Riesenzellarteriitis : Ätiologische Erkenntnisse und diagnostische Herausforderung für den Pathologen [Giant cell arteritis : Etiological knowledge and diagnostic challenge for pathologists].

Giant cell arteritis is a potentially systemic disease of medium-sized and large caliber arteries, showing a preferential manifestation in the extracranial branches of the carotid artery. The diagnosis is oriented to clinical and histomorphological criteria which will be critically reviewed. Particular emphasis is placed on the differentiation from normal aging processes and from healing stages under steroid therapy. In addition, the advances in our understanding of the disease pathomechanism during the last 10 years will be briefly presented as the basis for the hitherto empiric steroid treatment.

Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study.

ABSTRACT: INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype. METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients. RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.

Calprotectine fécale: outil diagnostique dans les maladies inflammatoires chroniques de l'intestin [Fecal calprotectin: a diagnostic tool for inflammatory bowel disease].

Fecal calprotectin (FC) is a valid biomarker to discriminate with a good sensitivity and specificity the presence of mucosal lesions of the gastrointestinal tube (e.g. ulcers in the context of inflammatory bowel disease (IBD)) from functional disorders (e.g. irritable bowel syndrome). FC is not specific for IBD and can be elevated also in gastrointestinal infections, ischemic colitis or neoplasia. An elevated FC should stimulate further investigations, notably an endoscopic workup. The level of FC correlates with the endoscopic score in Crohn's disease and ulcerative colitis. The correlation of FC and the endoscopic severity is better than the one of CRP or blood leukocytes. Thus, FC can also be used in the follow-up of IBD patients.

Simpson-Golabi-Behmel syndrome type 1 in a 27-week macrosomic preterm newborn: the diagnostic value of rib malformations and index nail and finger hypoplasia.

The Simpson-Golabi-Behmel syndrome type 1 (SGBS1, OMIM #312870) is an X-linked overgrowth condition comprising abnormal facial appearance, supernumerary nipples, congenital heart defects, polydactyly, fingernail hypoplasia, increased risk of neonatal death and of neoplasia. It is caused by mutation/deletion of the GPC3 gene. We describe a macrosomic 27-week preterm newborn with SGBS1 who presents a novel GPC3 mutation and emphasize the phenotypic aspects which allow a correct diagnosis neonatally in particular the rib malformations, hypoplasia of index finger and of the same fingernail, and 2nd-3rd finger syndactyly.

Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: a CYP2B6 gene resequencing study.

BACKGROUND: (S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics. METHODS: Resequencing of the CYP2B6 gene was performed in 12 and 35 selected individuals with high (S)-methadone plasma exposure and low (S)-methadone plasma exposure, respectively, from a previously described cohort of 276 patients undergoing methadone maintenance treatment. Selected genetic polymorphisms were then analyzed in the complete cohort. RESULTS: The rs35303484 (*11; c136A>G; M46V) polymorphism was overrepresented in the high (S)-methadone level group, whereas the rs3745274 (*9; c516G>T; Q172H), rs2279344 (c822+183G>A), and rs8192719 (c1294+53C>T) polymorphisms were underrepresented in the low (S)-methadone level group, suggesting an association with decreased CYP2B6 activity. Conversely, the rs3211371 (*5; c1459C>T; R487C) polymorphism was overrepresented in the low-level group, indicating an increased CYP2B6 activity. A higher allele frequency was found in the high-level group compared with the low-level group for rs3745274 (*9; c516G>T; Q172H), rs2279343 (*4; c785A>G; K262R) (together representing CYP2B6*6), rs8192719 (c1294+53C>T), and rs2279344 (c822+183G>A), suggesting their involvement in decreased CYP2B6 activity. These results should be replicated in larger independent cohorts. CONCLUSION: Known genetic polymorphisms in CYP2B6 contribute toward explaining extreme (S)-methadone plasma levels observed in a cohort of patients following methadone maintenance treatment.

Le cancer est-il une maladie nouvelle? A propos du diagnostic des maladies tumorales dans le De Medicina de Celse [Is cancer a new disease? Apropos of diagnosis of tumor diseases in De Medicina by Celsus]

Cancer is a particularly common disease in modern societies. Moreover, epidemiology considers it typical of contemporary pathology. Nevertheless, the abundant ancient literature-in the De Medicina by Celsus, among others-leads us to believe that numerous benign and malignant tumours were observed if not identified as such. Hence, it is possible that both the change in medical conceptualization and the real increase in the prevalence are responsible for the actual importance of cancer

Nouveautés dans la physiopathologie, le diagnostic et le traitement de la douleur neuropathique [New concepts in the pathophysiology, diagnosis and treatment of neuropathic pain].

We here summarize five articles bringing new advances in our knowledge on neuropathic pain and put them into perspective with our current understanding. The first uses a mechanism-based approach with a capsaicin test to stratify patients suffering from painful diabetic neuropathy before starting a topical clonidine treatment. The second reviews disinhibition as a critical mechanism and a promising target for chronic pain. The third evokes neuroglial interactions and its implication regarding the interplay between injuries in childhood and hypersensitivity in adulthood. The last articles remind us that interventional therapies, not always very invasive, have a future potential in the therapy of frequent conditions such as head pain disorders.

Light-induced racemization: artifacts in the analysis of the diastereoisomeric pairs of thioridazine 5-sulfoxide in the plasma and urine of patients treated with thioridazine.

The ring sulfoxidation of thioridazine (THD), a widely used neuroleptic agent, yields two diastereoisomeric pairs, fast- and slow-eluting (FE and SE) thioridazine 5-sulfoxide (THD 5-SO). Until now, studies in which concentrations of these metabolites were measured in THD-treated patients have revealed no significant differences in their concentrations. Preliminary experiments in our laboratory had shown that sunlight and, to a lesser extent, dim daylight led to racemization and probably also to photolysis of the diastereoisomeric pairs as measured by high-performance liquid chromatography. Similar results were also obtained with direct UV light (UV lamp). In appropriate light-protected conditions, THD, northioridazine, mesoridazine, sulforidazine, and FE and SE THD 5-SO were measured in 11 patients treated with various doses of THD for at least 1 week. Significantly higher concentrations of the FE stereoisomeric pair were found. The concentration ratios THD 5-SO (FE)/THD 5-SO (SE) ranged from 0.89 to 1.75 in plasma and from 1.15 to 2.05 in urine. Because it is known that the ring sulfoxide contributes to the cardiotoxicity of the drug even more potently than the parent compound does, these results justify further studies to determine whether there is stereoselectivity in the cardiotoxicity of THD 5-SO.

Chirurgie thoracique majeure et dénutrition préopératoire: rationnel, diagnostic et prise en charge [Thoracic surgery and underfeeding scientific evidences, diagnosis and treatment]

Underfeeding causes a significant increase of postoperative complications, particularly respiratory and infectious complications. Thoracic surgery is frequently required in patients suffering wasting diseases (cancer, COPD, cystic fibrosis), which increase the risk of malnutrition. The most important risk factors are preoperative hypoalbuminemia and BMI < 20. The deleterious effects of underfeeding may be corrected by a preoperative nutritional support for 7 to 15 days using oral supplements or enteral feeding: respiratory muscle strength is improved, immunity is restored, and overall complications are reduced. Therefore preoperative diagnosis of underfeeding is of utmost importance. In case of emergency surgery, the nutritional assessment on admission enables the introduction of early postoperative artificial feeding.

Single-step extraction of fluconazole from plasma by ultra-filtration for the measurement of its free concentration by high performance liquid chromatography.

High performance liquid chromatography (HPLC) is the reference method for measuring concentrations of antimicrobials in blood. This technique requires careful sample preparation. Protocols using organic solvents and/or solid extraction phases are time consuming and entail several manipulations, which can lead to partial loss of the determined compound and increased analytical variability. Moreover, to obtain sufficient material for analysis, at least 1 ml of plasma is required. This constraint makes it difficult to determine drug levels when blood sample volumes are limited. However, drugs with low plasma-protein binding can be reliably extracted from plasma by ultra-filtration with a minimal loss due to the protein-bound fraction. This study validated a single-step ultra-filtration method for extracting fluconazole (FLC), a first-line antifungal agent with a weak plasma-protein binding, from plasma to determine its concentration by HPLC. Spiked FLC standards and unknowns were prepared in human and rat plasma. Samples (240 microl) were transferred into disposable microtube filtration units containing cellulose or polysulfone filters with a 5 kDa cut-off. After centrifugation for 60 min at 15000g, FLC concentrations were measured by direct injection of the filtrate into the HPLC. Using cellulose filters, low molecular weight proteins were eluted early in the chromatogram and well separated from FLC that eluted at 8.40 min as a sharp single peak. In contrast, with polysulfone filters several additional peaks interfering with the FLC peak were observed. Moreover, the FLC recovery using cellulose filters compared to polysulfone filters was higher and had a better reproducibility. Cellulose filters were therefore used for the subsequent validation procedure. The quantification limit was 0.195 mgl(-1). Standard curves with a quadratic regression coefficient &gt; or = 0.9999 were obtained in the concentration range of 0.195-100 mgl(-1). The inter and intra-run accuracies and precisions over the clinically relevant concentration range, 1.875-60 mgl(-1), fell well within the +/-15% variation recommended by the current guidelines for the validation of analytical methods. Furthermore, no analytical interference was observed with commonly used antibiotics, antifungals, antivirals and immunosuppressive agents. Ultra-filtration of plasma with cellulose filters permits the extraction of FLC from small volumes (240 microl). The determination of FLC concentrations by HPLC after this single-step procedure is selective, precise and accurate.

Cytochrome P450 and ABCB1 genetics: association with quetiapine and norquetiapine plasma and cerebrospinal fluid concentrations and with clinical response in patients suffering from schizophrenia. A pilot study.

Variability in response to atypical antipsychotic drugs is due to genetic and environmental factors. Cytochrome P450 (CYP) isoforms are implicated in the metabolism of drugs, while the P-glycoprotein transporter (P-gp), encoded by the ABCB1 gene, may influence both the blood and brain drug concentrations. This study aimed to identify the possible associations of CYP and ABCB1 genetic polymorphisms with quetiapine and norquetiapine plasma and cerebrospinal fluid (CSF) concentrations and with response to treatment. Twenty-two patients with schizophrenia receiving 600 mg of quetiapine daily were genotyped for four CYP isoforms and ABCB1 polymorphisms. Quetiapine and norquetiapine peak plasma and CSF concentrations were measured after 4 weeks of treatment. Stepwise multiple regression analysis revealed that ABCB1 3435C > T (rs1045642), 2677G > T (rs2032582) and 1236C > T (rs1128503) polymorphisms predicted plasma quetiapine concentrations, explaining 41% of the variability (p = 0.001). Furthermore, the ABCB1 polymorphisms predicted 48% (p = 0.024) of the variability of the Δ PANSS total score, with the non-carriers of the 3435TT showing higher changes in the score. These results suggest that ABCB1 genetic polymorphisms may be a predictive marker of quetiapine treatment in schizophrenia.

The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity.

Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor gamma angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.