Concentrations plasmatiques et articulaires pendant l'administration de céfacétrile pour arthrite septique (6 cas) [Serum and joint levels of cefacetrile during its administration for septic arthritis]

Six patients, five of whom had normal and one impaired renal function, and all suffering from purulent arthritis caused by cephalosporin-sensitive germs, were given a seven-day course of 8 g cephacetrile daily. On the first day, 6 g were administered by continuous intravenous infusion at the rate of 500 mg/h, followed by 2 g over a further 45 min. On days 2 to 7, the patients received 2 short infusions of 4 g each at an interval of 12 h. In four patients with normal renal function, serum half-life ranged from 0.8 to 1.4 h, serum levels during continuous infusion from 19 to 31 microgram/ml, and total clearances from 265 to 434 ml/min. In one patients, these values were 1.6 h, 70 microgram/ml and 131 ml/min respectively (small volume of distribution). The concentrations in the synovial fluid varied from 2 to 29 mcirogram/ml; they were generally lower than the serum levels, but clearly exceeded the minimum inhibitory concentrations for germs commonly present in purulent arthritis. In five patients, the synovial fluid became germ-free and the arthritis was clinically cured. In the case presenting with renal insufficiency, the serum half-life was 5.8 h. During continuous administration, a steady state was not attained; peak serum levels amo9nted to 75 microgram/ml and the total clearance to 61 ml/min. The cephacetrile concentrations in the synovial fluid were very high (26 and 67 microgram/ml). In this case, in which the renal insufficiency associated with mycosis fungoides was present before the treatment, renal function deteriorated futher during treatment while the arthritis improved.

The rise of soluble TWEAK levels in severely obese subjects after bariatric surgery may affect adipocyte-cytokine production induced by TNFα.

CONTEXT Soluble TNF-like weak inducer of apoptosis (sTWEAK) is generated by the intracellular proteolytic cleavage of full-length membrane-bound TNF-like weak inducer of apoptosis (mTWEAK). sTWEAK levels are reduced in diseases with an inflammatory component. Additionally, sTWEAK hampers TNFα activity in human cells. OBJECTIVES The objectives of the study were as follows: 1) to determine circulating sTWEAK in severe obesity and after bariatric surgery; 2) to study m/sTWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) protein expression in sc adipose tissue (SAT) of severely obese subjects, in SAT stromal vascular fraction (SVF), and isolated adipocytes and in human monocyte-derived macrophages; and 3) to explore, on human adipocytes, the sTWEAK effect on TNFα proinflammatory activity. DESIGN sTWEAK levels were measured in cohort 1: severely obese subjects (n = 23) and a control group (n = 35); and in cohort 2: (n = 23) severely obese subjects before and after surgery. The m/sTWEAK and Fn14 expressions were determined in SAT biopsies, SVF, and isolated adipocytes from severely obese and control subjects and in human monocyte-derived macrophages. In human primary cultured adipocytes, sTWEAK pretreated and TNFα challenged, IL-6, IL-8, and adiponectin protein and gene expressions were determined and nuclear factor-κ B and MAPK signaling analyzed. RESULTS sTWEAK levels were reduced in severely obese subjects. After surgery, sTWEAK levels rose in 69% of patients. mTWEAK protein expression was increased in SAT and SVF of severely obese subjects, whereas Fn14 was up-regulated in isolated adipocytes. M2 human monocyte-derived macrophages overexpress mTWEAK. In human adipocytes, sTWEAK down-regulates TNFα cytokine production by hampering TNFα intracellular signaling events. CONCLUSION The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα.

Circadian expression of H,K-ATPase type 2 contributes to the stability of plasma K⁺ levels.

Maintenance by the kidney of stable plasma K(+) values is crucial, as plasma K(+) controls muscle and nerve activity. Since renal K(+) excretion is regulated by the circadian clock, we aimed to identify the ion transporters involved in this process. In control mice, the renal mRNA expression of H,K-ATPase type 2 (HKA2) is 25% higher during rest compared to the activity period. Conversely, under dietary K(+) restriction, HKA2 expression is ∼40% higher during the activity period. This reversal suggests that HKA2 contributes to the circadian regulation of K(+) homeostasis. Compared to their wild-type (WT) littermates, HKA2-null mice fed a normal diet have 2-fold higher K(+) renal excretion during rest. Under K(+) restriction, their urinary K(+) loss is 40% higher during the activity period. This inability to excrete K(+) "on time" is reflected in plasma K(+) values, which vary by 12% between activity and rest periods in HKA2-null mice but remain stable in WT mice. Analysis of the circadian expression of HKA2 regulators suggests that Nrf2, but not progesterone, contributes to its rhythmicity. Therefore, HKA2 acts to maintain the circadian rhythm of urinary K(+) excretion and preserve stable plasma K(+) values throughout the day.

Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine.

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D(2) receptor occupancy (DA-D(2)) using [(18)F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D(2), 41.4% (p<0.05, corrected for multiple comparisons). DA-D(2) receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels (p<0.01 and p<0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: (p<0.01) and HVA: (p<0.05)], caudate nucleus [HVA: (p<0.01)], thalamus [MHPG: (p<0.05)] and in the temporal cortex [HVA: (p<0.05) and 5-HIAA: (p<0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.

Variation of transaminases, HCV-RNA levels and Th1/Th2 cytokine production during the post-partum period in pregnant women with chronic hepatitis C.

This study analyses the evolution of liver disease in women with chronic hepatitis C during the third trimester of pregnancy and the post-partum period, as a natural model of immune modulation and reconstitution. Of the 122 mothers recruited to this study, 89 were HCV-RNA+ve/HIV-ve and 33 were HCV-RNA-ve/HIV-ve/HCVantibody+ve and all were tested during the third trimester of pregnancy, at delivery and post-delivery. The HCV-RNA+ve mothers were categorized as either Type-A (66%), with an increase in ALT levels in the post-partum period (>40 U/L; P<0.001) or as Type-B (34%), with no variation in ALT values. The Type-A mothers also presented a significant decrease in serum HCV-RNA levels in the post-delivery period (P<0.001) and this event was concomitant with an increase in Th1 cytokine levels (INFγ, P = 0.04; IL12, P = 0.01 and IL2, P = 0.01). On the other hand, the Type-B mothers and the HCV-RNA-ve women presented no variations in either of these parameters. However, they did present higher Th1 cytokine levels in the partum period (INFγ and IL2, P<0.05) than both the Type-A and the HCV-RNA-ve women. Cytokine levels at the moment of delivery do not constitute a risk factor associated with HCV vertical transmission. It is concluded that differences in the ALT and HCV-RNA values observed in HCV-RNA+ve women in the postpartum period might be due to different ratios of Th1 cytokine production. In the Type-B women, the high partum levels of Th1 cytokines and the absence of post-partum variation in ALT and HCV-RNA levels may be related to permanent Th1 cytokine stimulation.

Low-dose multidetector computed tomography of the cervical spine: optimization of iterative reconstruction strength levels.

BACKGROUND: Iterative reconstruction (IR) techniques reduce image noise in multidetector computed tomography (MDCT) imaging. They can therefore be used to reduce radiation dose while maintaining diagnostic image quality nearly constant. However, CT manufacturers offer several strength levels of IR to choose from. PURPOSE: To determine the optimal strength level of IR in low-dose MDCT of the cervical spine. MATERIAL AND METHODS: Thirty consecutive patients investigated by low-dose cervical spine MDCT were prospectively studied. Raw data were reconstructed using filtered back-projection and sinogram-affirmed IR (SAFIRE, strength levels 1 to 5) techniques. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured at C3-C4 and C6-C7 levels. Two radiologists independently and blindly evaluated various anatomical structures (both dense and soft tissues) using a 4-point scale. They also rated the overall diagnostic image quality using a 10-point scale. RESULTS: As IR strength levels increased, image noise decreased linearly, while SNR and CNR both increased linearly at C3-C4 and C6-C7 levels (P < 0.001). For the intervertebral discs, the content of neural foramina and dural sac, and for the ligaments, subjective image quality scores increased linearly with increasing IR strength level (P ≤ 0.03). Conversely, for the soft tissues and trabecular bone, the scores decreased linearly with increasing IR strength level (P < 0.001). Finally, the overall diagnostic image quality scores increased linearly with increasing IR strength level (P < 0.001). CONCLUSION: The optimal strength level of IR in low-dose cervical spine MDCT depends on the anatomical structure to be analyzed. For the intervertebral discs and the content of neural foramina, high strength levels of IR are recommended.

High levels of Bifidobacteria are associated with increased levels of anthocyanin microbial metabolites: a randomized clinical trial.

The health benefits associated with the consumption of polyphenol-rich foods have been studied in depth, however, the full mechanism of action remains unknown. One of the proposed mechanisms is through microbiota interaction. In the present study, we aimed to explore the relationship between changes in fecal microbiota and changes in urinary phenolic metabolites after wine interventions. Nine participants followed a randomized, crossover, controlled interventional trial. After the washout period, they received red wine, dealcoholized red wine or gin for 20 days each. Polyphenol metabolites (n > 60) in urine were identified and quantified by UPLC-MS/MS and the microbial content of fecal samples was quantified by real-time quantitative PCR. Interventions with both red wine and dealcoholized red wine increased the fecal concentration of Bifidobacterium, Enterococcus and Eggerthella lenta, compared to gin intervention and baseline. When participants were categorized in tertiles of changes in fecal bacteria, those in the highest tertile of Bifidobacteria had higher urinary concentration changes in syringic acid, p-coumaric acid, 4-hydroxybenzoic acid and homovanillic acid (all anthocyanin metabolites) than those in tertile 1 (P < 0.05, all). In addition, changes of Bifidobacteria correlated positively with changes of these metabolites (r = 0.5-0.7, P < 0.05, all). Finally, the 68.5% changes in Bifidobacteria can be predicted by syringic acid and 4-hydroxybenzoic acid changes. This study confirms the important role of polyphenols as bacterial substrates and their modulatory capacity as an important field in the research of new products with prebiotic and probiotic characteristics for the food industry.

Levels of immune cells in transcendental meditation practitioners.

CONTEXT Relationships between mind and body have gradually become accepted. Yogic practices cause modulation of the immune system. Transcendental meditation (TM) is a specific form of mantra meditation. We reported previously different plasma levels of catecholamines and pituitary hormones in TM practitioners comparing with a control group, and patterns of the daytime secretion of these hormones different from those normally described. AIMS The aim of the following study is to evaluate the immune system in these meditation practitioners, by determining leukocytes and lymphocytes subsets. METHODS TM group consisted of 19 subjects who regularly practice either TM or the more advanced Sidhi-TM technique. A control group consisted of 16 healthy subjects who had not previously used any relaxation technique. Total leukocytes, granulocytes, lymphocytes and monocytes were counted by an automated quantitative hematology analyzer, whereas lymphocytes subsets were determined by flow cytometry. Samples were taken from each subject at 0900 h after an overnight fast. RESULTS The results indicated that the TM group had higher values than the control group in CD3+CD4-CD8+ lymphocytes (P < 0.05), B lymphocytes (P < 0.01) and natural killer cells (P < 0.01), whereas CD3+CD4+CD8- lymphocytes showed low levels in meditation practitioners (P < 0.001). No significant differences were observed in total leukocytes, granulocytes, monocytes, total lymphocytes or CD3+ lymphocytes comparing both groups. CONCLUSIONS The technique of meditation studied seems to have a significant effect on immune cells, manifesting in the different circulating levels of lymphocyte subsets analyzed. The significant effect of TM on the neuroendocrine axis and its relationship with the immune system may partly explain our results.

Immunotherapy reduces allergen-mediated CD66b expression and myeloperoxidase levels on human neutrophils from allergic patients.

CD66b is a member of the carcinoembryonic antigen family, which mediates the adhesion between neutrophils and to endothelial cells. Allergen-specific immunotherapy is widely used to treat allergic diseases, and the molecular mechanisms underlying this therapy are poorly understood. The present work was undertaken to analyze A) the in vitro effect of allergens and immunotherapy on cell-surface CD66b expression of neutrophils from patients with allergic asthma and rhinitis and B) the in vivo effect of immunotherapy on cell-surface CD66b expression of neutrophils from nasal lavage fluid during the spring season. Myeloperoxidase expression and activity was also analyzed in nasal lavage fluid as a general marker of neutrophil activation. RESULTS CD66b cell-surface expression is upregulated in vitro in response to allergens, and significantly reduced by immunotherapy (p<0.001). Myeloperoxidase activity in nasal lavage fluid was also significantly reduced by immunotherapy, as were the neutrophil cell-surface expression of CD66b and myeloperoxidase (p<0.001). Interestingly, CD66b expression was higher in neutrophils from nasal lavage fluid than those from peripheral blood, and immunotherapy reduced the number of CD66+MPO+ cells in nasal lavage fluid. Thus, immunotherapy positive effects might, at least in part, be mediated by the negative regulation of the CD66b and myeloperoxidase activity in human neutrophils.

Musical training intensity yields opposite effects on grey matter density in cognitive versus sensorimotor networks.

Using optimized voxel-based morphometry, we performed grey matter density analyses on 59 age-, sex- and intelligence-matched young adults with three distinct, progressive levels of musical training intensity or expertise. Structural brain adaptations in musicians have been repeatedly demonstrated in areas involved in auditory perception and motor skills. However, musical activities are not confined to auditory perception and motor performance, but are entangled with higher-order cognitive processes. In consequence, neuronal systems involved in such higher-order processing may also be shaped by experience-driven plasticity. We modelled expertise as a three-level regressor to study possible linear relationships of expertise with grey matter density. The key finding of this study resides in a functional dissimilarity between areas exhibiting increase versus decrease of grey matter as a function of musical expertise. Grey matter density increased with expertise in areas known for their involvement in higher-order cognitive processing: right fusiform gyrus (visual pattern recognition), right mid orbital gyrus (tonal sensitivity), left inferior frontal gyrus (syntactic processing, executive function, working memory), left intraparietal sulcus (visuo-motor coordination) and bilateral posterior cerebellar Crus II (executive function, working memory) and in auditory processing: left Heschl's gyrus. Conversely, grey matter density decreased with expertise in bilateral perirolandic and striatal areas that are related to sensorimotor function, possibly reflecting high automation of motor skills. Moreover, a multiple regression analysis evidenced that grey matter density in the right mid orbital area and the inferior frontal gyrus predicted accuracy in detecting fine-grained incongruities in tonal music.

Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARβ/δ-null mice.

The role of peroxisome proliferator activator receptor (PPAR)β/δ in the pathogenesis of Alzheimer's disease has only recently been explored through the use of PPARβ/δ agonists. Here we evaluated the effects of PPARβ/δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPARβ/δ-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-κB in the cortex and increased expression of IL-6. In addition, two NF-κB-target genes involved in β-amyloid (Aβ) synthesis and deposition, the β site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPARβ/δ-null mice compared to wild type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPARβ/δ-null mice, which would suggest the presence of astrogliosis. Finally, tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 in the cortex of PPARβ/δ(-/-) mice. Collectively, our findings indicate that PPARβ/δ deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex.

Serum sCD163 levels are associated with type 2 diabetes mellitus and are influenced by coffee and wine consumption: results of the Di@bet.es study.

OBJECTIVE Serum levels of soluble TNF-like weak inducer of apoptosis (sTWEAK) and its scavenger receptor CD163 (sCD163) have been linked to insulin resistance. We analysed the usefulness of these cytokines as biomarkers of type 2 diabetes in a Spanish cohort, together with their relationship to food consumption in the setting of the Di@bet.es study. RESEARCH DESIGN AND METHODS This is a cross-sectional, matched case-control study of 514 type 2 diabetes subjects and 517 controls with a Normal Oral Glucose Tolerance Test (NOGTT), using data from the Di@bet.es study. Study variables included clinical and demographic structured survey, food frequency questionnaire and physical examination. Serum concentrations of sTWEAK and sCD163 were measured by ELISA. Linear regression analysis determined which variables were related to sTWEAK and sCD163 levels. Logistic regression analysis was used to estimate odd ratios of presenting type 2 diabetes. RESULTS sCD163 concentrations and sCD163/sTWEAK ratio were 11.0% and 15.0% higher, respectively, (P<0.001) in type 2 diabetes than in controls. Following adjustment for various confounders, the OR for presenting type 2 diabetes in subjects in the highest vs the lowest tertile of sCD163 was [(OR), 2,01 (95%CI, 1,46-2,97); P for trend <0.001]. Coffee and red wine consumption was negatively associated with serum levels of sCD163 (P = 0.0001 and; P = 0.002 for coffee and red wine intake, respectively). CONCLUSIONS High circulating levels of sCD163 are associated with type 2 diabetes in the Spanish population. The association between coffee and red wine intake and these biomarkers deserves further study to confirm its potential role in type 2 diabetes.

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-β during acute phase

Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN-I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon-α similarly (52,71 ± 7,40 and 49,05 ± 7,70, respectively), IFN- β were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- β which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- β in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis.

A multidimensional segmentation evaluation for medical image data.

Evaluation of segmentation methods is a crucial aspect in image processing, especially in the medical imaging field, where small differences between segmented regions in the anatomy can be of paramount importance. Usually, segmentation evaluation is based on a measure that depends on the number of segmented voxels inside and outside of some reference regions that are called gold standards. Although some other measures have been also used, in this work we propose a set of new similarity measures, based on different features, such as the location and intensity values of the misclassified voxels, and the connectivity and the boundaries of the segmented data. Using the multidimensional information provided by these measures, we propose a new evaluation method whose results are visualized applying a Principal Component Analysis of the data, obtaining a simplified graphical method to compare different segmentation results. We have carried out an intensive study using several classic segmentation methods applied to a set of MRI simulated data of the brain with several noise and RF inhomogeneity levels, and also to real data, showing that the new measures proposed here and the results that we have obtained from the multidimensional evaluation, improve the robustness of the evaluation and provides better understanding about the difference between segmentation methods.

Adaptive business intelligence for an open negotiation environment

Engineering of negotiation model allows to develop effective heuristic for business intelligence. Digital ecosystems demand open negotiation models. To define in advance effective heuristics is not compliant with the requirement of openness. The new challenge is to develop business intelligence in advance exploiting an adaptive approach. The idea is to learn business strategy once new negotiation model rise in the e-market arena. In this paper we present how recommendation technology may be deployed in an open negotiation environment where the interaction protocol models are not known in advance. The solution we propose is delivered as part of the ONE Platform, open source software that implements a fully distributed open environment for business negotiation