Malignant pheochromocytoma: current status and initiatives for future progress

Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors that are usually benign, but which may also present as or develop into a malignancy. Predicting such behavior is notoriously difficult and there are currently no curative treatments for malignant tumors. This report follows from a workshop at the Banbury Conference Center, Cold Spring Harbor, New York, on the 16th-18th November 2003, held to review the state of science and to facilitate future progress in the diagnosis and treatment of malignant pheochromocytoma. The rarity of the tumor and the resulting fragmented nature of studies, typically involving small numbers of patients, represent limiting factors to the development of effective treatments and diagnostic or prognostic markers for malignant disease. Such development is being facilitated by the availability of new genomics-based tools, but for such approaches to succeed ultimately requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data and tumor samples, and interdisciplinary collaborations among multiple specialist centers. Nevertheless, the well-characterized hereditary basis and the unique functional nature of these neuroendocrine tumors provide a useful framework that offers advantages for establishing the pathways of tumorigenesis and malignancy. Such findings may have relevance for understanding the basis of other more common malignancies where similar frameworks are not available. As the relevant pathways leading to pheochromocytoma are established it should be possible to take advantage of the new generation of drugs being developed to target specific pathways in other malignancies. Again the success of this will require well-designed and coordinated multi-center studies.     

Release of cardiac troponin I after temporally graded acute coronary ischaemia with electrocardiographic ST depression

BACKGROUND: Elevation of cardiac biochemical markers and ST segment depression in the electrocardiogram have important roles in the risk stratification of unstable coronary syndromes. We assessed graded duration of acute coronary ischaemia with ST depression versus release of cardiac troponin I (cTnI) and conventional cardiac markers in 15 ischaemic pigs and 11 controls. METHODS: Coronary ischaemia was induced via percutaneous technique by semiinflating an angioplasty balloon in the left circumflex artery. Blood velocity monitored by Doppler was reduced until ST depression > or =0.1 mV was obtained. Among 26 pigs, six controls had jugular vein sheath introduced only, five controls jugular vein and bilateral femoral sheaths, and 15 pigs were divided into three equal groups (n=5) in which ischaemia was maintained for 10, 20 and 30 min, respectively. RESULTS: Mean blood flow velocity (cm/s) at baseline was 16.3+/-6.5 and was reduced to 4.1+/-3.2 (25% of normal, range 20-29%) during ischaemia. cTnI (microg/l) did not increase in controls but increased from 0.05 to 0.52 (P<0.05) and 0.76 (P<0.05) with 10 and 20 min of ischaemia, and to 30.77 (P<0.05) with 30 min of ischaemia. A rise of myoglobin and conventional cardiac enzymes did not distinguish controls with arterial cut-down from the ischaemia groups. CONCLUSION: Release of cTnI depends on the duration of ST depression ischaemia. The critical time for a major release seems to be between 20 and 30 min. Thus, very early intervention in patients with prolonged ST depression ischemia should be focused on in future clinical trials.     

Investigation of the Mechanical Properties of Mn-Alloyed Tin-Silver-Copper Solder Solidified with Different Cooling Rates

Manganese can be an optimal alloying addition in lead-free SAC (SnAgCu) solder alloys because of its low price and harmless nature. In this research, the mechanical properties of the novel SAC0307 (Sn/Ag0.3/Cu0.7) alloyed with 0.7 wt.% Mn (designated as SAC0307-Mn07) and those of the traditionally used SAC305 (Sn96.5/Ag3/Cu0.5) solder alloys were investigated by analyzing the shear force and Vickers hardness of reflowed solder balls. During the preparation of the reflowed solder balls, different cooling rates were used in the range from 2.7 K/s to 14.7 K/s. After measuring the shear force and the Vickers hardness, the structures of the fracture surfaces and the intermetallic layer were investigated by SEM (Scanning Electron Microscopy). The mechanical property measurements showed lower shear force for the SAC0307-Mn07 alloy (20–25 N) compared with the SAC305 alloy (27–35 N), independent of the cooling rate. However, the SAC0307-Mn07 alloy was softer; its Vickers hardness was between 12 and 13 HV, whereas the Vickers hardness of the SAC305 alloy was between 19 and 20 HV. In addition, structural analyses revealed rougher intermetallic compound layers in the case of the SAC0307-Mn07 alloy, which can inhibit the propagation of cracks at the solder–substrate interface. These two properties of SAC0307-Mn07 alloy, the softer nature and the rougher intermetallic layer, might result in better thermomechanical behavior of the solder joints during the lifetime of electronic devices.     

Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in the PKLR gene (p.Arg518fs), and low hepcidin to ferritin ratios

Pyruvate kinase (PK) deficiency is an iron‐loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease‐causing PKLR mutations. Two of these mutations ‐ the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) ‐ have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease‐causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK‐deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor‐15, were increased in PK‐deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as‐yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency.     

Impact of heterogeneity and socioeconomic factors on individual behavior in decentralized sharing ecosystems

Tens of millions of individuals around the world use decentralized content distribution systems, a fact of growing social, economic, and technological importance. These sharing systems are poorly understood because, unlike in other technosocial systems, it is difficult to gather large-scale data about user behavior. Here, we investigate user activity patterns and the socioeconomic factors that could explain the behavior. Our analysis reveals that (i) the ecosystem is heterogeneous at several levels: content types are heterogeneous, users specialize in a few content types, and countries are heterogeneous in user profiles; and (ii) there is a strong correlation between socioeconomic indicators of a country and users behavior. Our findings open a research area on the dynamics of decentralized sharing ecosystems and the socioeconomic factors affecting them, and may have implications for the design of algorithms and for policymaking.Every month, ∼150 million users worldwide share files over the Internet using BitTorrent (1), the most widely used decentralized peer-to-peer (P2P) communication protocol. Eleven years after its inception, file sharing through BitTorrent is one of the top three major contributors to the overall Internet traffic, accounting for 9–27% of the total traffic, depending on the continent (2, 3).The expansion in scale and breadth of decentralized file-sharing has highlighted the conflicts between the interests of creators (musicians and writers, e.g.) and those of P2P users. Creators and creative industries argue that they are being deprived of fair compensation for their work (4), which is being widely distributed for free in violation of copyright laws. Users, however, argue that P2P can be (and is) used for sharing nonproprietary contents, and warn that widespread monitoring of online activity by corporations and law enforcement violates P2P users’ right to privacy. Proof of the complexity of the situation includes the rejection of the Anti-Counterfeiting Trade Agreement by the European Parliament and the controversy with the Stop Online Piracy Act in the United States.Despite the growing social, economic, and technological importance of BitTorrent (4), there is currently little understanding of how users behave in this complex technosocial (5, 6) ecosystem. Due to the decentralized structure of P2P ecosystems, it is very difficult to gather large-scale data about interactions and behavioral patterns of the users without their explicit consent; this is in contrast to other forms of online exchange where all of the information is stored in a central system, be it publicly accessible as in Wikipedia (7), partially accessible through a public interface as in Twitter (8, 9) or Google [through its search logs (10) or its public services (11, 12)], or restricted as in Facebook (13, 14) or in email communications within organizations (15–18).Because of the difficulty to collect complete user-level data of large and representative samples of users (3), studies of user behavior in P2P networks have so far been based on (i) small datasets; (ii) aggregate data collected from “trackers” or from individual Internet service providers (ISPs); and (iii) incomplete user data collected using a single crawler client connected to the network (19–23).Here, we investigate the complete activity patterns of a large and representative pool of BitTorrent users. Our analysis reveals that P2P sharing is highly heterogeneous, that users are specialized, giving rise to well-defined user profiles, and that the abundance of certain user profiles in a country is highly correlated with socioeconomic factors. Our findings open a research area on the dynamics of decentralized sharing ecosystems, and may have implications for the understanding and design of algorithms and for policymaking.     

Validation of a short food frequency questionnaire to evaluate nutritional lifestyles in hypercholesterolemic patients

ObjectivesThe purpose of our study was to develop and validate a short food frequency questionnaire which could assess the nutritional lifestyles of hypercholesterolemic patients consulting in daily practice.Material and methodsThe questionnaire explores 11 nutrient categories. Hundred and thirty-one patients were recruited for the construct validity and 58 patients for the external validity in La Pitié Hospital, Paris. The reference method used was the diet history. To measure the internal consistency and to test the sensibility to change on a large scale, the questionnaire was used in an observational study conducted in Spain in 1048 moderate hypercholesterolemic patients. Psychometric analyses included construct validity, internal consistency, test-retest reliability, external validity and sensibility to change.ResultsValidation of the questionnaire indicated a good internal consistency (Cronbach Coefficient Alpha at 0.69) and test-retest reliability (intraclass correlation coefficient = 0.89). The correlation between the scores of the FFQ and those of the diet history was significant with a Pearson correlation coefficient at 0.3 (P = 0.029). The comparison between the ranking of the patients showed an agreement of 72% with a kappa of 0.48 [0.10; 0.69]. The sensibility to change was good with a score evolution improving one and four months after nutrition advices: 28.2% of patients ranked in group 1 at inclusion versus 61.3% (P < 0.0001) at one month and 75.2% (P < 0.0001) at four months.ConclusionIn conclusion, we developed and validated a food questionnaire for hypercholesterolemic patients, which can be used as a therapeutic education tool in daily practice or in clinical research.