Received Royalty Payments Research Articles

MRI and DTI Characteristics of Natalizumab Associated PML during a Novel Treatment Protocol (P07.061)

Objective: To describe clinical and MRI features of natalizumab associated PML. Background Natalizumab is an effective therapy but is associated with risk of PML. PML is treated by removing natalizumab from blood by plasma exchange (PLEX). However, more active restoration of the immune cell migration may be associated with better outcome. Design/Methods: 26-year-old male developed PML after receiving 40 doses of natalizumab. PML produced new onset of nystagmus and left sided ataxia. MRI showed a non-enhancing left MCP lesion extending into the cerebellum. Treatment included PLEX, mefloquine 250mg daily, and mirtazapine 45mg daily; 1 week after PLEX: filgrastim 300mcg x 5 days, maraviroc 150 twice daily, zonisamide 100mg daily. Results: PML lesion volume on FLAIR MRI before PLEX was 9.8cc, but increased to 15.2 cc post PLEX and filgrastim. T1 volume increased from 5.6cc to 9.9cc. This was not associated with any gadolinium enhancement. After immune reconstitution inflammatory syndrome (IRIS) and post IV steroids, the T2 FLAIR volume increased to 18.1 cc and T1 volume to 16.3 cc with little contrast enhancement. MS lesion activity did not change. DTI of the PML lesion showed decreased in FA and axial diffusivity but increase in radial diffusivity compared to non-lesion side. Prior to PML, patient had an EDSS of 4.5. At the time of PML, EDSS increased to 6.5. Three months after treatment for PML, the EDSS decreased to 5.5. Conclusions: Using this protocol, our patient had a favorable outcome. The enlargement of T2 FLAIR and T1 signal without much contrast enhancement may represent unmasking of a greater area of PML lesion. The clinical worsening during PML therapy may be due to a combination of unmasking of a greater PML lesion and IRIS. DTI imaging suggests both an axonal and myelin loss within the PML lesion. Disclosure: Dr. Javed has received personal compensation for activities with Teva Neuroscience, Bayer Pharmaceuticals, Serono, Inc., Novartis, Questcor and Biogen Idec as a consultant and/or speaker. Dr. Ko has received personal compensation for activities with Biogen Idec, Serono, Inc., and Teva Neuroscience for consulting services. Dr. Balabanov has received personal compensation for activities with Biogen Idec, Teva Neuroscience and Genzyme as a consultant, and speaker bureau honoraria from Biogen Idec and Teva Neuroscience.Dr. Balabanov has received research support from Biogen Idec. Dr. Stefoski has received personal compensation for activities with Biogen Idec, Acorda, Serono, Elan, and Teva Neuroscience. Dr. Stefoski has received royalty payments from Acorda Therapeutics. Dr. Stefoski has received research support from Biogen Idec, Novartis, Serono, and Pfizer.

Flow Cytometric Immunophenotyping of the Blood and CSF of Patients with Multiple Sclerosis (P02.081)

Objective: To monitor intrathecal immune responses and to investigate their role in pathogenesis of multiple sclerosis (MS). Background Immune cells in the cerebrospinal fluid (CSF) better reflect intrathecal inflammation than peripheral blood. However, low cellularity and susceptibility to apoptosis makes immunophenotyping of CSF challenging. Design/Methods: CSF and concomitant peripheral blood was collected in prospective manner in untreated patients (N=36) who presented for the diagnostic work-up of neuroimmunological disorder. Cells were isolated from 10-15cc of CSF within 15 min of collection. An optimized 12 color flow cytometric immunophenotyping (FCI) protocol was used to identify immune subpopulations (CD4, CD8 T cells, B cells, CD56bright- and CD56dim NK cells, monocytes, myeloid and plasmacytoid dendritic cells (DCs)) and their activation markers. FCI results were analyzed in an unbiased manner with the absolute cell count in blood and CSF and with the diagnosis established by the clinicians. Results: Upon unblinding, our cohort consisted of clinically isolated syndrome (CIS, N=2), relapsing-remitting MS (RR-MS, N=18), primary progressive MS (PP-MS, N=4), secondary progressive MS (SP-MS, N=4), non-inflammatory neurological diseases (NIND, N=4) and other inflammatory neurological diseases (OIND, N=5) controls. CSF was enriched for T cells, HLA-DR+ (i.e. activated) T cells and CD56bright NK cells in comparison to blood. We observed positive correlations between blood and CSF B cells, and blood and CSF HLA-DR+ T cells and terminally-differentiated double negative T cells, suggesting a link between systemic and intrathecal immune activation. Intrathecal differences between MS patients and controls consisted of elevated B cell to monocyte ratio (p=0.0004) and elevated CD4/CD8 T cell ratio (p=0.0007). Conclusions: The CSF immunophenotyping has been adapted to all NIB clinical protocols, including interventional trials, so updated results will be presented. We expect that with expanded cohort and longitudinal data, CSF immunophenotyping will provide essential information about intrathecal immune responses in neuroimmunological diseases. Supported by: NIH Intramural Research Program. Disclosure: Dr. Han has nothing to disclose. Dr. Salgado has nothing to disclose. Dr. Alfahad has nothing to disclose. Dr. Bielekova has received royalty payments from NIH.

Did Carotid Stenting and Endarterectomy Outcomes Change over Time in the Carotid Revascularization Endarterectomy Versus Stenting Trial? (S09.005)

Objective: To detect changes in the periprocedural outcomes in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) following carotid endarterectomy (CEA) and carotid artery stenting (CAS) to detect temporal changes, if present. Background Improvements in training and technique as well as improvements in selection of surgeons and interventionists had the potential to influence differential outcomes in CREST for the 2502 patients randomized between December of 2000 and mid-July of 2008. Design/Methods: Enrollment was divided into 3 consecutive epochs, each with approximately 834 patients. Rates for the primary outcome of stroke, death, and MI (SDMI) and for stroke and death (SD) during the periprocedural period were calculated. Poisson regression was used to adjust rates for age, sex, dyslipidemia, and symptomatic status, all of which were found to influence outcomes. Results: For CAS, there was a 26% decline in SDMI (6.2% a 4.6%) and a 35% decline in SD (5.5% a 3.6%). For both composite endpoints in CEA there was no consistent pattern. As CREST progressed, it enrolled younger patients, more men, and patients more likely to be dyslipidemic (all p Conclusions: Periprocedural safety for CAS improved over time in CREST. Changes were inconsistent for CEA. Improvements for CAS in part appear to reflect changes in patient selection related to age, sex, risk factors, and symptomatic status because adjustment for those variables attenuated the decline in rates. Linking rates to operator experience was not feasible because of the large number of new interventionists and surgeons entering CREST over time. Supported by: The National Institute of Neurological Disorders and Stroke (NINDS) and the NIH (R01 NS 038384) and by supplemental funding from Abbott Vascular Solutions (formerly Guidant). Disclosure: Dr. Howard has received personal compensation for activities with Bayer Healthcare and Abbott Labratories as a consultant. Dr. Howard has received research support from Amgen Inc. and Bayer Healthcare. Dr.Roubin has received royalty payments from Abbott Vascular and Cook Inc. Dr. Hopkins has received personal compensation for activities with Boston Scientific, Micrus, Abbott Labratories, W. L. Gore, BARD, Cordis Corporation, Memorial Healthcare System as a consultant an/or speaker.Dr. Hopkins holds stock and/or stock options in Micrus, Boston Scientific, AccessClosure, Valor Medical, Claret Medical, Inc., and Augmenix.Dr. Hopkins has received research support from Toshiba. Dr. Moore has received personal compensation for activities with WL Gore. Dr. Gray has received personal compensation for activities with Abbott Vascular as a consultant and a participant on an advisory board. Dr. Rosenfield has received personal compensation for activities with Abbott Vascular, Complete Conf Management, Contego Medical, LLC, and HCRI as a consultant.Dr. Rosenfield has received personal compensation for serving on the Board of Directors of VIVA Physicians. Dr. Rosenfield has received royalty or license fee or contractual rights payments from Angiograd (Cordis).Dr. Rosenfield holds stock and/or stock options in Contego Medical, LLC and Medical Simulation Corp. Dr. Rosenfield has received research support from Abbott Vascular. Dr. Katzen has received personal compensation for activities with Boston Scientific, W.L. Gore, and Medtronic as a consultant and particpant on an advisory board. Dr. Chakhtoura has nothing to disclose. Dr. Morrish has nothing to disclose. Dr. Ferguson has nothing to disclose. Dr. Hye has nothing to disclose. Dr. Shawl has received research support from Abbott, Medtronic, Boston Scientific, Johnson & Johnson, and Ev3. Dr. Harrigan has nothing to disclose. Dr. Voeks has nothing to disclose. Dr. Lal has nothing to disclose. Dr. Meschia has nothing to disclose. Dr. Brott has received personal compensation for activities with 3D Communications.

Role of Surgical Decompression of Lower Extremity Nerves in Painful Neuropathy (P06.152)

Objective: To assess the efficacy of surgical decompression of lower extremity nerves in painful neuropathy. Background Surgical decompression of peripheral nerves is being increasingly used as an alternative approach to treatment for painful neuropathy. The procedure is however unproven (Neurology 66:1805–1808, 2006). In this prospective study, 4 patients were evaluated for benefits of decompression surgery. Design/Methods: 4 consecutive patients (3W, 1 M; mean age 53), who had already agreed to undergo decompressive surgery for their painful peripheral neuropathy underwent the following evaluations prior to surgery and at 3- and 6 months after surgery: directed history including the 11 point numerical rating of pain scale (0-10), a directed examination, nerve conduction study and skin biopsy. Total neuropathy score (TNS) was calculated. Quality of life (QoL) questionnaire (SF36) form was also administered. Surgical procedure consisted of decompression of medial plantar, lateral plantar, and calcaneal nerves at the tarsal tunnel region, common peroneal at fibular head, and deep peroneal nerve at the dorsal foot. Results: All patients had documentation of small fiber>larger fiber neuropathy and had reduced intraepidermal fiber density on skin biopsy. Neuropathy was from diabetes (2), glucose intolerance (1), and idiopathic (1). Mean TNS scores before and after surgery (6 month follow-up)were as follows: symptom score (3.2/3.2), examination score (5.2/5.25), nerve conduction score (3.2/4.0), and total neuropathy score (11.7/12.5). The mean pain and QoL(SF 36)scores from baseline to 6 months after surgery were 10/6.7 and 34/64 respectively. Overall 3 of 4 showed subjective improvement in pain and QoL. Postoperative complications included: serous drainage (1)and wound Infection requiring antibiotics and admission (1). Conclusions: Subjective improvement in pain and QoL can occur after decompressive surgery in painful neuropathy patients despite lack of improvement in objective measures of neuropathy. Supported by: The Neuropathy Association. Disclosure: Dr. Chaudhry has received personal compensation for activities with Novartis. Dr. Chaudhry has received personal compensation in an editorial capacity for the Neurologist. Dr. Chaudhry has received royalty payments from Abbott Laboratories, Inc. and Johnson & Johnson. Dr. Belzberg has nothing to disclose. Dr. Rosson has received (royalty or license fee or contractual rights) payments from Aegeria, LLC.Dr. Rosson has received research support from Lifecell, Corp.

Saccadic Abnormalities in Familial Parkinson's Disease Associated with -Synuclein (SNCA) Gene Mutation (PARK1) (P02.258)

Objective: To investigate saccadic characteristics of PARK1 and to compare them with those of other parkinsonian syndromes. Background Typical patterns of eye movement abnormalities have been described in both idiopathic (PD, CDB, LBD and MSA) and familial (PARK2 and PARK6) parkinsonian syndromes, providing not only useful diagnostic markers, but also insights in to the functions of the basal ganglia. Mutations in the SNCA gene are a rare cause of autosomal dominant early-onset Parkinson9s Diseases (PARK1); its gene product is the main component of Lewy bodies, the hallmark of parkinsonian neuronal degeneration. Design/Methods: Two symptomatic PARK1 patients were recorded during various saccadic paradigms: horizontal visually-guided saccades (VGS), anti-saccades, overlap, and memory-guided saccades (MGS) (10° and 18°). Data were statistically compared with those of 19 healthy controls. Results were related to findings reported in other parkinsonian syndromes. Results: Both patients showed saccadic abnormalities. VGS amplitude (10° p1:9.6±0.8°, p2:8.4±0.5° normal values (n.v.) 10.3±1.0° p Conclusions: PARK1 patients present peculiar abnormalities in both voluntary and reflexive saccades. Hypometric VGS, abnormal inhibition of reflexive saccades and staircase saccades have been described in other parkinsonian syndromes. The observation of slow VGS has never been reported in parkinsonian syndromes and may indicate the extension of the neuronal degeneration to other structures controlling saccade dynamics. The characteristic patterns of saccade abnormalities may help diagnosis as well as pointing to an understanding of the functions of the basal ganglia and how they become impaired in parkinsonian syndromes. Disclosure: Dr. Pretegiani has nothing to disclose. Dr. Leigh has nothing to disclose. Dr. Zee has received royalty payments from Oxford University Press. Dr. Federico has nothing to disclose. Dr. Piu has nothing to disclose. Dr. Rufa has nothing to disclose.

Angiographic Predictors of Stroke after Carotid Artery Stenting - A Qualitative and Quantitative Analysis of 1070 Patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (IN2-2.001)

Objective: To analyze the 1070 catheter-based angiograms performed on patients undergoing carotid artery stenting (CAS) in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Background CAS may be useful as an alternative to carotid endarterectomy in selected patients with symptomatic and asymptomatic carotid artery disease. The angiographic predictors of stroke following CAS have been incompletely described. Design/Methods: Of the 1070 CAS patients, 43 (4%) experienced periprocedural stroke. Angiograms were reviewed before and after CAS. Reviews were blinded to outcomes. Strokes were adjudicated by a committee blinded to results of angiography. The view showing the most severe stenosis was selected. Extreme tortuosity was defined as 2 severe bends >90 degrees (maximum angulation/20 mm segment) beyond the target lesion, sequential lesions as lesions separated by ≥10 mm, and narrow mouth ulcer as a discrete area of contrast extension beyond the normal arterial lumen with a narrow inlet into the ulceration. Results: The internal carotid artery mean reference diameter was 4.2 ± 0.8 mm, the minimal mean lumen diameter was 1.1 ± 0.6 mm, and the baseline mean % diameter stenosis was 74.1 ± 11.6%. There were no differences in vessel size or severity of the stenosis in patients with and without stroke. Morphologic predictors significantly related to the risk of subsequent stroke were lesion length (p=0.009), sequential lesions (p=0.007), severe distal tortuosity (p=0.025), and narrow mouth ulcer (p=0.05). Calcification, lesion eccentricity, baseline flow, and distance from the bifurcation were not predictive of periprocedural stroke (p > 0.05). Conclusions: In CREST, four angiographic variables were found to increase risk for stroke during and within 30 days after CAS: severe distal tortuosity, sequential lesions, lesion length > 20 mm, and narrow mouth ulcer. Angiographic characteristics beyond percent stenosis may help in patient selection in terms of best revascularization option. Supported by: The National Institute of Neurological Disorders and Stroke (NINDS) and the NIH (R01 NS 038384) and by supplemental funding from Abbott Vascular Solutions (formerly Guidant). Disclosure: Dr.Roubin has received royalty payments from Abbott Vascular and Cook Inc. Dr. Popma has received personal compensation for activities with Boston Scientific as a consultant.Dr. Popma has received research support from Boston Scientific, Cordis, Abbott Vascular, and Medtronic. Dr. Almonacid has nothing to disclose. Dr. Morrish has nothing to disclose. Dr. Katzen has received personal compensation for activities with Boston Scientific, W.L. Gore, and Medtronic as a consultant and particpant on an advisory board. Dr. Chakhtoura has nothing to disclose. Dr. Lal has nothing to disclose. Dr. Voeks has nothing to disclose. Dr. Meschia has nothing to disclose. Dr. Brott has received personal compensation for activities with 3D Communications.

Neuromyelitis Optica Relapse Associated with Pregnancy: Similarities to Multiple Sclerosis (P06.184)

Objective: To determine whether relapses of neuromyelitis optica (NMO) are associated with pregnancy. Background The risk of multiple sclerosis (MS) relapse is known to decrease markedly during pregnancy, particularly in the third trimester, and increase again in the first 3 months postpartum. However, little is known about the influence of pregnancy on the clinical course of NMO. Design/Methods: We retrospectively studied pregnant patients with NMO seen at Tokyo Women9s University Hospital, Tohoku University Hospital, or Juntendo University Hospital and diagnosed according to AQP4 antibody-positive findings and the revised criteria. We analyzed disease onset and/or relapse associated with pregnancy and investigated each trimester during pregnancy (1st, DP1; 2nd, DP2; 3rd, DP3) and each trimester postpartum (1st, PP1; 2nd, PP2; 3rd, PP3; 4th and over, PP4). Results: Among total 51 pregnant women diagnosed with NMO, we extracted 14 NMO patients (mean age at disease onset, 30.4±8.5 years; mean age at pregnancy, 32.6±6.6 years; these mean ages were lower than those of the general age at onset for NMO [39 years]). Total number of relapses was 17 among our patients. For each period, the number of relapses was 3 for DP1, 2 for DP2, 1 for DP3, 5 for PP1, 3 for PP2, 1 for PP3, 1 for PP4, and 1 immediately after elective abortion. NMO appeared to be associated with pregnancy in 6 patients, and the time of disease onset was more frequently postpartum (n=6) than during pregnancy (n=2) in these patients. Almost all of these patients delivered healthy babies. Conclusions: Our results suggest that NMO patients of childbearing age need to be aware of the potential for disease exacerbation and may be at a higher risk of relapse/disease onset postpartum compared to during pregnancy. The influence of pregnancy on NMO might bear some resemblance to MS. Supported by: A Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan. Disclosure: Dr. Shimizu has received personal compensation for activities with Bayer Yakuhin, Biogen Idec Japan, Teijin Pharma, and Novartis. Dr. Shimizu has received royalty payments for the Quick Reference Guide for Management. Dr. Ohashi has received personal compensation for activities with Bayer Yakuhin, Biogen Idec Japan, Teijin Pharma, and Novartis Pharma. Dr. Maruyama has nothing to disclose. Dr. Nakashima has received personal compensation for activities with Bayer Schering, Novartis, and Biogen Idec. Dr. Nakashima has received research support from Mitsubishi Chemical Medience Corporation and the Ministry of Education, Science, and Technology of Japan. Dr. Yokoyama has personal compensation for activities with Bayer Yakuhin, Biogen Idec Japan, Mitsubishi Tanabe Pharma, Teijin Pharma, Asteras Pharma, Daiichi Sankyo, Cosmic Corporation, Takeda Pharma, and AstraZeneca Pharmaceuticals. Dr. Fujihara has received personal compensation for Bayer Schering Pharma, Biogen Idec, Merck Serono, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, and Asahi Kasei Kuraray Medical Co., Ltd. Dr. Fujihara has received personal compensation in an editorial capacity for Clinical and Experimental Neuroimmunology. Dr. Fujihara has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, Eisai Inc., and Kyowa Pharmaceuticals America, Inc. Dr. Uchiyama has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Otsuka, Novartis, Boehringer Ingelheim Pharmaceuticals, Inc., and Daiichi Sankyo.

Correction: Extracranial Sources of S100B Do Not Affect Serum Levels

In our recent article [1], we did not declare several potential competing interests relevant to this work. We apologize for this omission and would like to disclose the following information: Dr. Janigro has received royalty payments from Roche Diagnostics and holds a patent on S100B for its use as a serum marker for blood-brain barrier leakage. The study was partly supported by Roche Diagnostics. The company does not currently develop any products related to the results described in the article. Reference: 1. Pham N, Fazio V, Cucullo L, Teng Q, Biberthaler P, Bazarian JJ, Janigro D (2010) Extracranial sources of S100B do not affect serum levels. PLoS One 5(9): e12691. doi:10.1371/journal.pone.0012691

Neutrophils, Hypercholesterolemia, and Atherogenesis

Neutrophils, Hypercholesterolemia, and Atherogenesis

Quality of life, stage severity and COPD

<b>OBJECTIVE:</b> To analyze the impact of the <i>BDNF</i> Val66Met variant on transcript levels, AD risk and cognitive function. <b>BACKGROUND:</b> Published meta-analyses show association of Val66Met with increased AD risk and cognitive decline. <b>DESIGN/METHODS:</b> The Val66Met variant was genotyped using a validated Taqman assay. Logistic or linear regression analyses with covariates were implemented in PLINK to test the correlation of the Val66Met genotypes with AD status in our Caucasian case-control series (2951 ADs, 4564 controls), and with gene expression levels from our published brain eGWAS (~200 AD and ~200 non-AD), as well as with baseline cognitive performance as measured by Logical Memory Delayed Recall score (MRLMD) from Mayo Clinic Study of Aging participants, respectively. <b>RESULTS:</b> We observed a <i>suggestive</i> trend of decreased cerebellar <i>BDNF</i> mRNA levels in the combined set of AD and non-ADs, and in non-ADs alone. There was no consistent trend in temporal cortex. We also observed a <i>suggestive</i> trend towards decreased AD risk (OR = 0.92, p = 0.098) in carriers. This trend is reversed in <i>APOE-</i>ε4 homozygotes, matching previously published data (OR =1.54, p = 0.13; 372 cases <i>vs</i>. 62 controls). Diagnosis of AD occurs at a suggestively lower age in Val66Met carriers (β = -0.39, p = 0.21), a finding that reaches nominal significance in <i>APOE</i>-ε4 homozygotes (β = -2.16, p = 0.01). We were unable to detect an association between Val66Met status and MRLMD, regardless of <i>APOE</i> genotype. <b>CONCLUSIONS:</b> Our results suggest that within the cerebellum, decreased <i>BDNF</i> mRNA transcript may be mediated through the Val66Met mutation. Effects of the polymorphism on AD risk appear to be dependent on <i>APOE</i>-ε4 genotype, but age of AD onset appears to be earlier in carriers of the minor allele. We did not detect an association between Val66Met status and cognitive performance as measured by MRLMD. <b>Disclosure:</b> Dr. Burgess has nothing to disclose. Dr. Carrasquillo has nothing to disclose. Dr. Zou has nothing to disclose. Dr. Chai has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Allen has nothing to disclose. Dr. Serie has nothing to disclose. Dr. Crook has nothing to disclose. Dr. Pankratz has nothing to disclose. Dr. Nair has nothing to disclose. Dr. Middha has nothing to disclose. Dr. Maharjan has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Malphrus has nothing to disclose. Dr. Lincoln has nothing to disclose. Dr. Bisceglio has nothing to disclose. Dr. Asmann has nothing to disclose. Dr. Pedraza has nothing to disclose. Dr. Roberts has nothing to disclose. Dr. Lucas has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Ivnik has nothing to disclose. Dr. Machulda has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman and Cytox as a scientific advisory board member or a consultant. Dr. Graff-Radford has received royalty payments for UpToDate. Dr. Petersen has received personal compensation for activities with Pfizer Inc. and Janssen Alzheimer9s Immunotherapy. Dr. Dickson has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Taner has nothing to disclose.

Belimumab

Belimumab is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. Belimumab is in phase III trials for the treatment of systemic lupus erythematosus (SLE) and has completed a phase II trial in rheumatoid arthritis (RA); the product may also have potential in the treatment of other autoimmune disorders. In May 2001, Cambridge Antibody Technology (now MedImmune) completed its discovery programme and Human Genome Sciences identified belimumab as a candidate for clinical development. More than 1000 distinct human antibodies specific to BLyS were characterized by the collaboration.B-lymphocyte stimulator is a naturally occurring protein discovered by Human Genome Sciences that stimulates B-lymphocytes to develop into mature B cells. Laboratory studies have indicated that higher than normal levels of B-lymphocyte stimulator may contribute to the pathogenesis of autoimmune diseases, such as SLE and RA. Human Genome Sciences (HGS) and Cambridge Antibody Technology signed a collaborative agreement in August 1999 to study the B-lymphocyte stimulator as a human protein target. HGS is also developing other BLyS products. In March 2000, HGS and Cambridge Antibody Technology expanded their agreement into a 10-year collaboration and product development alliance, providing Human Genome Sciences with the right to use the antibody technology of Cambridge Antibody Technology to fully develop human antibodies for therapeutic and diagnostic purposes. Cambridge Antibody Technology will receive royalty payments on product sales from HGS, as well as the development and milestone payments it has already received. Belimumab will be manufactured in Human Genome Sciences' manufacturing facility, located in Rockville, MD, USA. HGS holds commercial rights to the drug. In July 2005, GlaxoSmithKline (GSK) exercised its co-development and co-promotion option to belimumab. In an agreement made in June 1996, HGS had granted a 50/50 co-development and co-promotion option to GSK for certain therapies that complete phase IIa trials successfully. The companies subsequently entered into a definite worldwide, co-development and commercialization agreement in August 2006, under which HGS will be responsible for conducting phase III trials of the product, with assistance from GSK. The companies will share equally phase III/IV development costs, sales and marketing expenses, and profits. In October 2007, Cambridge Antibody Technology was integrated into MedImmune. Both companies were previously independent subsidiaries of AstraZeneca. MedImmune is now the operationally independent biologics business unit of AstraZeneca. Human Genome Sciences intends to initiate a phase II trial of subcutaneous belimumab by mid-2008. Results from a phase II trial in 449 patients with SLE demonstrated that belimumab improved or stabilized SLE over 2.5 years. The phase II trial was a double-blind, placebo-controlled, multicentre study that evaluated the safety, optimal dosing, and preliminary efficacy of belimumab in patients with active SLE over 52 weeks initially, followed by a continuation phase for a total of 2.5 years. Belimumab has received fast-track designation for the treatment of SLE from the US FDA and has also been selected for inclusion in the agency's continuous Marketing Application Pilot 2 programme.

The mosul question and the Turkish republic: Before and after the frontier treaty, 1926

The Mosul Vilayet was part of the Ottoman Empire until the end of the First World War. Following the war it was occupied by Britain and the Vilayet became the bone of contention between the Ottoman Empire and Britain. After the War of Independence, the new Turkish Republic considered Mosul one of the crucial issues determined in the National Pact. Despite constant resistance, Britain managed to bring the issue into the international arena, scaling it down to a frontier problem between Turkeyand Iraq. In the Turkish historical literature, the Mosul QuestIon has been studied until the Frontier Treaty (1926). According to these studies, the Turkish government, in accordance wIth the exchange of letters annexed to the Frontier Treaty (1926), agreed to receive a fixed q.sh settlement of 500,000 pounds, rather than calculating the amount on a ten percent basis. That is to say, the Turkish government received the 500 000 pounds and the folio of the Mosul Question was c1osed. But some findings proved that this was not the case. Some figures in the Turkish state budgets indicate that Turkey received payments on a ten percent basis instead of the fixed cash settlement. From 1931 to 1952 Turkey received royalty payments regularly. After 1952, two issues caused serious problems between Turkeyand Iraq; namely, the unpaid years and insufficient payments. In latter period, Turkey chose to pursue a conciliatory policyand the issue was pui aside for the purpose of establishing friendly relations with Iraq.

THE MOSUL QUESTION AND THE TURKISH REPUBLIC: BEFORE AND AFTER THE FRONTIER TREATY, 1926

The Mosul Vilayet was part of the Ottoman Empire until the end of the First World War. Following the war it was occupied by Britain and the Vilayet became the bone of contention between the Ottoman Empire and Britain. After the War of Independence, the new Turkish Republic considered Mosul one of the crucial issues determined in the National Pact. Despite constant resistance, Britain managed to bring the issue into the international arena, scaling it down to a frontier problem betvveen Turkey and Iraq. In the Turkish historical literatüre, the Mosul Question has been studied until the Frontier Treaty 1926 . According to these studies, the Turkish government, in accordance with the exchange of letters annexed to the Frontier Treaty 1926 , agreed to receive a fixed cash settlement of 500,000 pounds, rather than calculating the amount on a ten percent basis. That is to say, the Turkish government received the 500 000 pounds and the folio of the Mosul Question was closed. But some findings proved that this was not the case. Some fıgures in the Turkish state budgets indicate that Turkey received payments on a ten percent basis instead of the fixed cash settlement. From 1931 to 1952 Turkey received royalty payments regularly. After 1952, two issues caused serious problems betvveen Turkey and Iıaq; namely, the unpaid years and insuffıcient payments. In latter period, Turkey chose to pursue a conciliatory policy and the issue was put aside for the purpose of establishing friendly relations with Iraq

THE MEREENIE LEASE NEGOTIATIONS IN THE AMADEUS BASIN-AN HISTORICAL PERSPECTIVE

Following the discovery of oil and gas, the Mereenie Joint Venture (MJV) applied for a production lease in November 1973. However, the Aboriginal Land Rights Act NT 1976 came into operation in January 1977 and the MJV was thereby required to negotiate with the Central Land Council in order to be granted the lease. The CLC was reluctant to proceed with negotiations because of the difficulty of identifying traditional owners. After 22 communications with the Council, the MJV grew impatient and the Northern Territory Government advised them to engage the author to assist in expediting the negotiations. After an intense period from March to November 1979 in which the traditional owners were identified and some violent exchanges occurred, agreement was reached on the financial terms. The Mereenie lease, which was the first petroleum lease on Aboriginal land, was granted on 18 November 1981. At present oil is piped to Brewer Estate in Alice Springs and then transported by rail to Port Stanvac in South Australia. Gas is transported to the Channel Island Power Station near Darwin via a 1,485 km pipeline. Aboriginal traditional owners receive royalty payments from all petroleum produced from Mereenie, in addition to sharing a 10% statutory royalty under the NT petroleum ordinance. The Mereenie agreement stands as a precursor to all agreements on Aboriginal land in central Australia.

Urinary incontinence in the community--analysis of a MORI poll.

To investigate the prevalence of urinary incontinence among people living at home, their responses to it, and its emotional and social effects. Random sample of 4007 adults interviewed in their own homes. Random sample of 178 constituency sampling points throughout Great Britain. 1883 men, 2124 women aged 30 and over. Responses to questionnaire. 6.6% (125) men and 14.0% (297) women had been incontinent of urine at some time--2.8% (52) men and 7.5% (159) women in the previous two months and 61% (124) of these for more than four years. 52% (108) had consulted their general practitioner at the onset of incontinence and a further 31% (65) later. Doctors commonly took a urine sample (163, 54%), referred the patient to a specialist (127, 42%), and prescribed tablets (109, 36%); only 22% (66) carried out an abdominal, rectal, or vaginal examination. Patients were not embarrassed in seeing their doctor and most thought they were treated sympathetically. 60% (265) of all those affected were concerned or worried about their incontinence, and in almost half incontinence limited their daily social activities. More people with incontinence seem to be consulting their doctors about it than has been found in previous studies, but the procedures carried out by general practitioners still seem to be suboptimal. Urinary incontinence has a profound effect on the day to day lives of most of those who suffer from it.

Strategies for Exploiting Technological Innovations: When and When Not to License

Given the limits of the patent systems, an innovating firm faces a difficult strategic conundrum: should it license its new technology to competitors or not? If the innovating firm does not license its new technology, competitors may quickly develop their own, possibly better, version of the technology. On the other hand, if imitation of the new technology is difficult, by denying its technology to competitors the innovating firm may be able to establish a competitive advantage. If the innovating firm does license its new technology to competitors, it runs the risk of losing control over that technology (of giving away its competitive advantage to competitors). On the other hand, if competitors are able to rapidly imitate the new technology anyway, by licensing its technology the innovating firm may ensure that its version of the technology becomes the dominant design in an industry. Moreover, the innovating firm will receive royalty payments in this scenario. Given these different scenarios, what should an innovating firm do? In this paper a theoretical framework is constructed that identifies the factors that influence an innovating firm's choice between licensing and not licensing. This suggests that the speed of imitation, the extent of first mover advantages, and the transaction costs of licensing play a major role in determining the appropriate choice.