Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II.

Mucopolysaccharidosis I and II are lysosomal storage disorders that, despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT), continue to cause significant skeletal abnormalities leading to pain, stiffness, physical dysfunction, and short stature. Tumor necrosis factor - alpha (TNF-α) is elevated in individuals with MPS I and II and associated with pain and physical dysfunction. Therefore, we evaluated the safety and effects of the TNF-α inhibitor adalimumab in patients with MPS I and II in a 32-week, randomized, double blind, placebo-controlled, crossover study of adalimumab at a dose of 20 mg (weight 15-<30 kg) or 40 mg (weight ≥ 30 kg) administered subcutaneously every other week or saline placebo for 16 weeks. Participants were evaluated at baseline, week 16, and week 32 with the Children's Health Questionnaire - Parent Form 50 (CHQ-PF50), the Pediatric Pain Questionnaire (PPQ), range-of-motion (ROM) measurements, anthropometry, six-minute walk test (6MWT), hand dynamometer, and laboratory evaluations for safety. The primary outcome was safety and primary efficacy outcome was bodily pain (BP) measured by the CHQ-PF50. Two subjects, one with MPS I and one with MPS II, completed the study. Adalimumab was well tolerated and there were no serious adverse events. Standardized BP scores for age and gender were higher (i.e. less pain) at the end of the treatment versus placebo phase for both subjects. Subject #1 became unblinded during treatment due to skin erythema. Behavior measured by both CHQ-PF50 and parental report improved during treatment compared to placebo in both subjects. ROM improved by > 5° in seven of eight joints in Subject #1 and five of eight joints in Subject #2 (range 7.0° to 52.8°). There was no change in the PPQ, 6MWT, or hand dynamometer. Data from this small pilot study suggest that treatment with adalimumab is safe, tolerable, and may improve ROM, physical function, and possibly pain, in children with MPS I or II. However, additional clinical trials are needed before this therapy should be recommended as part of clinical care

Innovation as a Nonlinear Process, the Scientometric Perspective, and the Specification of an "Innovation Opportunities Explorer"

The process of innovation follows non-linear patterns across the domains of science, technology, and the economy. Novel bibliometric mapping techniques can be used to investigate and represent distinctive, but complementary perspectives on the innovation process (e.g., "demand" and "supply") as well as the interactions among these perspectives. The perspectives can be represented as "continents" of data related to varying extents over time. For example, the different branches of Medical Subject Headings (MeSH) in the Medline database provide sources of such perspectives (e.g., "Diseases" versus "Drugs and Chemicals"). The multiple-perspective approach enables us to reconstruct facets of the dynamics of innovation, in terms of selection mechanisms shaping localizable trajectories and/or resulting in more globalized regimes. By expanding the data with patents and scholarly publications, we demonstrate the use of this multi-perspective approach in the case of RNA Interference (RNAi). The possibility to develop an "Innovation Opportunities Explorer" is specified.Comment: Technology Analysis and Strategic Management (forthcoming in 2013

Are MNCs norm entrepreneurs or followers? The changing relationship between host country institutions and MNC HRM practices

Rooted in the literature on comparative capitalism, we examine the effects of host country institutions on the intra-organizational practices of multinational corporations (MNCs), using transnational level survey data, exploring change over time. We found that the less comprehensive institutional mediation of the Liberal Market Economies correlated with greater diversity and a more pronounced difference between domestic firms and foreign MNCs. However, rather than being the predicted norm entrepreneurs, MNCs tended to follow the lead of local firms in adjusting HRM policies and practices towards liberalization. Those most prone to challenging existing orders were in industries facing particular crises of competitiveness. Finally, we found that single regulatory features rather than complex assemblies of institutions exerted particularly strong effects on the individual firms’ practices encompassed in this study

Aphrati and Kato Syme: Pottery, Continuity, and Cult in Late Archaic and Classical Crete

The analysis of ceramics from Aphrati sheds valuable new light on the history of this Cretan settlement and on its relationship with a nearby rural sanctuary at Kato Syme in the Late Archaic and Classical periods. It has long been held that Aphrati was deserted from ca. 600 to 400 B.C. A pottery deposit from the domestic quarter, however, now supports occupation of the city during this period. A ceramic classification system is presented and the morphological development and absolute chronology of several key shapes at Aphrati and Kato Syme are plotted. Historical implications of the ceramic evidence are also explored

Human Cytomegalovirus: detection of congenital and perinatal infection in Argentina

BACKGROUND: Human cytomegalovirus (CMV) is one of the most commonly found agents of congenital infections. Primary maternal infection is associated with risk of symptomatic congenital diseases, and high morbidity is frequently associated with very low birth weight. Neonates with asymptomatic infection develop various sequelae during infancy. This is the first Argentine study performed in neonates with congenital and postnatal HCMV infection. The purpose of this study was to evaluate the performance of the polymerase chain reaction (PCR) technique with different pairs of primers, to detect cytomegalovirus isolated in tissue cultures and directly in urine and dried blood spot (DBS) specimens. Results were compared with IgM detection. METHODS: The study was performed between 1999 and 2001 on routine samples in the Laboratory. A total of 61 urine and 56 serum samples were selected from 61 newborns/infants, 33 patients whose samples were analyzed during the first two to three weeks of life were considered congenital infections; the remaining 28 patients whose samples were taken later than the third week were grouped as perinatal infections, although only in 4 the perinatal transmission of infection was determined unequivocally Cytomegalovirus diagnosis was made by isolating the virus from urine samples in human foreskin fibroblast cells. Three different primer pairs directed to IE, LA and gB genes were used for the HCMV PCR assay in viral isolates. Subsequently, PCR and nested PCR (nPCR) assays with gB primers were performed directly in urine and in 11 samples of dried blood spot (DBS) on Guthrie Card, these results were then compared with serology. RESULTS: The main clinical manifestations of the 33 patients with congenital infection were purpura, jaundice, hepatomegaly and anaemia. Three patients presented low birth weight as single symptom, 10, intracranial calcifications, and 2, kidney failure. In the 28 patients grouped as with perinatal infection, anaemia, hepatosplenomegaly and enzymatic alteration were predominant, and 4 patients were HIV positive. The primers used to amplify the gB region had a PCR positivity rate of 100%, whereas those that amplified IE and LA regions had a PCR positivity rate of 54% and 61% respectively, in CMV isolates. Amplification by PCR of urine samples (with no previous DNA extraction), using primers for the gB region, detected 34/61 positive samples. Out of the 33 samples from patients with congenital infection, 24 (73%) were positive. When nPCR was used in these samples, all were positive, whereas in the remaining 28 patients, two negative cases were found. Cytomegalovirus DNA detection in 11 samples was also carried out in DBS: 7 DBS samples were positive and 4 were negative. CONCLUSIONS: Primers directed to the gB fragment region were the best choice for the detection of CMV DNA in positive isolates. In congenital infections, direct PCR in urine was positive in a high percentage (73%) of samples; however, in patients grouped as with perinatal infection only 36% of the cases were positive. With n-PCR, total sample positivity reached 97%. PCR technique performed in DBS allowed identifying congenital infection in four patients and to be confirmed in 3. These results show the value of nPCR for the detection of all cases of CMV infection. The assay offers the advantage that it may be performed within the normal working day and provides reliable results in a much shorter time frame than that required for either traditional tissue culture or the shell-viral assay

AGRICULTURAL POLICY REFORM IN THE WTO: THE ROAD AHEAD

Agricultural trade barriers and producer subsidies inflict real costs, both on the countries that use these policies and on their trade partners. Trade barriers lower demand for trade partners' products, domestic subsidies can induce an oversupply of agricultural products which depresses world prices, and export subsidies create increased competition for producers in other countries. Eliminating global agricultural policy distortions would result in an annual world welfare gain of $56 billion. High protection for agricultural commodities in the form of tariffs continues to be the major factor restricting world trade. In 2000, World Trade Organization (WTO) members continued global negotiations on agricultural policy reform. To help policymakers and others realize what is at stake in the global agricultural negotiations, this report quantifies the costs of global agricultural distortions and the potential benefits of their full elimination. It also analyzes the effects on U.S. and world agriculture if only partial reform is achieved in liberalizing tariffs, tariff-rate quotas (limits on imported goods), domestic support, and export subsidies.Agricultural and Food Policy, International Relations/Trade,

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Physical Electronics

Contains reports on three research projects