A molecular signature in superficial bladder carcinoma predicts clinical outcome.

PURPOSE: Cancer of the urinary bladder is a common malignant disease in the western countries. The majority of patients presents with superficial tumors with a high recurrence frequency, a minor fraction of these patients experience disease progression to a muscle invasive stage. No clinical useful molecular markers exist to identify patients showing later disease progression. The purpose of this study was to identify markers of disease progression using full-genome expression analysis. EXPERIMENTAL DESIGN: We did a full-genome expression analysis (59,619 genes and expressed sequence tags) of superficial bladder tumors from 29 bladder cancer patients (13 without later disease progression and 16 with later disease progression) using high-density oligonucleotide microarrays. We used supervised learning for identification of the optimal genes for predicting disease progression. The identified genes were validated on an independent test set (74 superficial tumor samples) using in house-fabricated 60-mer oligonucleotide microarrays. RESULTS: We identified a 45-gene signature of disease progression. By monitoring this progression signature in an independent test set, we found a significant correlation between our classifications and the clinical outcome (P < 0.03). The genes identified as differentially expressed were involved in regulating apoptosis, cell differentiation, and cell cycle and hence may represent potential therapeutic targets. CONCLUSIONS: Our results indicate that it may be possible to identify patients with a high risk of disease progression at an early stage using a molecular signature present already in the superficial tumors. In this way, better treatment and follow-up regimens could be assigned to patients suffering from superficial bladder cancer.     

Metastatic testicular cancer and extragonadal germ cell tumor presenting with neurological symptoms

Summary We present two patients with testicular cancer and extragonadal germ cell tumor respectively in whom neurological symptoms due to metastases preceded the correct diagnosis. Testicular cancer and extragonadal germ cell tumor are today curable malignancies even when distant metastases are present at diagnosis. The diagnosis of germ cell tumor should be considered whenever a young man presents with metastases of uncertain origin, and all histological specimens should be revised with the diagnosis of germ cell tumor in mind.     

How to perform a comprehensive search for FDG-PET literature

In this study, a comprehensive, unbiassed search strategy for identifying literature on fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in Medline, Embase and Current Contents was developed, with specific search strategies for each database, using MeSH terms as well as free text words for PET and FDG. To examine which text words apply to FDG, we evaluated the ways of spelling FDG in a random sample of FDG-PET articles (n=100). These words were used as free text words in the two databases and overlap was determined. PET publications were identified using the text words ”positron emission tomography” and ”pet$” combined with the respective MeSH terms for each database. To compare the yield of the combined FDG-PET strategy in each database, the retrieved citations were downloaded to Pro-Cite 4.0. Finally, we added search terms for lung cancer, breast cancer, melanoma, head and neck cancer and lymphoma to our strategy and to a short strategy (consisting of the text words ”positron emission tomography” and ”fdg”). In order to measure the yield and precision (positive predictive value, PPV) of our search strategy and compare it with the short one, we screened the title and abstract of the retrieved citations. Reviewing a random sample of the FDG-PET literature yielded 56 different ways of spelling FDG. We confined the list to 11 text words, without missing articles. Of the publications retrieved by these text words, only 4% were indexed by the MeSH term ”Fludeoxyglucose F18” in Medline and 29% by the MeSH-term ”Fluorodeoxyglucose F18” in Embase. Only 51% of PET articles were indexed by the MeSH term ”Tomography, emission-computed” in Medline and 40% by the MeSH term ”Positron emission tomography” in Embase. The combined search strategy for identifying studies on FDG and PET resulted in 2865 publications in Medline and 2646 in Embase. Medline identified 1662 publications not found by Embase; Embase identified 1422 publications not found by Medline. Compared with the short strategy, our search strategy yielded on average 52% more publications (94%, 41% and 20% more in Medline, Embase and Current Contents, respectively). The PPV of our strategy (percent of publications that were really on PET, FDG and the specified subject) was 70%, compared with 76% using the short strategy. Regardless of the strategy used, Embase yielded more publications and was also slightly more specific than Medline. With the recommended strategy, FDG-PET publications can be identified more efficiently. We have shown the importance of searching more than one database and emphasize the use of both MeSH terms and text words in a search strategy. Standardization of the spelling of FDG and indexing of articles on FDG would substantially simplify searching. Received 5 July and in revised form 25 September 1999     

Influence of three potential genetic risk factors for thrombosis in 43 families carrying the factor V Arg 506 to Gln mutation

The factor V (FV) Arg 506 to Gln mutation is the most common abnormality observed in familial thrombophilia. Many studies have shown that its clinical expression differs among families and among carriers. Some thrombotic patients carry an additional genetic risk factor such as protein C, protein S or antithrombin deficiency. We sought to identify other genetic risk factors potentially favouring expression of the thrombotic phenotype in 370 members of 43 families with the FV Arg 506 to Gln mutation. We analysed three candidate polymorphisms in genes involved in the PC anticoagulant pathway, consisting of two polymorphic sites in the 5' non-transcribed region of the PC gene, -1654 C/T and -1641 A/G, with three known combinations (TA, CA and CG) that influence the protein C plasma level; one polymorphic site (4070 A/G) in exon 13 of the FV gene, which influences the plasma factor V concentration, and one polymorphic site (677 C/T) in the methylenetetrahydrofolate reductase gene, which is often associated with moderate hyperhomocysteinaemia. The distribution of these different polymorphisms was similar in patients with a history of thrombosis and those who remained asymptomatic, ruling out the possibility that each of these polymorphisms alone can play a role in the onset of thrombosis in carriers of the FV Arg 506 to Gln mutation.     

Volunteer bias in nonrandomized evaluations of the efficacy of needle-exchange programs

Objective Nonrandomized comparisons of the incidence of HIV and hepatitis B and C between injection drug users (IDUs) who do and do not attend voluntary needle-exchange programs may be subject to bias. To explore possible sources of bias, we examined characteristics associated with voluntarily beginning or ceasing to participate in the Seattle needle exchange. Methods In a cohort of 2,879 IDUs, a standardized questionnaire measured characteristics present at enrollment. We examined the relation of these characteristics to the proportion of IDUs who began to use the program during the ensuing 12-month follow-up period and to the proportion of current exchangers who dropped out during that period of time. Results Of the 494 never-exchangers at baseline, 32% attended the exchange program during follow-up; those who reported sharing syringes or who were homeless at enrollment were more likely to become new exchange users (adjusted risk ratio [ARR] for becoming an exchange user = 1.8 for those who shared syringes, and ARR=2.2, for those who were homeless). Of 1,274 current exchangers, 16% stopped using the exchange during follow-up, with daily injectors (ARR=0.6) and those who reported backloading (ARR=0.6) being relatively less likely to drop out of the exchange. Conclusions The analysis suggests that IDUs participating in needle-exchange programs at a given point in time may include a particularly high proportion of those injectors whose pattern of drug use puts them at elevated risk of blood-borne viral infections.     

Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse

Aim:  Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. Thus, our aim was to assess if CTS-1027 is hepato-protective and anti-fibrogenic during cholestatic liver injury.
Methods:  C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage.
Results:  BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals ( P  < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (α-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals ( P  < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug ( P  < 0.05).
Conclusion:  The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury.     

High Cup Angle and Microseparation Increase the Wear of Hip Surface Replacements

High wear rates and high patient ion levels have been associated with high (> 55°) cup inclination angles for metal-on-metal surface replacements. Wear rates and patterns have been simulated for ceramic-on-ceramic bearings by applying microseparation to replicate head offset deficiency. We tested 39-mm metal-on-metal surface replacements (n = 5) in a hip simulator with (A) an increased cup inclination angle of 60° and (B) an increased cup inclination angle and microseparation over 2 million cycles. (A) resulted in a ninefold increase in wear rate and (B) resulted in a 17-fold increase in wear rate compared to a standard gait condition study. Wear particles produced under microseparation conditions were larger than those produced under standard conditions but of similar shape (round to oval). The data suggest both head and cup position influence the wear of surface replacements; we believe it likely bearings with high wear either have a high cup inclination angle, an offset deficient head, or a combination of both. One or more of the authors have received funding from The Engineering and Physical Sciences Research Council (JF, EI), the Arthritis Research Campaign (JF, EI, PC,IL), and the National Institute for Health Research (JF). Graham Isaac is an employee of DePuy International (Leeds, UK). John Fisher and Sophie Williams are paid consultants of DePuy International.     

Dy-DTPA derivatives as relaxation agents for very high field MRI: the beneficial effect of slow water exchange on the transverse relaxivities.

Proton longitudinal and transverse relaxivities of Dy(DTPA)(2-) and Dy-DTPA bisamide derivatives (Dy(DTPA-BA): Dy-DTPA bisamide, Dy(DTPA-BEA): Dy-DTPA bisethylamide, Dy(DTPA-BnBA): Dy-DTPA bis-n-butylamide, and Dy(DTPA-BBMA): Dy-DTPA bisbismethylamide) were analyzed between 0.47 T and 18.8 T. Curie longitudinal relaxation was clearly observed at magnetic fields larger than 2.4 T, but the longitudinal relaxivities are limited by the fast rotation of the complexes. Rotational correlation times were separately assessed by deuterium relaxometry of the diamagnetic deuterated lanthanum analogs. Transverse relaxivity, which depends on the square of the magnetic field and on the residence time of the coordinated water molecule (tau(M)), was more than 7.5 times larger at 18.8 T and 310 K for Dy(DTPA-BA) and Dy(DTPA-BEA) as compared to Dy(DTPA)(2-). This difference is mainly related to the slower water exchange of the bisamide complexes, as confirmed by the values of tau(M) measured by oxygen-17 relaxometry. Such Dy-complexes, characterized by relatively long tau(M) values (tauM310 larger than 100 ns but smaller than 1 micros), thus appear to be useful as negative T(2) (or transverse) contrast agents for high-field imaging. This was demonstrated by the spin-echo images of phantoms obtained at 4.7 T on samples containing Dy(DTPA)(2-) and Dy(DTPA-BEA).     

Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery

BackgroundThe public health cost impact of complex regional pain syndrome type I (CRPS I) is considerable in both emergency and scheduled orthopaedic surgery. We proposed to assess the effectiveness of vitamin C in prevention of CRPS I in foot and ankle surgery.MethodsWe carried out a “before–after” quasi-experimental study comparing two chronologically successive groups without (Group I: July 2002–June 2003) and with (Group II: July 2003–June 2004) preventive 1 g daily vitamin C treatment. All patients having surgery on the foot or ankle were enrolled, with the exception of diabetic foot cases. Several factors were analysed: sex, age, type of pathology, history of CRPS I, psychological context, tourniquet time, and cast immobilisation time.Results420 feet (392 patients) were included in the study: 185 in Group I, 235 in Group II. CRPS I occurred in 18 cases in Group I (9.6%) and 4 cases in Group II (1.7%) (p < 10^?4), with history of CRPS I as a significantly correlated factor (relative risk = 10.4). The psychological context (anxio-depressive state) showed a (sub-significant) tendency to increase the risk of CRPS I (relative risk = 2.6).ConclusionVitamin C has been shown to be effective in preventing CRPS I secondary to wrist fracture, but few data are available with respect to foot and ankle cases. The present study demonstrates the effectiveness of vitamin C in preventing CRPS I of the foot and ankle—a frequent complication in our control group (9.6%). The authors recommend preventive management by vitamin C.     

Souffrance des institutions, souffrance en institution. La formation comme espace de relation

At the present time, quantitative administrative logic, necessity of productivity-profitability, gain of time and consensus, tend to depose thought and subject, leading dehumanization and decline of collective. Hospital institution has difficulties in coming to terms with sociopolitical changes which penetrate it. Group and institutional ties are affected; they participate largely in suffering of institutions as well as that of medical persons and patients. The authors show that mental institution reveals a part of society in suffering and the possible existence of spaces for elaborating. After having thoroughed their issue through the questions of a hollow subject, lack of linkage, conflict in primary task and crisis of transmission, the authors question resorts that institution finds to change and they present a situation of formation. They show that this one can be revealing about institutional suffering, but also creative of a space for elaborated thought in institution. According to them, “spaces of relation” exist, as this space of formation, in a transitional link and, as relational and emotional bond. Those ones enable medical person to abandon the time of immediacy which reinforce them in urgency and act, and to start elaboration.