Processes of International Negotiations

Negotiations are essential mechanisms for the peaceful resolution of disputes and for maintaining stability in international relations. Negotiations can and should contribute to predictability, equity, and security among states. In achieving these goals, negotiations become important confidence-building measures. The increasing role of negotiations and of international organizations for managing the system of international order and for pursuing/achieving states' interests/policies through peaceful means has produced a fundamental evolution in the agenda, functions, and intensity of international negotiations. In the view of both researchers and negotiators over the recent past, the negotiations process that is organized along traditional lines is becoming more complex, difficult, and less effective. The processes of negotiations are in general taking more and more time and lagging behind the evolution of the international environment. Not only are the issues themselves more complex, but also, in the implementation of any agreements reached, the resolution of the issues involved will need to take place over a longer time and therefore to be managed jointly or multilaterally. Because of the increasing complexity of issues and the fast pace of changes affecting both national and international interests, it has become essential for international agreements to contain sufficient flexibility in certain of their provisions to permit dealing with uncertainty and the needs of the parties to adapt to new and changing circumstances. In this sense, international negotiations and agreements must be not only reactive but also anticipatory. These considerations indicate that a much-needed approach is one which is concerned specifically with bringing about a multinational, multicultural, and multidisciplinary understanding of and perspective on international negotiations and which also bridges the gap between practitioners and researchers. A specific objective and unique aspect of the IIASA Project on the Processes of International Negotiations (PIN Project), which started in April 1986 and was funded by the Carnegie Corporation, is the international, multidisciplinary approach brought to bear on all of the Project's activities. This was especially evident at the IIASA Conference on the Processes of International Negotiations, held in May 1987. The PIN networks in IIASA's member countries played an essential role in this Conference. To keep the focus of the work on substantive issues and on relevant applications-oriented results, while taking into account the importance and impact of different cultural and political systems in the various national approaches to negotiations, both practitioners and researchers involved in the processes of negotiations made presentations at the PIN Conference and took part in the panel discussions. These presentations form the basis for the chapters of this book. The goals of the Conference were to foster increased communication and understanding between practitioners and researchers and among various research disciplines, to present and discuss research results, and to identify possible future research activities. The participation and interaction of both high-level negotiations practitioners and researchers were considered especially valuable and unique aspects of the Conference. All of the subjects dealt with at the Conference have direct and obvious relevance to improving negotiations outcomes on, and the ability to deal effectively with, such issues as the transboundary effects (environmental, economic, etc.) of technological risk, security and confidence-building measures, and international economic cooperation -- all of which are high on the negotiations agenda of many countries

Mutations and Allelic Loss of the NF2 Gene in Neurofibromatosis 2-Associated Skin Tumors

Schwannomas in the skin are frequently observed in neurofibromatosis 2 patients. In about one-quarter of the cases, skin tumors are the first clinical symptoms of this disease. Recognizing neurofibromatosis-2-related skin tumors is therefore important for early diagnosis of neurofibromatosis 2, especially in pediatric patients. In this study, we examined 40 skin tumors (36 schwannomas and four neurofibromas) from 20 neurofibromatosis 2 patients for NF2 mutations and allelic loss. NF2 mutations have been identified in blood from 15 (75%) of the 20 patients. We found NF2 mutations in five (13%) and NF2 allelic loss in 18 (45%) of the 40 analyzed tumors. Genetic alterations (allelic loss or mutation) were thus found in 50 (63%) out of the total of 80 examined alleles. In 17 (43%) tumors, alterations were found on both NF2 alleles. These results suggest that, as in the case of vestibular schwannomas and meningiomas, loss of functional NF2 gene product is also the critical event in the development of skin schwannomas. Identification of genetic alterations of the NF2 gene in skin tumors may help to identify neurofibromatosis-2-associated skin tumors, thus assisting in the diagnosis of neurofibromatosis 2 in ambiguous cases, and excluding neurofibromatosis 1 in unclear cases. We also report that the detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%)

Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone (Exisulind) are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients. RESULTS: Exisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 μM and 63 μM, respectively. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 μM Exisulind and 125 μM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1/2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen. CONCLUSIONS: Our results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST

Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients

AbstractBackgroundCognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition?MethodsWe used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls.FindingsNF1 patients experienced substantial decline in motor skill acquisition (F=9.2, p=0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T=2.8, p=0.014), especially evident after the early acquisition phase.InterpretationsCollectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work

Pronounced maternal parent-of-origin bias for type-1 NF1 microdeletions

Neurofibromatosis type 1 (NF1) is caused, in 4.7–11% of cases, by large deletions encompassing the NF1 gene and its flanking regions within 17q11.2. Different types of large NF1 deletion occur which are distinguishable by their breakpoint location and underlying mutational mechanism. Most common are the type-1 NF1 deletions of 1.4 Mb which exhibit recurrent breakpoints caused by nonallelic homologous recombination (NAHR), also termed unequal crossover. Here, we analyzed 37 unrelated families of patients with de novo type-1 NF1 deletions by means of short tandem repeat (STR) profiling to determine the parental origin of the deletions. We observed that 33 of the 37 type-1 deletions were of maternal origin (89.2% of cases; p < 0.0001). Analysis of the patients’ siblings indicated that, in 14 informative cases, ten (71.4%) deletions resulted from interchromosomal unequal crossover during meiosis I. Our findings indicate a strong maternal parent-of-origin bias for type-1 NF1 deletions. A similarly pronounced maternal transmission bias has been reported for recurrent copy number variants (CNVs) within 16p11.2 associated with autism, but not so far for any other NAHR-mediated pathogenic CNVs. Region-specific genomic features are likely to be responsible for the maternal bias in the origin of both the 16p11.2 CNVs and type-1 NF1 deletions

Macdonald Polynomials from Sklyanin Algebras: A Conceptual Basis for the pp-Adics-Quantum Group Connection

We establish a previously conjectured connection between $p$-adics and quantum groups. We find in Sklyanin's two parameter elliptic quantum algebra and its generalizations, the conceptual basis for the Macdonald polynomials, which ``interpolate'' between the zonal spherical functions of related real and $p$\--adic symmetric spaces. The elliptic quantum algebras underlie the $Z_n$\--Baxter models. We show that in the n \air \infty limit, the Jost function for the scattering of {\em first} level excitations in the $Z_n$\--Baxter model coincides with the Harish\--Chandra\--like $c$\--function constructed from the Macdonald polynomials associated to the root system $A_1$. The partition function of the $Z_2$\--Baxter model itself is also expressed in terms of this Macdonald\--Harish\--Chandra\ $c$\--function, albeit in a less simple way. We relate the two parameters $q$ and $t$ of the Macdonald polynomials to the anisotropy and modular parameters of the Baxter model. In particular the $p$\--adic ``regimes'' in the Macdonald polynomials correspond to a discrete sequence of XXZ models. We also discuss the possibility of ``$q$\--deforming'' Euler products.Comment: 25 page

On unitarizability in the case of classical p-adic groups

In the introduction of this paper we discuss a possible approach to the unitarizability problem for classical p-adic groups. In this paper we give some very limited support that such approach is not without chance. In a forthcoming paper we shall give additional evidence in generalized cuspidal rank (up to) three.Comment: This paper is a merged and revised version of ealier preprints arXiv:1701.07658 and arXiv:1701.07662. The paper is going to appear in the Proceedings of the Simons Symposium on Geometric Aspects of the Trace Formul

Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2

Background Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). Aims The aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas Methods We conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. Results Eight patients with NF2 and symptomatic ependymoma were treated with bevacizumab. All patients had subjective clinical improvement with bevacizumab, although only five of eight patients evaluated had radiographic response. All tumors expressed VEGF-R2. Four of five evaluated ependymomas expressed VEGF-R1; one without VEGF-R1 expression was from a patient who showed clinical but not radiographic response. Conclusions Treatment using bevacizumab improved symptoms related to NF2-associated ependymomas, often without concurrent radiographic respo

Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease.We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors.WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10).WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations