[New insights into diagnosis and management of gestational diabetes mellitus: recommendations of the Swiss Society for Endocrinology and Diabetes]

Physiology and current knowledge about gestational diabetes which led to the adoption of new diagnostic criterias and blood glucose target levels during pregnancy by the Swiss Society for Endocrinology and Diabetes are reviewed. The 6th International Workshop Conference on Gestational Diabetes mellitus in Pasedena (2008) defined new diagnostic criteria based on the results of the HAPO-Trial. These criteria were during the ADA congress in New Orleans in 2009 presented. According to the new criteria there is no need for screening, but all pregnant women have to be tested with a 75 g oral glucose tolerance test between the 24th and 28th week of pregnancy. The new diagnostic values are very similar to the ones previously adopted by the ADA with the exception that only one out of three values has to be elevated in order to make the diagnosis of gestational diabetes. Due to this important difference it is very likely that gestational diabetes will be diagnosed more frequently in the future. The diagnostic criteria are: Fasting plasma glucose > or = 5.1 mmol/l, 1-hour value > or = 10.0 mmol/l or 2-hour value > or = 8.5 mmol/l. Based on current knowledge and randomized trials it is much more difficult to define glucose target levels during pregnancy. This difficulty has led to many different recommendations issued by diabetes societies. The Swiss Society of Endocrinology and Diabetes follows the arguments of the International Diabetes Federation (IDF) that self-blood glucose monitoring itself lacks precision and that there are very few randomized trials. Therefore, the target levels have to be easy to remember and might be slightly different in mmol/l or mg/dl. The Swiss Society for Endocrinology and Diabetes adopts the tentative target values of the IDF with fasting plasma glucose values < 5.3 mM and 1- and 2-hour postprandial (after the end of the meal) values of < 8.0 and 7.0 mmol/l, respectively. The last part of these recommendations deals with the therapeutic options during pregnancy (nutrition, physical exercise and pharmaceutical treatment). If despite lifestyle changes the target values are not met, approximately 25 % of patients have to be treated pharmaceutically. Insulin therapy is still the preferred treatment option, but metformin (and as an exception glibenclamide) can be used, if there are major hurdles for the initiation of insulin therapy.

Wavelet-denoising of electroencephalogram and the absolute slope method: a new tool to improve electroencephalographic localization and lateralization

OBJECTIVE: In ictal scalp electroencephalogram (EEG) the presence of artefacts and the wide ranging patterns of discharges are hurdles to good diagnostic accuracy. Quantitative EEG aids the lateralization and/or localization process of epileptiform activity. METHODS: Twelve patients achieving Engel Class I/IIa outcome following temporal lobe surgery (1 year) were selected with approximately 1-3 ictal EEGs analyzed/patient. The EEG signals were denoised with discrete wavelet transform (DWT), followed by computing the normalized absolute slopes and spatial interpolation of scalp topography associated to detection of local maxima. For localization, the region with the highest normalized absolute slopes at the time when epileptiform activities were registered (>2.5 times standard deviation) was designated as the region of onset. For lateralization, the cerebral hemisphere registering the first appearance of normalized absolute slopes >2.5 times the standard deviation was designated as the side of onset. As comparison, all the EEG episodes were reviewed by two neurologists blinded to clinical information to determine the localization and lateralization of seizure onset by visual analysis. RESULTS: 16/25 seizures (64%) were correctly localized by the visual method and 21/25 seizures (84%) by the quantitative EEG method. 12/25 seizures (48%) were correctly lateralized by the visual method and 23/25 seizures (92%) by the quantitative EEG method. The McNemar test showed p=0.15 for localization and p=0.0026 for lateralization when comparing the two methods. CONCLUSIONS: The quantitative EEG method yielded significantly more seizure episodes that were correctly lateralized and there was a trend towards more correctly localized seizures. SIGNIFICANCE: Coupling DWT with the absolute slope method helps clinicians achieve a better EEG diagnostic accuracy.

Orphanhood, Poverty and the Care Dilemma: Review of Global Policy Trends

The care and protection of children experiencing orphanhood presents a major child-care policy challenge. This paper draws on a review of the literature to document divergent conceptualizations of orphanhood, how the hurdles for the care of orphans reflect wider issues of poverty and inequality, as well as the ways in which different care interventions (familial, institutional, community-based and rights-based) might be appropriated for children in need. It is argued that the map of contemporary orphanhood overlaps with the contours of global poverty, inequality, age-based deprivations and marginalization. An example of a ‘globalised’ model of orphan care, namely SOS Children’s Villages, is presented and its implications for policy are examined. The paper highlights the significance of fighting poverty and enhancing the care-giving capabilities of extended families in the care and protection of children from a rights-based perspective. It suggests that external interventions should primarily address the structural causes of poverty and marginality, rather than amplifying inequalities through the selective support of orphans in economically vulnerable communities.

Novel biomarkers for the prediction of metastasis in colorectal cancer

INTRODUCTION In patients with metastatic colorectal cancers, multimodal management and the use of biological agents such as monoclonal antibodies have had major positive effects on survival. The ability to predict which patients may be at 'high risk' of distant metastasis could have major implications on patient management. Histomorphological, immunohistochemical or molecular biomarkers are currently being investigated in order to test their potential value as predictors of metastasis. AREAS COVERED Here, the author reviews the clinical and functional data supporting the investigation of three novel promising biomarkers for the prediction of metastasis in patients with colorectal cancer: tumor budding, Raf1 kinase inhibitor protein (RKIP) and metastasis-associated in colon cancer-1 (MACC1). EXPERT OPINION The lifespan of most potential biomarkers is short as evidenced by the rare cases that have successfully made their way into daily practice such as KRAS or microsatellite instability (MSI) status. Although the three biomarkers reviewed herein have the potential to become important predictive biomarkers of metastasis, they have similar hurdles to overcome before they can be implemented into clinical management: standardization and validation in prospective patient cohorts.

Cryo-electron tomography of Kaposi's sarcoma-associated herpesvirus capsids reveals dynamic scaffolding structures essential to capsid assembly and maturation.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a recently discovered DNA tumor virus that belongs to the gamma-herpesvirus subfamily. Though numerous studies on KSHV and other herpesviruses, in general, have revealed much about their multilayered organization and capsid structure, the herpesvirus capsid assembly and maturation pathway remains poorly understood. Structural variability or irregularity of the capsid internal scaffolding core and the lack of adequate tools to study such structures have presented major hurdles to earlier investigations employing more traditional cryo-electron microscopy (cryoEM) single particle reconstruction. In this study, we used cryo-electron tomography (cryoET) to obtain 3D reconstructions of individual KSHV capsids, allowing direct visualization of the capsid internal structures and systematic comparison of the scaffolding cores for the first time. We show that B-capsids are not a structurally homogenous group; rather, they represent an ensemble of "B-capsid-like" particles whose inner scaffolding is highly variable, possibly representing different intermediates existing during the KSHV capsid assembly and maturation. This information, taken together with previous observations, has allowed us to propose a detailed pathway of herpesvirus capsid assembly and maturation.

Tel Aviv - Mumbai - Tel Aviv: Same-Sex couples seeking parenthood in India

In Israel religious belonging remains a central category of citizenship. Laws concerning reproductive technologies such as the surrogacy law from 1996 are strongly informed by Orthodox rabbis’ kinship concepts (Kahn 2000, Shalev 1998, Weisberg 2005). A set of regulations secures that heterosexual Jewish couples bring into being children who are unequivocally Jewish themselves. The Israeli surrogacy law can therefore be understood as part of a policy seeking to reproduce the boundaries of the Jewish-Israeli collective. Same-sex couples do not fit this narrow definition of family and have no access to surrogacy in Israel. Yet gay couples maintain that parenthood is a universal civil right and bypass their exclusion through surrogacy arrangements abroad. The proposed paper follows these couples to Mumbai, which has become a popular destination for surrogacy in recent years. After their children’s birth the couples spend three to five weeks in India. In this time they not only take on their new tasks as fathers. They are also occupied with the bureaucracy of disconnecting the children from India and turning them into Israeli citizens. The paper elaborates on the bureaucratic processes and the hurdles same-sex couples encounter when seeking recognition of their parenthood and citizenship for their children. It unveils the intricacies and ramifications of Israel’s contradicting surrogacy policy of enforcing narrow definitions of family inside the country and simultaneously outsourcing problematic cases.

Cell therapy for intervertebral disc repair: advancing cell therapy from bench to clinics

Intervertebral disc (IVD) degeneration is a major cause of pain and disability; yet therapeutic options are limited and treatment often remains unsatisfactory. In recent years, research activities have intensified in tissue engineering and regenerative medicine, and pre-clinical studies have demonstrated encouraging results. Nonetheless, the translation of new biological therapies into clinical practice faces substantial barriers. During the symposium "Where Science meets Clinics", sponsored by the AO Foundation and held in Davos, Switzerland, from September 5-7, 2013, hurdles for translation were outlined, and ways to overcome them were discussed. With respect to cell therapy for IVD repair, it is obvious that regenerative treatment is indicated at early stages of disc degeneration, before structural changes have occurred. It is envisaged that in the near future, screening techniques and non-invasive imaging methods will be available to detect early degenerative changes. The promises of cell therapy include a sustained effect on matrix synthesis, inflammation control, and prevention of angio- and neuro-genesis. Discogenic pain, originating from "black discs" or annular injury, prevention of adjacent segment disease, and prevention of post-discectomy syndrome were identified as prospective indications for cell therapy. Before such therapy can safely and effectively be introduced into clinics, the identification of the patient population and proper standardisation of diagnostic parameters and outcome measurements are indispensable. Furthermore, open questions regarding the optimal cell type and delivery method need to be resolved in order to overcome the safety concerns implied with certain procedures. Finally, appropriate large animal models and well-designed clinical studies will be required, particularly addressing safety aspects.

An educational review of cartilage repair: precepts & practice - myths & misconceptions - progress & prospects.

OBJECTIVE The repair of cartilaginous lesions within synovial joints is still an unresolved and weighty clinical problem. Although research activity in this area has been indefatigably sustained, no significant progress has been made during the past decade. The aim of this educational review is to heighten the awareness amongst students and scientists of the basic issues that must be tackled and resolved before we can hope to escape from the whirlpool of stagnation into which we have fallen: cartilage repair redivivus! DESIGN Articular-cartilage lesions may be induced traumatically (e.g., by sports injuries and occupational accidents) or pathologically during the course of a degenerative disease (e.g., osteoarthritis). This review addresses the biological basis of cartilage repair and surveys current trends in treatment strategies, focussing on those that are most widely adopted by orthopaedic surgeons [viz., abrasive chondroplasty, microfracturing/microdrilling, osteochondral grafting and autologous-chondrocyte implantation (ACI)]. Also described are current research activities in the field of cartilage-tissue engineering, which, as a therapeutic principle, holds more promise for success than any other experimental approach. RESULTS AND CONCLUSIONS Tissue engineering aims to reconstitute a tissue both structurally and functionally. This process can be conducted entirely in vitro, initially in vitro and then in vivo (in situ), or entirely in vivo. Three key constituents usually form the building blocks of such an approach: a matrix scaffold, cells, and signalling molecules. Of the proposed approaches, none have yet advanced beyond the phase of experimental development to the level of clinical induction. The hurdles that need to be surmounted for ultimate success are discussed.

Taking personalized medicine seriously: Biomarker approaches in phase IIb/III studies in major depression and schizophrenia

The success rate in the development of psychopharmacological compounds is insufficient. Two main reasons for failure have been frequently identified: 1) treating the wrong patients and 2) using the wrong dose. This is potentially based on the known heterogeneity among patients, both on a syndromal and a biological level. A focus on personalized medicine through better characterization with biomarkers has been successful in other therapeutic areas. Nevertheless, obstacles toward this goal that exist are 1) the perception of a lack of validation, 2) the perception of an expensive and complicated enterprise, and 3) the perception of regulatory hurdles. The authors tackle these concerns and focus on the utilization of biomarkers as predictive markers for treatment outcome. The authors primarily cover examples from the areas of major depression and schizophrenia. Methodologies covered include salivary and plasma collection of neuroendocrine, metabolic, and inflammatory markers, which identified subgroups of patients in the Netherlands Study of Depression and Anxiety. A battery of vegetative markers, including sleep-electroencephalography parameters, heart rate variability, and bedside functional tests, can be utilized to characterize the activity of a functional system that is related to treatment refractoriness in depression (e.g., the renin-angiotensin-aldosterone system). Actigraphy and skin conductance can be utilized to classify patients with schizophrenia and provide objective readouts for vegetative activation as a functional marker of target engagement. Genetic markers, related to folate metabolism, or folate itself, has prognostic value for the treatment response in patients with schizophrenia. Already, several biomarkers are routinely collected in standard clinical trials (e.g., blood pressure and plasma electrolytes), and appear to be differentiating factors for treatment outcome. Given the availability of a wide variety of markers, the further development and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the "Taking Personalized Medicine Seriously-Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014.

PARP Inhibitor Resistance - What Is Beyond BRCA1 or BRCA2 Restoration?

Nearly 10 years ago the usefulness of poly(ADP-ribose) polymerase (PARP) inhibitors to kill BRCA1 or BRCA2-deficient cells was reported, and this finding has served as a prime example of the concept of synthetic lethality in the context of anticancer therapy. The clinical translation of this finding has undergone several ups and downs, however. Despite spectacular responses seen in some patients with BRCA-deficient breast or ovarian cancers, other patients did not show the expected benefit from PARP inhibitor therapy. Thus, like for all novel tailored anti-cancer drugs, upfront and secondary resistance remain major hurdles in the implementation of the initial preclinical finding. We know at least one clinically relevant mechanism of PARP inhibitor resistance: the reversion of BRCA function by secondary mutations. Nevertheless, it is also clear that this mechanism does not explain all cases of resistance. At the moment, we only have a poor understanding of BRCA reversion-independent resistance mechanisms. Preclinical data have pointed in several directions, e.g. increased drug efflux, reduced drug target levels, or alternative DNA repair. Here, we discuss these mechanisms with a focus on potential DNA repair adaptations.

Music Piracy on Peer-to-Peer Networks

Content providers from the music industry argue that peer-to-peer (P2P) networks such as KaZaA, Morpheus, iMesh, or Audiogalaxy are an enormous threat to their business. They furthermore blame these networks for their recent decline in sales figures. For this reason, an empirical investigation was conducted during a period of 6 weeks on one of the most popular files-sharing systems, in order to determine the quantity and quality of pirated music songs shared. We present empirical evidence as to what extent and in which quality music songs are being shared. A number of hypotheses are outlined and were tested. We studied, among other things, the number of users online and the number of flies accessible on such networks, the free riding problem, and the duration per search request. We further tested to see if there are any differences in the accessibility of songs based on the nationality of the artist, the language of the song, and the corresponding chart position. Finally, we outline the main hurdles users may face when downloading illegal music and the probability of obtaining high quality music tracks on such peer-to-peer networks.

Greening electricity through taxing: An analysis of GATT constraints

This paper examines the legal feasibility of different design options for implementing a differentiated electricity tax based on renewable energy (RE) certificates aimed at promoting green electricity generation. It discusses the issue of likeness in light of the recent WTO jurisprudence and looks at the possibility of justification of differentiated tax rates under the general exceptions of the GATT. It also scrutinizes the potential legal hurdles for the implementation of different tax design options including the use of certificates for RE tax exemption. It argues that the placing of a quota on the number of foreign RE certificates eligible for tax exemptions would likely affect the volumes of imported green electricity and therefore trigger a violation of GATT rules. At the same time, restrictions on the eligibility of RE certificates might be defended under WTO law if they are based on qualitative criteria, such as the attachment of RE certificates to green electricity flows or to a green electricity label that is equally available to domestic and foreign suppliers of RE electricity.

Perfecting the Catching-up: The Case of Taiwan's Motorcycle Industry

The final stage of the catching-up process has formidable hurdles. This paper examines the case of Taiwan’s motorcycle industry and shows how latecomers overcame the hurdles. In the early 1990s, the two largest motorcycle makers in Taiwan, Sanyang and Kwang Yang, had completed the catching-up process and became independent from Honda, on which they had technologically depended since the early 1960s. The requisite for independence was acquiring the capacity for product innovation. The two assemblers could cultivate technological capacity by investing abundant resources, which they accumulated in the protected market. It should be noted that although the market was protected and highly concentrated, it was also very competitive. Another condition was the solid local suppliers of parts and components. The local suppliers had also grown under the government’s industrial policies. However, their development beyond imitators can be attributed to their own initiatives.

Role of supply chains in adopting product related environmental regulations : case studies of Vietnam

This paper shows some findings how product related environmental regulations, especially those that relate to management of chemical substances affect firms in Asia. Interviews were conducted for some firms in Vietnam that are part of global supply chains of electrical and electronic, furniture, and plastic industries. The global supply chains with MNC lead firms have helped local firms in developing countries to adopt technical PRERs overseas. On the other hand, indigenous firms that do not belong to global value chains might face hurdles to keep exporting to the regulated markets. PRERs could become a barrier for firms that attempt to the regulated markets without supports by MNC lead firms.

Comparison of CO2 From Coal Capture Processes and Valorisation Technologies

Coal is the most plentiful and evenly distributed fossil fuel worldwide. Based on current production, it is estimated that the reserves will last approximately 130 years. Its use worldwide has been increasing, mainly due to consumption by emerging countries. CO2 emissions generated by combustion and the repercussions of such on climate change support the view that it could no longer be used. CO2 capture may be the solution to continue using it, which would cater for the growing energy demand worldwide. The aim of this study is to compare different processes concerning CO2 capture that may be economically viable, ultimately showing that coal, a fossil energy source widely distributed around the world, can, as a result of using different CO2 capture processes, be used as a clean source of electricity. Hence, in places where geological hurdles may render the costs of CO2 storage considerably higher, since it might have to travel far, coal may be used for other purposes, thus valorising CO2 within the industrial sector. This research is focused on the technical and economic comparison of the most relevant CO2 capture projects designed in Spain using different existing technologies. The oxyfuel project in Ciuden (Leon, Spain), the IGCC Elcogas, precombustion CO2-capture project (Puertollano, Spain) and the postcombustion project in Carboneras (Almeria, Spain) will be analyzed in order to assess the options available to valorise captured CO2. Valorising captured CO2 may be an adequate solution in areas where, although CO2 capture is still possible, storage is not equally so, thus generating a further benefit. The possible uses of CO2 will be assessed in vegetable growing greenhouses, harnessing CO2 in vegetable life cycles. This will also be used in growing algae for subsequent biodiesel production. Both CO2 capture and valorising will eventually lead to the clean use of coal, which will thus enhance the level of self-supply, aiding the development of electric vehicles, which require large amounts of electricity, as well as improve the level of energy autonomy in countries around the world. Another type of fuel, biodiesel, will also be obtained, without this affecting international food prices.