An initial MRI picture of limbic encephalitis in subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare and severe long-term complication of measles. Hallmarks of this entity include progressive cognitive decline, myoclonia, a generalized periodic pattern on EEG and deep white matter abnormalities on MRI. However, imaging can be normal in early stages. AIM: We report herein the case of a previously healthy 13-years-old girl with an unusual radiological presentation. RESULTS: She presented with unilateral myoclonia, cognitive decline with memory impairment and a first brain MRI with swelling of both hippocampi mimicking limbic encephalitis. Measles antibodies were positive in CSF and the EEG showed slow periodic complexes. CONCLUSION: This unusual radiological presentation has never been described in SSPE. Relationship between virus and limbic system are discussed.

Qualitative and Hierarchical Analysis of Protective Factors against Illicit Use of Doping Substances in Athletes Calling a National Anti-Doping Phone-Help Service

Evidence of a sport-specific hierarchy of protective factors against doping would thus be a powerful aid in adapting information and prevention campaigns to target the characteristics of specific athlete groups, and especially those athletes most vulnerable for doping control. The contents of phone calls to a free and anonymous national anti-doping service called 'ecoute dopage' were analysed (192 bodybuilders, 124 cyclists and 44 footballers). The results showed that the protective factors that emerged from analysis could be categorised into two groups. The first comprised 'Health concerns', 'Respect for the law' and 'Doping controls from the environment' and the second comprised 'Doubts about the effectiveness of illicit products, 'Thinking skills' and 'Doubts about doctors'. The ranking of the factors for the cyclists differed from that of the other athletes. The ordering of factors was 1) respect for the law, 2) doping controls from the environment, 3) health concerns 4) doubts about doctors, and 5) doubts about the effectiveness illicit products. The results are analysed in terms of the ranking in each athlete group and the consequences on the athletes' experience and relationship to doping. Specific prevention campaigns are proposed to limit doping behaviour in general and for each sport.

The inflammasome, autoinflammatory diseases, and gout.

IL-1beta is a cytokine with major roles in inflammation and innate immune responses. IL-1beta is produced as an inactive proform that must be cleaved within the cell to generate biologically active IL-1beta. The enzyme caspase-1 catalyzes the reaction. Recent work showed that caspase-1 must be activated by a complex known as the inflammasome. The inflammasome comprises NALP, which is an intracellular receptor involved in innate immunity, and an ASC adapter that ensures caspase-1 recruitment to the receptor. The most extensively described inflammasome to date is formed by the NALP3 receptor within monocytes. Mutations involving the NALP3 gene cause hereditary periodic fever syndromes in humans. Increased inflammasome activity responsible for uncontrolled IL-1beta production occurs in these syndromes. Inhibition of the IL-1beta pathway by IL-1 receptor antagonist (anakinra) is a highly effective treatment for inherited periodic fever syndromes. A major role for inflammasome activity in the development of gout attacks was established recently. Urate monosodium crystals are specifically detected via the NALP3 inflammasome, which results in marked IL-1beta overproduction and initiation of an inflammatory response. This finding opens up new possibilities for the management of gouty attacks.

Continuous electroencephalography in the medical intensive care unit.

OBJECTIVES: To examine predictors and the prognostic value of electrographic seizures (ESZs) and periodic epileptiform discharges (PEDs) in medical intensive care unit (MICU) patients without a primary acute neurologic condition. DESIGN: Retrospective study. SETTING: MICU in a university hospital. PATIENTS: A total of 201 consecutive patients admitted to the MICU between July 2004 and January 2007 without known acute neurologic injury and who underwent continuous electroencephalography monitoring (cEEG) for investigation of possible seizures or changes in mental status. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Median time from intensive care unit (ICU) admission to cEEG was 1 day (interquartile range 1-4). The majority of patients (60%) had sepsis as the primary admission diagnosis and 48% were comatose at the time of cEEG. Ten percent (n = 21) of patients had ESZs, 17% (n = 34) had PEDs, 5% (n = 10) had both, and 22% (n = 45) had either ESZs or PEDs. Seizures during cEEG were purely electrographic (no detectable clinical correlate) in the majority (67%) of patients. Patients with sepsis had a higher rate of ESZs or PEDs than those without sepsis (32% vs. 9%, p < 0.001). On multivariable analysis, sepsis at ICU admission was the only significant predictor of ESZs or PEDs (odds ratio 4.6, 95% confidence interval 1.9-12.7, p = 0.002). After controlling for age, coma, and organ dysfunction, the presence of ESZs or PEDs was associated with death or severe disability at hospital discharge (89% with ESZs or PEDs, vs. 39% if not; odds ratio 19.1, 95% confidence interval 6.3-74.6, p < 0.001). CONCLUSION: In this retrospective study of MICU patients monitored with cEEG, ESZs and PEDs were frequent, predominantly in patients with sepsis. Seizures were mainly nonconvulsive. Both seizures and periodic discharges were associated with poor outcome. Prospective studies are warranted to determine more precisely the frequency and clinical impact of nonconvulsive seizures and periodic discharges, particularly in septic patients.

Role of the NALP3 Inflammasome in the Development of Two-Kidney, One Clip Hypertension in Mice

Objective: The NALP3 inflammasome functions as a sensor of danger signals and triggers processing and release of IL-1b. Mutations of NALP3 are responsible for the cryopyrin associated periodic syndromes, a group of autoinflammatory disorders that respond to IL1 inhibition. Genetic studies have also linked NALP3 to hypertension in man, but the mechanism is not understood. The aim of this study is to investigate the role of NAPL3 inflammasome in the development of hypertension in an animal model. Design and Method: Six-week old male WT and NALP3 KO mice were used for generating a two-kidney, one clip (2K1C) renovascular hypertension. A U-shaped stainless steel clip (O^ ¼0.12mm) was placed on left renal artery under anaesthesia. The same surgery without clipping was performed in sham mice. At week 6 and 12 after the clipping, intra-arterial blood pressure (BP) was measured in conscious mice. Blood was collected for plasma renin analysis. Heart and kidney were excised and stored for molecular and morphological examinations. n¼5-6 mice per group. Data are mean_SEM. Results: Mean BP was significantly increased at week 6 and 12 in WT-2K1C mice compared to WT-sham group (MBPweek6: 138_2 vs.124_3 mmHg, p<0.01 and MBPweek12: 141_5 vs.122_3 mmHg, p<0.01) followed with an significant increase in heart weight (HW) and a decrease in clipped kidney weight indices in WT-2K1C mice compared to the WT-sham (HW/ BWweek6: 4.65_0.04 vs. 3.99_0.12 mg/g, p<0.001 and HW/BWweek12: 4.94_0.15 vs. 4.22_0.12 mg/g, p<0.001). Interestingly, NALP3 KO-2K1C mice did not develop hypertension. The MBP of KO-2K1C mice was comparable to the KO-sham (MBPweek6: 122_3 vs. 119_3 mmHg, p>0.05 and MBPweek6: 128_5 vs.122_4 mmHg, p>0.05). There was also no significant change in heart and kidney weight indices between KO- 2K1C and KO-sham mice. Conclusion: The preliminary results suggest that absence of NALP3 protects mice from the development of renin-dependent hypertension. Further molecular and morphological examinations are ongoing for the confirmation and mechanism explanation.

Natural classification of knots

The principal objective of the knot theory is to provide a simple way of classifying and ordering all the knot types. Here, we propose a natural classification of knots based on their intrinsic position in the knot space that is defined by the set of knots to which a given knot can be converted by individual intersegmental passages. In addition, we characterize various knots using a set of simple quantum numbers that can be determined upon inspection of minimal crossing diagram of a knot. These numbers include: crossing number; average three-dimensional writhe; number of topological domains; and the average relaxation value

Substance P-like-immunoreactive sensory neurons in dorsal root ganglia of the chick embryo: ontogenesis and influence of peripheral targets.

The expression of substance P (SP) was studied in sensory neurons of developing chick lumbosacral dorsal root ganglia (DRG) by using a mixture of periodic acid, lysine and paraformaldehyde as fixative and a monoclonal antibody for SP-like immunostaining. The first SP-like-immunoreactive DRG cells appeared first at E5, then rapidly increased in number to reach a peak (88% of ganglion cells) at E8, and finally declined (59% at E12, 51% after hatching). The fall of the SP-like-positive DRG cells resulted from two concomitant events affecting a subset of small B-neurons: a loss of neuronal SP-like immunoreactivity and cell death. After one hindlimb resection at an early (E6) or late (E12) stage of development (that is before or after establishment of peripheral connections), the DRG were examined 6 days later. In both cases, a drastic neuronal death occurred in the ispilateral DRG. However, the resection at E6 did not change the percentage of SP-like-positive neurons, while the resection at E12 severely reduced the proportion of SP-like-immunoreactive DRG cells (25%). In conclusion, connections established between DRG and peripheral target tissues not only promote the survival of sensory neurons, but also control the maintenance of SP-like-expression. Factors issued from innervated targets such as NGF would support the survival of SP-expressing DRG cells and enhance their SP content while other factors present in skeletal muscle or skin would hinder SP expression and therefore lower SP levels in a subset of primary sensory neurons.

The cost of inappropriateness of coagulation testing [I costi dell'inappropriatezza in coagulazione]

Background. Laboratory utilization has steadily increased with a corresponding increase in overall costs; several authors have attempted to measure the impact of inappropriateness on clinical outcomes but data are insufficient. The aim of the study is to assess the cost of inappropriateness of test-ordering behaviour for second-level coagulation tests (hemorrhagic diathesisand thrombophilia). Methods. We reviewed all second-level coagulation testrequests received by our department during a six months period. Clinicians must fill out a specific order form for these kind of tests, containing all informations deemed necessary for the laboratory specialist to evaluatethe appropriateness of the request. We identified all inappropriate requests and counted the numbers and types of all coagulation tests that were not performed during the period. An analysis of the laboratory activity costs was done in order to calculate the global costof each test in our department and to estimate the savings achieved. Results. On a total of 1664 second-level coagulationtest requests, we estimated 150 as completely inappropriate. We found an overall of 295 inappropriate testswhich were not performed. This resulted in an economic saving of 20.000 euro in 6 months. Conclusions. The analysis of cost of our intervention shows the urgent need for a definite and sustained reduction in inappropriate requests of second-level coagulation tests. Even though we estimated only the economic aspect of inappropriate testing, this is also associated with the overuse of diagnostic tests which entailsthe risk of generating erroneous results with potentialnegative consequences on patients' health.

DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region.

The three subtypes of the peroxisome proliferator-activated receptors (PPARalpha, beta/delta, and gamma) form heterodimers with the 9-cis-retinoic acid receptor (RXR) and bind to a common consensus response element, which consists of a direct repeat of two hexanucleotides spaced by one nucleotide (DR1). As a first step toward understanding the molecular mechanisms determining PPAR subtype specificity, we evaluated by electrophoretic mobility shift assays the binding properties of the three PPAR subtypes, in association with either RXRalpha or RXRgamma, on 16 natural PPAR response elements (PPREs). The main results are as follows. (i) PPARgamma in combination with either RXRalpha or RXRgamma binds more strongly than PPARalpha or PPARbeta to all natural PPREs tested. (ii) The binding of PPAR to strong elements is reinforced if the heterodimerization partner is RXRgamma. In contrast, weak elements favor RXRalpha as heterodimerization partner. (iii) The ordering of the 16 natural PPREs from strong to weak elements does not depend on the core DR1 sequence, which has a relatively uniform degree of conservation, but correlates with the number of identities of the 5'-flanking nucleotides with respect to a consensus element. This 5'-flanking sequence is essential for PPARalpha binding and thus contributes to subtype specificity. As a demonstration of this, the PPARgamma-specific element ARE6 PPRE is able to bind PPARalpha only if its 5'-flanking region is exchanged with that of the more promiscuous HMG PPRE.

Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review.

OBJECTIVE: To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review. METHODS: The response to treatment was studied in a web-based registry in which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase. RESULTS: 22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative. CONCLUSIONS: In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.

Post-detection analysis for grating-based ultra-small angle X-ray scattering.

Until recently, the hard X-ray, phase-sensitive imaging technique called grating interferometry was thought to provide information only in real space. However, by utilizing an alternative approach to data analysis we demonstrated that the angular resolved ultra-small angle X-ray scattering distribution can be retrieved from experimental data. Thus, reciprocal space information is accessible by grating interferometry in addition to real space. Naturally, the quality of the retrieved data strongly depends on the performance of the employed analysis procedure, which involves deconvolution of periodic and noisy data in this context. The aim of this article is to compare several deconvolution algorithms to retrieve the ultra-small angle X-ray scattering distribution in grating interferometry. We quantitatively compare the performance of three deconvolution procedures (i.e., Wiener, iterative Wiener and Lucy-Richardson) in case of realistically modeled, noisy and periodic input data. The simulations showed that the algorithm of Lucy-Richardson is the more reliable and more efficient as a function of the characteristics of the signals in the given context. The availability of a reliable data analysis procedure is essential for future developments in grating interferometry.

Paleobiology and skeletochronology of Jurassic dinosaurs: implications from the histology and oxygen isotope compositions of bones

Fossil biogenic phosphate of fast-growing primary bone tissue of dinosaurs can preserve a histologic and isotopic time-series of annual seasonality in temperature variations, similar to tooth enamel and other accretionary skeletal phases such as corals or wood. On two bone fragments from sympatric dinosaurs with different histologic patterns of bone growth, high-resolution oxygen isotope profiles were analyzed along the radial direction of bone growth. The investigated specimens are from the Jurassic Shishugou Formation in the Junggar Basin, NW China and have distinct patterns of compositional variation. A fibrolamellar dinosaur bone with multiple lines of arrested growth (LAGs) and periodic growth cycles of decreasing bone laminae thickness displays a cyclic intra-bone variation in delta(18)O values of about 2parts per thousand corresponding with the LAGs. These growth cycles in fast-growing fibrolamellar bone provide evidence for seasonal growth of dinosaurs in lower latitudes ( similar to 45degreesN), possibly influenced by a monsoon-type paleoclimate. Seasonal changes in temperature and water supply are consistent with the oxygen isotope composition measured in dinosaur bone phosphate as well as with growth rings in contemporaneous fossil conifer wood from the same locality. In contrast, a plexiform sympatric sauropod bone displays continuous growth, free of LAGs and has a lower intra-bone variation of less than or equal to 0.8parts per thousand. Differences in bone histology are also reflected in the oxygen isotopic composition and its intra-bone variability, indicating different physiological responses to external climatic stress between sympatric dinosaur species. Seasonal intra-bone oxygen isotope variations combined with bone histology may thus yield new insights into species-specific response to climatic stress and its influence on dinosaur growth, formation of growth marks, growth rates, as welt as dinosaur thermophysiology. (C) 2004 Elsevier B.V All rights reserved.

Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.

OBJECTIVE: To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, for the treatment of acute gouty arthritis. METHODS: In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS: Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION: Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

DNA-DNA interactions in bacteriophage capsids are responsible for the observed DNA knotting.

Recent experiments showed that the linear double-stranded DNA in bacteriophage capsids is both highly knotted and neatly structured. What is the physical basis of this organization? Here we show evidence from stochastic simulation techniques that suggests that a key element is the tendency of contacting DNA strands to order, as in cholesteric liquid crystals. This interaction favors their preferential juxtaposition at a small twist angle, thus promoting an approximately nematic (and apolar) local order. The ordering effect dramatically impacts the geometry and topology of DNA inside phages. Accounting for this local potential allows us to reproduce the main experimental data on DNA organization in phages, including the cryo-EM observations and detailed features of the spectrum of DNA knots formed inside viral capsids. The DNA knots we observe are strongly delocalized and, intriguingly, this is shown not to interfere with genome ejection out of the phage.