period, to determine the 30-day morbidity and mortality. MATERIALS AND METHODS: A total of 119 patients undergoing 193 PBD procedures were identified over a 6 year period. Of the patients, 6.7% (eight patients) had stone disease, 63% (75 patients) had a malignancy, and the remainder were diagnosed with other conditions. Standard techniques of PBD and biliary stent insertion were applied, with 73 patients (61%) having same-day procedures and all undergoing gelfoam embolisation of percutaneous tracts. All patients received intravenous prophylactic antibiotics and intravenous hydration prior to PBD. RESULTS: The technical success rate was 97%, with a mean drop of 105 mmol/l between pre- and post-procedure bilirubin. Thirty-day mortality was 10.9% (13 deaths), with major and minor morbidities of 5% (six patients) and 7.6% (nine patients), respectively. Major complications included sepsis in two patients, major haemorrhage in two patients, and renal failure in two patients. Minor complications included infection in seven patients, bile leak causing self-limiting pain in one patient, and minor haemorrhage in one patient. CONCLUSION: The study confirms that PBD and stent insertion is a safe and effective technique in Beaumont Hospital, associated with an overall acceptable morbidity and mortality comparable with other studies.

HER2 drives Mucin-like 1 to control proliferation in breast cancer cells.

Mucin-like 1 (MUCL1) was first identified as a breast-specific gene over a decade ago. Based on its highly restricted mRNA expression in breast tissue and continued expression during breast tumorigenesis and progression, MUCL1 is an attractive tumor-associated antigen and a potential therapeutic target. However, very little is known about the cellular location, biological functions and regulation of the MUCL1 protein, which will have a major impact on its druggability. Here we describe our efforts to fully characterize the cellular localization of MUCL1, investigate its regulation by key breast cancer oncogenes such as human epidermal growth factor receptor 2 (HER2) and discover its functional roles in breast cancer. Although some mucins are membrane bound, our data indicate that MUCL1 is secreted by some breast cancer cells, whereas others only express high levels of intracellular MUCL1. MUCL1 expression is highest in HER2-amplified breast tumors and inhibiting HER2 activity in tumor cells resulted in a decreased MUCL1 expression. In-depth investigation demonstrated that phosphoinositide3-kinase/Akt pathway, but not Ras/MEK pathway, controls MUCL1 expression downstream of HER2. Phenotypic assays revealed a strong dependence of HER2-positive cells on MUCL1 for cell proliferation. We further identified the mechanism by which MUCL1 regulates cell growth. Knockdown of MUCL1 induced a G1/S phase arrest concomitant with decreased cyclin D and increased p21 and p27 levels. Finally, we investigated the impact of MUCL1 loss on kinase signaling pathways in breast cancer cells through phospho-kinase array profiling. MUCL1 silencing abrogated phospho-focal adhesion kinase (FAK), Jun NH2-terminal kinase (JNK) and c-Jun signals, but not extracellular signal-regulated kinase or Akt pathway activities, thereby pointing to FAK/JNK pathway as the downstream effector of MUCL1 signaling. We are the first to identify an important role for MUCL1 in the proliferation of breast cancer cells, probably mediated via the FAK/JNK signaling pathway. Taken together, these data suggest a potential utility for therapeutic targeting of this protein in breast cancer.

Inhibitor development in non-severe haemophilia across Europe.

Evidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95% confidence intervals (95% CI) were calculated according to diagnosis and concentrate used. Between 1-10-2008 and 31-12-2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95% CI 0.30-0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20-80); with 72% occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001-0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII.

Spiral plasmonic nanoantennas as circular polarization transmission filters.

We present simulation and experimental results for easily fabricated spiral plasmonic antenna analogues providing circular polarization selectivity. One circular polarization state is concentrated and transmitted through a subwavelength aperture, while the opposite circular state is blocked. The spectral bandwidth, efficiency, and extinction ratios are tunable through geometric parameters. Integration of such structures onto a focal plane array in conjunction with linear micropolarizers enables complete Stokes vector imaging, that, until now, has been difficult to achieve. An array of these structures forms a plasmonic metamaterial that exhibits high circular dichroism.

Ultra-high extinction ratio micropolarizers using plasmonic lenses.

The design of a new type of plasmonic ultra-high extinction ratio micropolarizing transmission filter is presented along with an experimental demonstration. A pair of dielectric coated metal gratings couple incident TM polarized light into surface plasmons, which are fed into a central metal-insulator-metal (MIM) waveguide, followed by transmission through a sub-wavelength aperture. Extinction ratios exceeding 10¹¹ are predicted by finite element simulation. Good absolute agreement for both the spectral and polarization response is obtained between measurement and simulations using measured geometric parameters. The filters can be easily fabricated and sized to match the pixel pitch of current focal plane arrays.

Hybrid plasmon/dielectric waveguide for integrated silicon-on-insulator optical elements.

VLSI compatible optical waveguides on silicon are currently of particular interest in order to integrate optical elements onto silicon chips, and for possible replacements of electrical cross-chip/inter-core interconnects. Here we present simulation and experimental verification of a hybrid plasmon/dielectric, single-mode, single-polarization waveguide for silicon-on-insulator wafers. Its fabrication is compatible with VLSI processing techniques, and it possesses desirable properties such as the absence of birefringence and low sensitivity to surface roughness and metallic losses. The waveguide structure naturally forms an MOS capacitor, possibly useful for active device integration. Simulations predict very long propagation lengths of millimeter scale with micron scale confinement, or sub-micron scale confinement with propagation lengths still in excess of 100 microns. The waveguide may be tuned continuously between these states using standard VLSI processing. Extremely long propagation lengths have been simulated: one configuration presented here has a simulated propagation length of 34 cm.

Interference and resonant cavity effects explain enhanced transmission through subwavelength apertures in thin metal films.

Transmission through an opaque Au film with a single subwavelength aperture centered in a smooth cavity between linear grating structures is studied experimentally and with a finite element model. The model is in good agreement with measured results and is used to investigate local field behavior. It shows that a surface plasmon polariton (SPP) is launched along the metal surface, while interference of the SPP with the incident light along with resonant cavity effects give rise to suppression and enhancement in transmission. Based on experimental and modeling results, peak location and structure of the enhancement/suppression bands are explained analytically, confirming the primary role of SPPs in enhanced transmission through small apertures in opaque metal films.

Pneumococcal pneumonia in the UK--how herd immunity affects the cost-effectiveness of 7-valent pneumococcal conjugate vaccine (PCV).

This study examines the potential clinical and economic benefits for adults arising from paediatric pneumococcal vaccination in the UK. A UK birth cohort model with a 10-year horizon and using a primary 4-dose paediatric 7-valent pneumococcal conjugate vaccine (PCV) schedule was populated with 1999 morbidity and mortality data scaled up to the UK population. Herd immunity effects on adult pneumococcal hospital-treated pneumonia, meningitis and septicaemia, but not on community-treated pneumonia, were calculated using the lower end of the confidence intervals published for the effects in the US. Universal paediatric pneumococcal immunisation would prevent 1168 deaths (1141 adults) and 7147 cases (1791 adults constituted by 32 meningitis, 37 septicaemia and 1722 pneumonia) of serious pneumococcal infection (meningitis, septicaemia, pneumonia) with a resultant direct (payor) cost per life year gained of 4360 pounds. The 7-valent PCV appears to be highly cost effective.

Physiological function of alcohol dehydrogenases and long-chain (C(30)) fatty acids in alcohol tolerance of Thermoanaerobacter ethanolicus.

A mutant strain (39E H8) of Thermoanaerobacter ethanolicus that displayed high (8% [vol/vol]) ethanol tolerance for growth was developed and characterized in comparison to the wild-type strain (39E), which lacks alcohol tolerance (<1.5% [vol/vol]). The mutant strain, unlike the wild type, lacked primary alcohol dehydrogenase and was able to increase the percentage of transmembrane fatty acids (i.e., long-chain C(30) fatty acids) in response to increasing levels of ethanol. The data support the hypothesis that primary alcohol dehydrogenase functions primarily in ethanol consumption, whereas secondary alcohol dehydrogenase functions in ethanol production. These results suggest that improved thermophilic ethanol fermentations at high alcohol levels can be developed by altering both cell membrane composition (e.g., increasing transmembrane fatty acids) and the metabolic machinery (e.g., altering primary alcohol dehydrogenase and lactate dehydrogenase activities).

Can airway complications following multilevel anterior cervical surgery be avoided?

OBJECT: The authors conducted a study to determine how to avoid emergency postoperative reintubation and its associated morbidity in patients who have undergone multilevel anterior-posterior cervical spine surgery. METHODS: In a group effort between the departments of anesthesia and neurosurgery, a protocol was developed to avoid having to reintubate patients postoperatively. As a preventative measure, patients remained intubated overnight; on the 1st postoperative day or thereafter, based on direct fiberoptic visualization of reactive tracheal swelling, an anesthesiologist extubated the patients. Fifty-eight patients underwent multilevel anterior corpectomy with fusion (ACF; with 41 receiving plates and 17 not receiving plates), posterior wiring and fusion (PWF), and application of a halo. On average, ACF involved three levels, whereas PWF included 6.5 levels. Surgery typically lasted 10 hours, and an average 2.6 U of blood was required. Forty patients were successfully extubated on the 1st, five on the 2nd, three on the 3rd, two on the 4th, two on the 5th, and three on the 7th postoperative day. Three elective tracheostomies were performed on the 7th postoperative day. Risk factors associated with delayed extubation or tracheostomy in 18 patients included: operative time longer than 10 hours (12 patients), obesity greater than 220 lbs (12 patients), transfusion of more than 4 U of blood (10 patients), ACF reoperations (nine patients), ACF including C-2 (seven patients), four-level ACF (five patients), and asthma (five patients). In the only case in which emergency reintubation was required, three risk factors were present. CONCLUSIONS: Emergency reintubation following anterior-posterior cervical surgery and fusion can be avoided by maintaining intubation overnight and subsequently having an anesthesiologist remove the tube after healing is fiberoptically confirmed. Familiarity with major risk factors contributing to airway compromise, combined with this protocol, should minimize the significant morbidity associated with reintubation following multilevel anterior-posterior cervical fusion.

A general approach to the synthesis of dideoxy and trideoxyiminoalditols from beta-D-glycosides.

Imino sugars (also called azasugars), a class of compounds of which the 1,5-dideoxy and 1,5,6-trideoxyiminoalditols are members, are important glycosidase inhibitors with very high potential as drugs. Their potential therapeutic applications range from the treatment of diabetes to cancer and AIDS. We present here a general method for the preparation of such compounds with the D-gluco and D-galacto configurations starting from beta-D-glycosides. The procedure is especially appealing because of its high stereoselectivity and straightforwardness. The key steps are the selective oxidation of the glycosides to hexulosonic acids and reduction of the oxime derivatives to lactams, which are further reduced to the target compounds. The C-6 position can be deoxygenated during the reduction if it bears an acetoxy group. Trideoxy imino sugars are then produced. Deacetylation prior to oxime reduction gives dideoxy compounds.

Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta.

We have identified and characterized the human Mnk2 gene (HGMW-approved gene symbol MKNK2) through a yeast two-hybrid screen in which the Mnk2 protein interacted with the ligand-binding domain of estrogen receptor beta (ERbeta). Human Mnk2 is homologous to murine Mnk2 ( approximately 94% identical) and human Mnk1 (71% identical), both of which encode MAP kinase interacting kinases that are phosphorylated and activated by ERK1 and 2. This report presents a thorough genomic sequence analysis revealing that the human Mnk2 gene has two C-terminal splice variants, designated here as Mnk2a and Mnk2b. These two isoforms are identical over the first 385 amino acids of the coding sequence and differ only in the final exon which encodes an additional 80 residues for Mnk2a and 29 residues for Mnk2b. A more detailed biological analysis in yeast showed that the Mnk2 interaction was selective for ERbeta as opposed to ERalpha and that the interaction was specific to Mnk2b as opposed to Mnk2a or Mnk1. This pattern was reproduced in a mammalian two-hybrid system using a completely different set of fusion partners; and in both yeast and mammalian systems, the addition of estradiol decreased the interaction. While it remains unknown whether ERbeta is a substrate of Mnk2, the interaction of these two proteins is reminiscent of ERalpha and ribosomal S6 kinase (p90-RSK), another MAP kinase-regulated kinase homologous to Mnk2 that is known to phosphorylate ERalpha.

Anterior cervical micro-dural repair of cerebrospinal fluid fistula after surgery for ossification of the posterior longitudinal ligament. Technical note.

BACKGROUND: Cerebrospinal fluid (CSF) fistulas may occur during anterior cervical surgery performed for the resection of ossification of the posterior longitudinal ligament (OPLL), as OPLL occasionally erodes to and through the dura. These fistulas have been variously managed with gelfoam, dural substitutes sutured in place, fibrin glue, lumbar drains, and lumboperitoneal shunts. However, more adequate dural repair is now feasible with the 1.4-mm microdural titanium stapler. METHODS: A 59-year-old female with OPLL and moderate to severe myelopathy (Nurick Grade IV) had a C3-C7 anterior corpectomy with fusion using Orion plates followed by a C3-T1 posterior wiring and fusion with halo application. During the anterior approach, a 5-mm CSF fistula at C4-C5 was directly repaired under the operating microscope using a 1.4-mm microdural stapler, bovine pericardial graft, and fibrin glue. Immediately postoperatively, a lumboperitoneal shunt was also placed. RESULTS: Postoperatively, her myelopathy improved to a mild to moderate level (Nurick Grade II). Her acute left deltoid plegia resolved within 3 months. CONCLUSIONS: The 1.4-mm microdural stapler makes "watertight" closure of anterior cervical CSF fistulas more feasible.