Prognostic relevance of caspase 8 -652 6N InsDel and Asp302His polymorphisms for breast cancer.

BACKGROUND: The minor allele of two caspase 8 polymorphisms, namely CASP8 -652 6N InsDel (rs3834129) and CASP8 Asp302His (rs1045485), were repeatedly associated with reduced breast cancer susceptibility. Contrarily, the presence of the -652 6N Del or the CASP8 302His variant was reported to be an unfavorable prognostic factor in colorectal cancer or neuroblastoma. However, prognostic relevance of these genetic variants for breast cancer is completely unknown and is therefore adressed by the current study. METHODS: Genotyping was performed by pyrosequencing. Caspase 8 mRNA expression was quantified by comparative RT-qPCR. RESULTS: We observed an allele-dose dependent association between CASP8 -652 6N InsDel and caspase 8 mRNA expression in breast cancer tissue, with homozygous deletion carriers showing lowest relative caspase 8 expression (p = 0.0131). Intriguingly, the presence of the -652 6N Del or the 302His variant was shown to be a negative prognostic factor for breast cancer in terms of an allele-dose dependent influence on overall survival (OS, p = 0.0018, p = 0.0150, respectively). Moreover, both polymorphisms were independent predictors of OS after adjusting for co-variats (p = 0.007, p = 0.037, respectively). Prognostic relevance of both polymorphisms were confirmed to be independent from each other and combined analysis of diplotypes revealed an additive influence upon OS (p = 0.0002). CONCLUSION: This is the first report, showing negative and independent prognostic impact of the CASP8 -652 6N Del and the 302His variant for breast cancer. Our data provide rationale to further validate clinical utility of these polymorphisms for breast cancer and to extend this investigation to a broad scope of other malignancies.

Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study.

BACKGROUND: Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). PATIENTS AND METHODS: Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily. RESULTS: The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days). CONCLUSION: Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.

Analytical approaches for MCPD esters and glycidyl esters in food and biological samples: a review and future perspectives.

Esters of 2 - and 3-monochloropropane-1,2-diol (MCPD) and glycidol esters are important contaminants of processed edible oils used as foods or food ingredients. This review describes the occurrence and analysis of MCPD esters and glycidol esters in vegetable oils and some other foods. The focus is on the analytical methods based on both direct and indirect methods. Methods of analysis applied to oils and lipid extracts of foods have been based on transesterification to free MCPD and determination by gas chromatography-mass spectrometry (indirect methods) and by high-performance liquid chromatography-mass spectrometry (direct methods). The evolution and performance of the different methods is described and their advantages and disadvantages are discussed. The application of direct and indirect methods to the analysis of foods and to research studies is described. The metabolism and fate of MCPD esters and glycidol esters in biological systems and the methods used to study these in body tissues studies are described. A clear understanding of the chemistry of the methods is important when choosing those suitable for the desired application, and will contribute to the mitigation of these contaminants.

Impact of beta-amyloid-specific florbetaben PET imaging on confidence in early diagnosis of Alzheimer's disease.

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) may be corroborated by imaging of beta-amyloid plaques using positron emission tomography (PET). Here, we performed an add-on questionnaire study to evaluate the relevance of florbetaben imaging (BAY 949172) in diagnosis and consecutive management of probable AD patients. METHODS: AD patients with a clinical diagnosis in accordance with the NINCDS-ADRDA criteria or controls were imaged using florbetaben. Referring physicians were asked on a voluntary basis about their confidence in initial diagnosis, significance of PET imaging results, and their anticipated consequences for future patient care. RESULTS: 121 questionnaires for probable AD patients and 80 questionnaires for controls were evaluated. In 18% of patients who had initially received the diagnosis of probable AD, PET scans were rated negative, whereas in controls 18% of scans were positive. An increase in confidence in the initial diagnosis was frequently reported (80%). Imaging results had a significant impact on the intended patient care, as judged by the referring physicians; this was most prominent in those patients with a contradicting scan and/or a low confidence in the initial diagnosis. CONCLUSION: Florbetaben amyloid imaging increases the overall confidence in diagnosis of AD and may frequently influence clinical decisions and patient management.

[Hands and feet of prosimians primates. Attempts of morphologic characterization]. / Mains et pieds des primates prosimiens. Essai de caractérisation morphologique.

The length of the carpus and tarsus, the metacarpus and metatarsus, the fingers and toes of 142 prosimian apes was measured. The relationship expressed as a percentage was drawn up for each individual between the length of each osseous part and that of its third metacarpal in order to eliminate the differences related to the size of the rest of the body. This ratio was compared with that of man. The characteristic variations appeared at the level of the subfamilies. CONCERNING THE HAND: The carpus presented the same values as that of man except for that of the indris, which was shorter. The thumb had proportionally the same length as that of man, sometimes longer and sometimes smaller as in the Eulemurs, Hapalidea, Megalapidea, Indrises, Daubentonia and Perodictus. The different metacarpals, including the fourth, were a little shorter than the third. In these subfamilies, the second ray was also often shorter and even much shorter in the Megalapidea and the Perodictus. The other rays were a little longer, in particular the fourth which could exceed the third in rather many subfamilies. CONCERNING THE FOOT: The length of the tarsus was extremely variable. It was twice larger in the Galagoidae, definitely larger in the tarsius and discreetly in the Hapalidae, a little smaller in the other Lemurs and much smaller in the other Prosimian apes, joining in that the near totality of the simians. The hallux was proportionally as long as that of man and sometimes even longer. The metatarsals were sometimes a little longer, sometimes less long, but always appreciably of the same length between them. The other toes were short at the aye aye (daubentonia), of which the foot appeared even smaller than that of man. The toes of the other prosimious resembled much to the fingers and in the propithecus and the perodictus, the fourth took gigantic proportions. There has been establishment of an anatomical relation and functional calculus between the length of the last three rays of the hands and the feet of prosimian apes and the biomechanics of their trapezometacarpal and their first cuneometacarpal joints.

[The first ray of the hand and the foot in the primates (II). Functional anatomy]. / Le premier rayon de la main et du pied chez les primates (II). Anatomie fonctionnelle.

To study the articular amplitude of the first ray of both hands and feet using passive mobilisation, either on fresh human cadavers or on living primates after anesthesia (namely eight pongidae, 15 cercopithecidae, two platirrhinii, eight lemuroidae, three daubentonidae, two loridae and two galagonidae). Plans slightly parasagittal and parafrontal have been chosen to obtain the maximum dorsal and palmar or plantar inclinations and the maximum lateral and medial inclinations. The pronosupination of the first ray has been evaluated in relation of these plans and alike for the hand of the simian primates on the plan of the concavity and the convexity of trapezial surface. The results have been compared with these obtained in the man. The pronosupination of the first ray, so denominated by analogy with the pronosupination of the fore-arm is the movement which allows the pulp of the thumb or of the hallux to look now forward or now backward in order to be opposed at the other fingers during the pollici- or the hallucidigital pinch. It can be considered like "effective" unless if there is rotation around the longitudinal axis of its metacarpus (or metatarsus). The prosimian primates had great and sensibly similar circular amplitude of their first metacarpus and first metatarsus, which reached more than 90 degrees in all the directions. It allowed a pronosupination of 90 degrees, but this was only "apparent" because it has been obtained by the alone combined action of the two orthogonal axes at the basis of the ray by simple effect of cardan joint. The anthropoids had only limited circular amplitude, not exceeding 45 degrees. It was associated with an "effective" pronosupination according to a longitudinal axis. The rotation reached 90 degrees. It was produced around the point of anchorage made up by the medial ligaments for the trapezometacarpal articulation and the lateral ligaments for the cuneometatarsal. This movement was possible because of the peculiar relief of the articular surfaces: modified cardan for the trapezometacarpal and spiraled trochoid for the cuneometacarpal joint. The man was the sole primate, which had practically no mobility at the level of the first ray of his foot. However, the morphology of his cuneometatarsal articulation was similar to that of the other anthropomorphous primates. The muscles which was inserted on the first metacarpus (or metatarsus) played an active role in the circular amplitude and in the apparent circular amplitude, but very discreet in the effective circumduction. The transversal fascicle of the short abductor of the thumb and of the hallux had a little pronator effect. At the level of the foot, the tendon of the fibular longus had an action of pronation and the abductor longus muscle an action of supination. The metacarpophalangeal and the metatarsophalangeal articulations of all the primates were condylar with laterality movements, which were able to reach 40 degrees and which were then unsteady. The metacarpophalangeal articulation of the man was the single exception. He was the sole one with a really steady thumb.

Mapping of phosphorylation-dependent anti-tau monoclonal antibodies in immunoblots using human tau-constructs synthesized by native chemical ligation.

In Alzheimer's disease (AD) neurofibrillary tangles (NFT) are formed by hyperphosphorylated microtubule-associated tau protein. It is still a matter of controversy which phosphorylation sites are AD-specific and how these might be linked to the cause or progress of the disease. Whereas most research projects in this field rely on phosphorylation-dependent tau-specific monoclonal antibodies (mAbs), the phosphorylation patterns recognized by these mAbs are often not characterized in detail. Therefore, we synthesized unphosphorylated, two monophosphorylated (pThr231, pSer235), and the bisphosphorylated (pThr231+pSer235) tau226-240 peptides. The phosphopeptides were ligated via an N-terminal cysteine to the thioester-activated C-terminus of human aldo/keto reductase AKR1A1. After purification by preparative gel electrophoresis, the ligation products were analyzed by Western blotting and probed with phosphorylation-dependent anti-tau mAbs HPT-101, HPT-103, HPT-104, and HPT-110. The obtained specificities were very similar to the data obtained by ELISA, showing that ELISA-based epitope mapping studies are also valid for immunoblot analyses.

Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response.

AIMS: To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). METHODS: Nonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. RESULTS: Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where V(max) (microg h(-1)) was [1020 x (WBC count/10 x 10(9) l(-1))(0.194)], K(m) was 338 microg l(-1), V(1) was 11.3 l, Q was 1.05 l h(-1) and V(2) was 41.5 l. Intersubject variability (ISV) in V(max), K(m), V(1) and V(2) was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for E(max), 306 microg l(-1) for EC(50), 1.56 x 10(9) cells l(-1) h(-1) for K(in) and 0.029 per h for K(out). The probability of achieving a complete or partial response was >/=50% when the maximal trough concentration exceeded 13.2 microg ml(-1) or when AUC(0-tau) exceeded 484 microg h(-1) ml(-1). CONCLUSIONS: Alemtuzumab displayed time- and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.

The applications of biomarkers in early clinical drug development to improve decision-making processes.

Selecting and evaluating biomarkers in drug discovery and early drug development can substantially shorten clinical development time or the time to reach a critical decision point in exploratory drug development. Critical decisions such as candidate selection, early proof of concept/principle, dose ranging, development risks, and patient stratification are based on the appropriate measurements of biomarkers that are biologically and/or clinically validated. The use of biomarkers helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects and will increase the success rate in the confirmatory stage of clinical development. Appropriateness of biomarkers depends on the stage of development, development strategy, and the nature of the medical indication. Even if a biomarker fails in the validation process there may be still a benefit of having used it. More knowledge about pathophysiology of the disease and the drug has been obtained. Different levels of validation exist at different development phases. Biomarkers are perhaps most useful in the early phase of clinical development when measurement of clinical endpoints may be too time-consuming or cumbersome to provide timely proof of concept or dose-ranging information. Examples of biomarkers are illustrated for the development of new drugs in variant cardiovascular, pulmonary, and CNS diseases.

Synthesis of palmitoylated Ras-peptides and -proteins.

In this review, an overview is given and details are provided for the synthesis of lipidated Ras (rat-adeno-sarcoma)-peptides and -proteins. The progress made in the synthesis of the lipidated peptides from the Ras superfamily is discussed with special emphasis on the recently developed solid-phase synthesis methods, since these methods have turned out to be the preferred synthesis method for the majority of the required peptides. Solid-phase lipopeptide synthesis has given access to native and modified peptides on a scale that allows peptide-consuming studies like for ligation to proteins and concomitant X-ray crystal structure determination. The access to these peptides has also enabled biological questions concerning these peptides and proteins to be resolved. The review describes different solid-phase methods, which are individually suited for different types of lipopeptides, differing for example in lipidation pattern or amino acid side-chain functionality, and their ligation to proteins. Finally, an example is provided how these peptides can serve to resolve biological aspects of the Ras family GTPases.

Intein-mediated in vitro synthesis of lipidated Ras proteins.

Fully functional lipid-modified Ras proteins suitable for the study of Ras-membrane interactions and embodying exclusively native amide bonds can be synthesized in preparative amounts by means of Expressed Protein Ligation.

[Hands and feet of Simian primates: an attempt at morphological characterization]. / Mains et pieds des primates simiens: Une tentative de caractérisation morphologique.

The carpal height, the length of the metacarpus, the metatarsus, and of all the phalanges of 269 simians were measured, then for each specimen, converted to percentage taking the 3rd metacarpus as the reference unit. They were then compared despite differences between specimens. The average values were determined for the different species, subspecies or families. Mathematical ratios were established: height of the carpus divided by the 3rd metacarpus, carpus divided by the 1st metacarpus, 1st ray of the hand divided by the 2nd, 1st ray of the hand divided by the 1st ray of the foot. CONCERNING THE HAND: For little monkeys, the length of the carpus and the medial metacarpus were similar to those observed in humans. Colobinae exhibited a relatively short thumb column. The length of the thumb was slightly shorter for the platyrrhinii and cercopithecinae, especially macacus. Some hapalidae had a relatively longer thumb than humans. All of their medial fingers were longer than those observed in humans. The big monkeys had a smaller carpus and thumb column, sometimes much smaller than in humans, with a similar length for the metacarpi and the medial fingers, except for gibbons, whose medial fingers were longer. CONCERNING THE FOOT: The 1st ray in humans is nearly as long as the 2nd toe, the other toes being very short. The 1st ray of the hallux of all monkeys was always longer than the ray of the thumb, but shorter than the hallux of humans. The other metatarsi of little monkeys were similar to those in humans, except for the platyrrhinii which had a shorter 2nd metatarsus. The lateral toes, which were much longer than in humans, were very similar to fingers though slightly longer, except for platyrrhinii with much longer toes. The big monkeys had very short metatarsi and slightly smaller lateral toes than humans.

Correlation between insulin resistance and intramyocellular lipid levels in rats.

Increased intramyocellular lipid (IMCL) content has been proposed as biomarker for insulin resistance (IR). An inverse correlation between IMCL and insulin sensitivity (IS) was found in nonathletic humans, whereas in animal models only a few validation studies have been performed. The aim of this study was to investigate the interrelation between IS indices determined by the glucose clamp technique (glucose disposal (GD), exogenous glucose infusion rates (GIR)) and IMCL content in the tibialis (TIB) and the soleus (SOL) muscle obtained by magnetic resonance spectroscopy in different rat models of IR. Diet-induced insulin-resistant Wistar rats as well as genetic disease models (ZDF rats) were used. In both muscles, elevated IMCL correlated with an impaired IS in all models of IR. The correlation of IMCL with both parameters for IS was comparable in TIB and SOL. The best fit between IMCL and IS was obtained using TIB and GIR data (r = -0.69, P < 0.001). Diabetic male ZDF rats exhibited comparatively low IMCL levels due to their catabolic state: exclusion of this group improved r. In summary, IMCL, especially in TIB, is a valid biomarker for IS in various rat models of IR with the advantage of a fast repeatable noninvasive measurement in individual animals.

Adverse events in volunteers participating in phase I clinical trials: a single-center five-year survey in 1,559 subjects.

OBJECTIVE: This report analyzes all adverse events (AEs) which occurred in healthy volunteers in a phase I center over a five-year period. It included 142 phase I studies with a total of 1,559 participants receiving 2,955 treatments with 32 different active drugs and placebo (ratio 6.5 : 1 in terms of follow-up days). The observation period covered a total of 29,664 follow-up days. METHODS: All adverse events (AEs) as well as clinically relevant laboratory findings were counted. The incidence of AEs was defined as the ratio between the number of AEs and the number of follow-up days. Severity of AEs was classified as mild, moderate and severe; serious AEs were analyzed separately. A chi2-test was used to compare incidence rates of the AEs. Statistical tests based on the normal distribution were used for comparison of demographic data and relative frequencies; p < 0.05 was defined as the minimum level of significance. RESULTS: There were 2,604 AEs and 291 different types of AEs with headache (2.23%), diarrhea (1.37%) and common cold (0.72%) being the most frequent. The overall incidence of AEs was 8.8% with no significant difference between those occurring with active drug and those on placebo when the studies were taken as a whole (8.5% vs. 9.1%), but the incidence of AEs in the active treatment groups was higher than under placebo (14.1% vs. 9.1%; p < 0.001) in placebo-controlled studies. The overall rate of AEs was 1.7 per subject and 0.9 per treatment. The vast majority of AEs were of mild or moderate intensity (99.2%). Only six AEs were serious as defined by GCP but two, a pseudoallergic reaction and a prolonged orthostatic dysregulation were rated as possibly or probably drug-related and these resolved completely. The incidence of AEs was three-fold (all AEs) and six-fold (AEs with probable relationship to study medication) higher (p < 0.001) in multiple-dose studies than in single-dose trials, and within multiple-dose trials the difference between AEs on active drug and on placebo was also significant (22.9% vs. 12.5%; p < 0.001). Irrespective of whether on active drug or placebo, AEs occurred with a significantly higher incidence on the first day of the study drug administration, in the first study period, with respect to the overall population in elderly subjects and in volunteers with a high body weight. CONCLUSION: AEs in phase I studies are common, but usually of mild or moderate intensity. Placebo effects and study conditions contribute significantly to the rate of their occurrence. Multiple-dose placebo-controlled studies are of particular importance in determining the substance-specific AE profile.

[Bilateral testicular gunshot injuries]. / Doppelseitige Hodenschussverletzung.

Gunshot injuries to the testicles are rare and usually result in testicular atrophy. In the case of severe bilateral testicular injuries, this could cause not only infertility but also the need for lifetime testosterone-substitution. We report an 18-year-old patient with bilateral testicular gunshot injury. During the surgical exploration an orchiectomy of the complete ruptured left testicle was necessary. Debridement of the damaged tissue and a partial orchiectomy was performed on the right side. After the operation, the patient developed an incretory hypogonadism and oligozoospermia. During follow-up, an improvement in the sperm count and of the hormonal status occurred. These finally reached normal levels. After genital traumata, immediate surgical exploration should be performed. Based on the above results, the patient benefits from conservative debridement and primary repair of the injured testicle, if possible. An improvement in hormonal status and sperm parameters after testicular injury and consecutive testicular malfunction can occur. Regeneration of the testicular tissue seems possible.

Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype.

The metabolism of acetaminophen (paracetamol) is thought to be altered in patients with Gilbert's syndrome (GS), a chronic unconjugated hyperbilirubinemia. The underlying cause of GS is a polymorphism in the promotor region of the uridine diphosphate glucuronosyltransferase isoform 1A1 gene (UGT1A1*28), its encoded enzyme being responsible for the glucuronidation of bilirubin and presumably acetaminophen. Decreased enzyme activity results in elevated bilirubin levels and may activate various metabolic pathways leading to higher amounts of potentially hepatotoxic acetaminophen metabolites. Patients with GS might be more susceptible to unexpected side effects while taking acetaminophen and other drugs which are substrates of UGT1A1. The possibility of a correlation between glucuronidation capacity with respect to acetaminophen, UGT1A1 promotor polymorphism and the bilirubin serum level were investigated in 23 healthy male volunteers selected for UGT1A1 genotype (6 wildtypes, 9 mutants and 8 heterozygotes). One gram acetaminophen was administered p.o. and urine was collected over 2 4-hour periods. Unchanged acetaminophen and its glucuronide metabolite were determined using HPLC. The metabolic ratios unchanged acetaminophen/acetaminophen glucuronide in UGT1A1-wildtypes, heterozygotes and mutants showed no statistically significant differences. An association between metabolic ratio and serum bilirubin level could not be detected in any of the urine collection periods. These data confirm that there is no correlation between the capacity to glucuronidate acetaminophen, the UGT1A1 genotype and the bilirubin serum level. Acetaminophen is likely to be substrate of a UGT isoform other than the UGT1A1.

[Tumeral calcinosis: case report of an erosive form affecting the long finger]. / Calcinose circonscrite erosive d'un doigt long: a propos d'une observation.

Tumoral calcinosis is characterised by deposits of hydroxyapatite in the soft tissues. The authors report an observation of localization at the level the P.I.P. joint of a ring finger. The lesion appeared to be a subcutaneous tumour but had completely eroded the distal epiphysis of the middle phalanx. The diagnosis was made radiographically and was confirmed by histology. Calcinosis presents in two very different forms; either disseminated or localised. The localised form can invade the juxta-articular gliding spaces. It may exhibit one of two clinical courses: one is acute and diffuse. The other is chronic, localised and insidious and gives rise to tumoral masses arising near joints, but without invading them. An erosive tumoral calcinosis is exceptional. It is characterized by bony right up to the articular surfaces. At the level of the wrist and the hand, tumoral forms are rare and we could only find one other case in the literature and it was localized in the middle finger.

Vascularised pisiform bone graft. Indications, technique and long-term results.

The authors report their experience with the use of a vascularised pisiform bone graft based on the dorsal branch of the ulnar artery to provide osseous support and an efficient vascular aid especially in non-unions of the carpal navicular bone with avascular necrosis of its proximal pole and in stage III Kienböck's disease. The pisiform can replace the proximal pole of the navicular bone in totality. When implanted into the lunate, it stops its collapse and helps to revascularize it. The authors present the results achieved in 14 patients (12 male, 2 female), of which eight had a follow-up longer than 5 years The technique appears as an interesting alternative to carpectomies and partial intracarpal fusions which are usually proposed in advanced cases of these conditions.

[Ganglions of the wrist: proposals for topographical systematization and natural history]. / Kystes dits "synoviaux" du poignet: systématisation topographique et pathogénie.

PURPOSE OF THE STUDY: We looked for the anatomic origin and mechanism of constitution of the so-called "ganglions" of the wrist. MATERIAL AND METHODS: Fifty-nine formations considered to be synovial ganglions were dissected and removed according to the same protocol by the same surgeon. Eleven were re-examined by a pathologist. All ganglions were extra-articular but had intra- and extra-capsular components. The extra-capsular part was the clinically palpable main cyst. The intra-capsular part was composed of the cystic stalk and its base of implantation. An intra-capsular stalk was present in 58 cases. The stalk was situated between the joint synovium and the capsula which it perforated at a weak point between two ligaments, forming a collar before expanding outwardly. Based on our findings, we propose a topographical systematization and natural history of ganglions of the wrist. RESULTS: The stalk's implantation base was always located on bone and found in the intermediate area of Colomniati and Soubbotine, which lies outside the articular cartilage between the synovium and the ligamentous capsula. This area is exposed to mechanical stress initiating histological degenerative lesions, particularly mucoid degeneration. At the radiocarpal joint, the stalk's base of implantation was located at the distal end of the lateral dorsal or volar edge of the lunate bone or at the corresponding part of the scaphoid. The collar of the proximal ganglions was situated between the dorsal radiocarpal and transverse scaphotriquetral ligament. The collar of distal dorsal ganglions was situated between the transverse scaphotriquetral and the trapezotriquetral ligament. The collar of the lateral ganglions was situated between the lateral collateral and the transverse ligament. The collar of the volar ganglions was situated between the stylocarpal ligament and the radiolunotriquetral ligament, or between the different stylocarpal ligaments. At the level of the scaphotrapezal joint, the stalk's base of implantation was located near the collateral edge of the distal surface of the joint with the collar between the distal scaphoidal ligaments. The palmar cysts exhibited a collar between the stylocarpal ligaments and the radiolunotriquetral ligament or between the different stylocarpal ligaments. DISCUSSION: At pathology examination, the lesions were not found to be different from those observed in other connective tissues exposed to overuse or repeated microtrauma (sports, occupational exposure). Anatomic conditions inside the joint capsula excluded extension of the mucoid degeneration transversally. The only issue was through the capsula, allowing the mucus enclosed in the connective tissue fibers to form the main cyst. CONCLUSION: Knowledge of these different processes enabled a topographical systematization useful for complete surgical or arthroscopic removal of the ganglion. Complete resection would prevent recurrence.

Predicting the risk of sporadic elevated bilirubin levels and diagnosing Gilbert's syndrome by genotyping UGT1A1*28 promoter polymorphism.

Elevated fluctuating levels of bilirubin are a common problem in clinical studies. Differentiation between a drug-related adverse event and the diagnostic symptom for Gilbert's syndrome (GS), an idiopathic unconjugated hyperbilirubinemia, is more or less impracticable since the diagnosis of GS is by exclusion. The aim of this investigation was to evaluate the correlation of unspecific elevated bilirubin levels and the occurrence of GS with a described polymorphism in the uridine diphosphat glucuronosyltransferase 1A1 (UGT1A1) in a predominately Caucasian population. 304 volunteers (152 male, 152 female) were genotyped for the UGT1A1 promoter polymorphism by PCR amplification and polyacrylamide gel electrophoresis. Serum bilirubin levels and liver enzymes were determined and GS was diagnosed using clinico-chemical criteria. 23/13 subjects displayed the homocygote variant, 73/66 the heterozygote variant and 56/72 wildtype (male/female, respectively). 23 male and 3 female volunteers fulfilled the clinical criteria for GS (15.1, respectively 2.0%). Men exhibited higher serum bilirubin levels than women with a mean (SD) of 14.37 (8.92) micromol/l compared to 10.17 (5.37) micromol/l, respectively (p < 0.001). The homocygote mutant promoter length correlated well with serum bilirubin levels and with the clinical diagnosis of GS (p < 0.001 each). Genotyping of the UGT1A1 promoter polymorphism is a cheap and unequivocal method for predicting elevated and fluctuating bilirubin levels. It is better suited to this purpose than the clinical diagnosis which is based on exclusion. The genotyping of UGT1A1 promoter polymorphism can help to improve safety and the reliable assessment of adverse events in clinical studies. Our data additionally support the demand to refine the bilirubin reference values.