Phenotype assessment for neurodegenerative murine models with ataxia and application to Niemann-Pick disease, type C1.

Identifying meaningful predictors of therapeutic efficacy from preclinical studies is challenging. However, clinical manifestations occurring in both patients and mammalian models offer significant translational value. Many neurological disorders, including inherited, metabolic Niemann-Pick disease, type C (NPC), exhibit ataxia. Both individuals with NPC and murine models manifest ataxia, and investigational therapies impacting this phenotype in mice have been reported to slow disease progression in patients (e.g. miglustat, intrathecal 2-hydroxypropyl-beta-cyclodextrin, and acetyl-L-leucine). Reproducible phenotypic scoring of animal models can facilitate comparisons between genotypes, sexes, disease course, and therapies. Previously, other groups have developed a composite phenotypic scoring system (CPSS), which was subsequently used to distinguish strain-dependent phenotypes and, with modifications, to evaluate potential therapies. However, high inter-rater reliability is paramount to widespread use. We have created a comprehensive, easy-to-follow phenotypic assessment based on the CPSS and have verified its reproducibility using murine models of NPC disease. Application of this scoring system is not limited to NPC disease and may be applicable to other models of neurodegeneration exhibiting motor incoordination, thereby increasing its utility in translational studies.

Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1.

Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3ß,5α,6ß-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3ß,5α,6ß-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-ß-cyclodextrin (HPßCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPßCD treatment.

Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPßCD treatment. In an intravenous (IV) HPßCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPßCD treatment.

Collaborative development of 2-hydroxypropyl-ß-cyclodextrin for the treatment of Niemann-Pick type C1 disease.

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-ß-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-ß-CD for the benefit of the NPC patient community.

Urbanization, migration, and Vietnam's spatial structure.

PIP: In North Vietnam during the war years from the mid-1960s to the mid-1970s, cities were evacuated to minimize damage from bombing. As such, the urbanization process was checked. In the South, however, urban areas grew rapidly as people fled the fighting in the villages. Reunification of the country led to an outflow of residents from the largest southern cities back to the North or into new economic zones. From the mid-1970s to the early 1980s, Vietnam's total urban population remained static before beginning to increase slowly during the latter half of the 1980s. The rate of urbanization accelerated in the first half of the 1990s, although that process is not reflected in the available statistics. During 1979-89, the smaller cities grew faster than the larger ones, while most interprovincial migration occurred from North to South. Unemployment is a major problem in Vietnam's growing cities. The country's economic reforms require a more fluid labor market with fewer restrictions upon labor mobility. These needs are gradually undermining the strategy designed to contain urbanization, forcing planners to rethink urban development. The author discusses developing Vietnam's three main urban development corridors.^ieng

Eye movement desensitization and reprocessing in posttraumatic stress disorder: a pilot study using assessment measures.

Spectacular claims have been made regarding the efficacy of eye movement desensitization and reprocessing (EMDR) in the treatment of posttraumatic stress disorder (PTSD), but almost entirely on the basis of patients' reports and without objective criteria. This study reports on the treatment of eight patients with a diagnosis of PTSD who received EMDR treatment over four sessions. Assessment measures included two structured interviews, three self-report inventories, and the electromyogram (EMG). Assessments were conducted pre and posttreatment, and at 3-month follow-up. Despite some residual pathology at posttreatment and follow-up, significant improvements were obtained on all measures and across all PTSD symptom clusters. Compared with other treatments of PTSD, change was achieved in far fewer sessions.

Conservative management of temporomandibular disorders: a posttreatment comparison between patients from a university clinic and from private practice.

Long-term (1 to 7.5 years) follow-up evaluations of 110 adult patients who were seen for diagnosis and treatment of symptoms related to myofascial problems (MP), internal derangement (ID), or both were conducted by means of telephone interview. One half of the patients were seen at the Northwestern University Dental School TMJ Clinic, while the other half were seen in the private office of one author (H. T. P.). The purpose of this study was to evaluate patient response to conservative therapy combined with advice about self-management, as compared with the response to advice only. Further, we desired to compare treatment outcomes among (1) diagnostic categories ID, MP, and ID plus MP, (2) clinic patients and private patients, and (3) patients with acute disease and those with chronic disease. Chronic disease was identified as that in which pretreatment symptoms had persisted for more than 4 months. The ridit analysis was used to assess differences in outcomes for patients in the three diagnostic categories and for clinic patients compared with private patients. The results revealed no significant differences. There was a trend for patients with acute conditions to improve more than those with chronic problems; however, further research is needed to determine whether a correlation exists between symptom duration and treatment outcome. At the time of the follow-up evaluation, 88% of all patients reported substantial or total improvement in their symptoms of pain and dysfunction. Therefore, conservative therapy, including advice about self-management, was found to be both adequate and appropriate for most of these patients.

Production, reproduction, and underdevelopment: petty commodity producers in Ujung Pandang, Indonesia.

PIP: This discussion is based on a case study of the Indonesian city of Ujung Pandang. A group of petty commodity producers is examined. It is argued that in order to understand the reasons for the stagnation of petty production in Ujung Pandang, it is necessary to appreciate the internal stucture of petty production and the relationship between petty production and the capitalist and peasant sectors of the economy. The transfer of economic surplus out of petty commodity production which characterizes these relations is important to an understanding of the poverty of the petty producers in the city, whereas the class formation this promotes perpetuates the underdeveloped character of the economy. The same processes also mean that petty commodity production has an important role in the reproduction of the dominant capitalist sector of production because of the support it unwittingly gives to the wage labor force. These processes represent only a small part of the processes of social and economic change in Ujung Pandang, and by the same token, the concept of transfer of economic surplus is a relatively small part of a full explanation of underdevelopment. Yet, the social and geographic transfer of economic surplus can make a substantial contribution to an understanding of the broader processes associated with underdevelopment. There are 2 areas where more critical analysis can be directed and which will improve an understanding of the processes examined in this discussion: there should be more debate about the nature and theoretical significance of articulation especially transfers of value and surplus, and a greater input of empirical research to supplement this understanding; and it is necessary to focus more explicitly on the relations of production in the capitalist and precapitalist modes of production in the Indonesian city.^ieng