IV thrombolysis and renal function.

OBJECTIVE: To investigate the association of renal impairment on functional outcome and complications in stroke patients treated with IV thrombolysis (IVT). METHODS: In this observational study, we compared the estimated glomerular filtration rate (GFR) with poor 3-month outcome (modified Rankin Scale scores 3-6), death, and symptomatic intracranial hemorrhage (sICH) based on the criteria of the European Cooperative Acute Stroke Study II trial. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients without IVT treatment served as a comparison group. RESULTS: Among 4,780 IVT-treated patients, 1,217 (25.5%) had a low GFR (<60 mL/min/1.73 m(2)). A GFR decrease by 10 mL/min/1.73 m(2) increased the risk of poor outcome (OR [95% CI]): (ORunadjusted 1.20 [1.17-1.24]; ORadjusted 1.05 [1.01-1.09]), death (ORunadjusted 1.33 [1.28-1.38]; ORadjusted 1.18 [1.11-1.249]), and sICH (ORunadjusted 1.15 [1.01-1.22]; ORadjusted 1.11 [1.04-1.20]). Low GFR was independently associated with poor 3-month outcome (ORadjusted 1.32 [1.10-1.58]), death (ORadjusted 1.73 [1.39-2.14]), and sICH (ORadjusted 1.64 [1.21-2.23]) compared with normal GFR (60-120 mL/min/1.73 m(2)). Low GFR (ORadjusted 1.64 [1.21-2.23]) and stroke severity (ORadjusted 1.05 [1.03-1.07]) independently determined sICH. Compared with patients who did not receive IVT, treatment with IVT in patients with low GFR was associated with poor outcome (ORadjusted 1.79 [1.41-2.25]), and with favorable outcome in those with normal GFR (ORadjusted 0.77 [0.63-0.94]). CONCLUSION: Renal function significantly modified outcome and complication rates in IVT-treated stroke patients. Lower GFR might be a better risk indicator for sICH than age. A decrease of GFR by 10 mL/min/1.73 m(2) seems to have a similar impact on the risk of death or sICH as a 1-point-higher NIH Stroke Scale score measuring stroke severity.

Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-gamma-induced MHCII expression on a wide variety of non-bone marrow-derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4(+) T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-gamma-activated cells of the macrophage lineage. pIV(-/-) mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

Task force IV: Clinical use of ambulatory blood pressure monitoring. Participants of the 1999 Consensus Conference on Ambulatory Blood Pressure Monitoring

OBJECTIVE: To reach a consensus on the clinical use of ambulatory blood pressure monitoring (ABPM). METHODS: A task force on the clinical use of ABPM wrote this overview in preparation for the Seventh International Consensus Conference (23-25 September 1999, Leuven, Belgium). This article was amended to account for opinions aired at the conference and to reflect the common ground reached in the discussions. POINTS OF CONSENSUS: The Riva Rocci/Korotkoff technique, although it is prone to error, is easy and cheap to perform and remains worldwide the standard procedure for measuring blood pressure. ABPM should be performed only with properly validated devices as an accessory to conventional measurement of blood pressure. Ambulatory recording of blood pressure requires considerable investment in equipment and training and its use for screening purposes cannot be recommended. ABPM is most useful for identifying patients with white-coat hypertension (WCH), also known as isolated clinic hypertension, which is arbitrarily defined as a clinic blood pressure of more than 140 mmHg systolic or 90 mmHg diastolic in a patient with daytime ambulatory blood pressure below 135 mmHg systolic and 85 mmHg diastolic. Some experts consider a daytime blood pressure below 130 mmHg systolic and 80 mmHg diastolic optimal. Whether WCH predisposes subjects to sustained hypertension remains debated. However, outcome is better correlated to the ambulatory blood pressure than it is to the conventional blood pressure. Antihypertensive drugs lower the clinic blood pressure in patients with WCH but not the ambulatory blood pressure, and also do not improve prognosis. Nevertheless, WCH should not be left unattended. If no previous cardiovascular complications are present, treatment could be limited to follow-up and hygienic measures, which should also account for risk factors other than hypertension. ABPM is superior to conventional measurement of blood pressure not only for selecting patients for antihypertensive drug treatment but also for assessing the effects both of non-pharmacological and of pharmacological therapy. The ambulatory blood pressure should be reduced by treatment to below the thresholds applied for diagnosing sustained hypertension. ABPM makes the diagnosis and treatment of nocturnal hypertension possible and is especially indicated for patients with borderline hypertension, the elderly, pregnant women, patients with treatment-resistant hypertension and patients with symptoms suggestive of hypotension. In centres with sufficient financial resources, ABPM could become part of the routine assessment of patients with clinic hypertension. For patients with WCH, it should be repeated at annual or 6-monthly intervals. Variation of blood pressure throughout the day can be monitored only by ABPM, but several advantages of the latter technique can also be obtained by self-measurement of blood pressure, a less expensive method that is probably better suited to primary practice and use in developing countries. CONCLUSIONS: ABPM or equivalent methods for tracing the white-coat effect should become part of the routine diagnostic and therapeutic procedures applied to treated and untreated patients with elevated clinic blood pressures. Results of long-term outcome trials should better establish the advantage of further integrating ABPM as an accessory to conventional sphygmomanometry into the routine care of hypertensive patients and should provide more definite information on the long-term cost-effectiveness. Because such trials are not likely to be funded by the pharmaceutical industry, governments and health insurance companies should take responsibility in this regard.

Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-gamma-induced MHCII expression on a wide variety of non-bone marrow-derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4(+) T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-gamma-activated cells of the macrophage lineage. pIV(-/-) mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

Induction of calmodulin kinase IV by the thyroid hormone during the development of rat brain.

This communication reports the specific induction of calmodulin kinase IV by the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) in a time- and concentration-dependent manner at a very early stage of brain differentiation using a fetal rat telencephalon primary cell culture system, which can grow and differentiate under chemically defined conditions. The induction of the enzyme that can be observed both on the mRNA and on the protein level is T3-specific, i.e. it cannot be induced by retinoic acid or reverse T3, and can be inhibited on both the transcriptional and the translational level by adding to the culture medium actinomycin D or cycloheximide, respectively. The earliest detection of calmodulin kinase IV in the fetal brain tissue of the rat is at days E16/E17, both on the mRNA as well as on the protein level. This is the first report in which a second messenger-dependent kinase involved in the control of cell regulatory processes is itself controlled by a primary messenger, the thyroid hormone.

Small Bowel Bacterial Overgrowth is found in 71% of IBS patients and associated symptoms respond wel to Rifaximin in a phase IV trial

Background: The prevalence of small intestinal bowel bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) ranges from 43% to 78% as determined by the lactulose hydrogen breath (LHBT) test. Although rifaximine, a non-absorbable antibiotic, has been able to decrease global IBS symptoms as well as bloating in placebo-controlled randomized trials, these results were not repeated in phase IV studies in daily clinical practice. Aim: To assess the prevalence of SIBO in an IBS cohort and to evaluate the treatment response in the IBS cohort affected by SIBO. Methods: Enrolled patients were diagnosed with IBS using the following criteria: fulfillment of the Rome III criteria, absence of alarm symptoms (anemia, weight loss, nocturnal symptoms etc), normal fecal calproectin, normal endoscopic workup including histology. Celiac disease was excluded by serology and/or duodenal biopsy. All patients underwent lactulose hydrogen breath testing (LHBT) for SIBO diagnosis. Patients with SIBO were treated with rifaximine tablets (400mg twice daily for 14 days). Both before and at week 6 after rifaximin treatment, patients completed a questionnaire, where the following criteria were assessed individually using 11-point Likert scales: the bloating, flatulence, abdominal pain, diarrhea, and overall well-being. Results: Hundred-fifty IBS patients were enrolled (76% female, mean age 44 ± 16 years), of whom 106 (71%) were diagnosed with SIBO and consequently treated with rifaximine. Rifaximine treatment significantly reduced the following symptoms as assessed by the symptom questionnaire: bloating (5.5 ± 2.6 before vs. 3.6 ± 2.7 after treatment, p <0.001), flatulence (5 ± 2.7 vs. 4 ± 2.7, p = 0.015), diarrhea (2.9 ± 2.4 vs. 2 ± 2.4, p = 0.005), abdominal pain (4.8 ± 2.7 vs. 3.3 ± 2.5, p <0.001) and resulted in improved overall well-being (3.9 ± 2.4 vs. 2.7 ± 2.3, p <0.001). Thirteen of the 106 treated patients were lost to follow-up (12%). The LHBT was repeated 2-4 weeks after rifaximine treatment in 65/93 (70%) patients. Eradication of SIBO was documented in 85% of all patients (55/65), whereas 15% of patients (10/65) tested positive for SIBO as determined by the LHBT testing. Conclusions: The results of our phase IV trial indicate that a high proportion of IBS patients tested positive for SIBO. IBS symptoms (bloating, flatulence, diarrhea, pain, overall well-being) were significantly diminished following a 2-week treatment with rifaximine. These results support the previous findings of randomized controlled trials that the presence of SIBO is associated with symptom generation in IBS patients and that reduction and/or elimination of SIBO may help to alleviate IBSassociated symptoms.

Treatment of symphysitis pubis with one unique iv injection of Ibandronate: report of two cases

Objective: Osteitis pubis is a noninfectious painful inflammatorydisorder of the symphysis pubis. Etiologic factors are numerous, themost common are: osseous extension of adductor, enthesis due tosport overuse, irritation after urological and abdominal procedures,and systemic inflammatory disorders in particularspondylarthropathies. Many cases are idiopathic. The symptomsconsist of regional chronic mechanical and sometime nocturnal pain.Diagnosis is usually confirmed by either bone scintigraphy or by MRI.There are no standard treatments but conservative approachesincluding rest and NSAIDS are generally recommended. In 2001, agood clinical and radiological response of three refractory cases with3 to 6 monthly perfusions of pamidronate was reported [1].Ibandronate is a much more powerful and long-lasting bisphosphonatethan pamidronate, and has not yet been reported in literature to ourknowledge in this indication.Patients and Methods: We present two cases of idiopathic origin:one woman (63 years old) and one man (36 years old).The symptomswere present >3 months in the first patient and one year in the second.The diagnosis was confirmed by MRI which showed bone edemaon both sizes of symphysis and in the second case bony erosionsadjacent to the joint were seen. Both cases failed to respond toconservative measures. Both patients received one single direct ivInjection of 3 mg of Ibandronate.Results: The injections resulted in a rapid (within a few days)resolution of pain that lasted more than 6 months in both patients.No side effects were observed. In the first case, an isotope bone scanperformed 4 months after the injection showed no residual uptake. Thesecond patient had a repeated MRI after 6 months. It demonstrated anattenuation of bone edema compared to the first MRI.Conclusion: IV Ibandronate may constitute a safe and effectivetreatment option for patients with refractory osteitis pubis.References1 Maksymowych WP, Aaron SL, Russell AS. Treatment of refractorysymphysitis pubis with intravenous pamidronate. J Rheumatol.2001;28(12):2754, 2001.

Structural Validity of the Wechsler Intelligence Scale for Children (WISC-IV) in a French-speaking Swiss sample

The Wechsler Intelligence Scale for Children-fourth edition (i.e. WISC-IV) recognizes a four-factor scoring structure in addition to the Full Scale IQ (FSIQ) score: Verbal Comprehension (VCI), Perceptual Reasoning (PRI), Working Memory (WMI), and Processing Speed (PSI) indices. However, several authors suggested that models based on the Cattell-Horn-Carroll (CHC) theory with 5 or 6 factors provided a better fit to the data than does the current four-factor solution. By comparing the current four-factor structure to CHC-based models, this research aimed to investigate the factorial structure and the constructs underlying the WISC-IV subtest scores with French-speaking Swiss children (N = 249). To deal with this goal, confirmatory factor analyses (CFAs) were conducted. Results showed that a CHC-based model with five factors better fitted the French-Swiss data than did the current WISC-IV scoring structure. All together, these results support the hypothesis of the appropriateness of the CHC model with French-speaking children.

Toxic cardenolides: chemical ecology and coevolution of specialized plant-herbivore interactions.

CONTENTS: Summary 28 I. Historic background and introduction 29 II. Diversity of cardenolide forms 29 III. Biosynthesis 30 IV. Cardenolide variation among plant parts 31 V. Phylogenetic distribution of cardenolides 32 VI. Geographic distribution of cardenolides 34 VII. Ecological genetics of cardenolide production 34 VIII. Environmental regulation of cardenolide production 34 IX. Biotic induction of cardenolides 36 X. Mode of action and toxicity of cardenolides 38 XI. Direct and indirect effects of cardenolides on specialist and generalist insect herbivores 39 XII. Cardenolides and insect oviposition 39 XIII. Target site insensitivity 40 XIV. Alternative mechanisms of cardenolide resistance 40 XV. Cardenolide sequestration 41 Acknowledgements 42 References 42 SUMMARY: Cardenolides are remarkable steroidal toxins that have become model systems, critical in the development of theories for chemical ecology and coevolution. Because cardenolides inhibit the ubiquitous and essential animal enzyme Na(+) /K(+) -ATPase, most insects that feed on cardenolide-containing plants are highly specialized. With a huge diversity of chemical forms, these secondary metabolites are sporadically distributed across 12 botanical families, but dominate the Apocynaceae where they are found in > 30 genera. Studies over the past decade have demonstrated patterns in the distribution of cardenolides among plant organs, including all tissue types, and across broad geographic gradients within and across species. Cardenolide production has a genetic basis and is subject to natural selection by herbivores. In addition, there is strong evidence for phenotypic plasticity, with the biotic and abiotic environment predictably impacting cardenolide production. Mounting evidence indicates a high degree of specificity in herbivore-induced cardenolides in Asclepias. While herbivores of cardenolide-containing plants often sequester the toxins, are aposematic, and possess several physiological adaptations (including target site insensitivity), there is strong evidence that these specialists are nonetheless negatively impacted by cardenolides. While reviewing both the mechanisms and evolutionary ecology of cardenolide-mediated interactions, we advance novel hypotheses and suggest directions for future work.

Clinical evaluation of a method for detecting superficial surgical transitional cell carcinoma of the bladder by light-induced fluorescence of protoporphyrin IX following the topical application of 5-aminolevulinic acid: preliminary results.

BACKGROUND AND OBJECTIVE: In bladder cancer, conventional white light endoscopic examination of the bladder does not provide adequate information about the presence of "flat" urothelial lesions such as carcinoma in situ. In the present investigation, we examine a new technique for the photodetection of such lesions by the imaging of protoporphyrin IX (PpIX) fluorescence following topical application of 5-aminolevulinic acid (ALA). STUDY DESIGN/MATERIALS AND METHODS: Several hours after bladder instillation of an aqueous solution of ALA in 34 patients, a Krypton ion laser or a filtered Xenon arc-lamp was used to excite PpIX fluorescence. Tissue samples for histological analysis were taken while observing the bladder wall either by means of a video camera, or by direct endoscopic observation. RESULTS: A good correlation was found between the PpIX fluorescence and the histopathological diagnosis. On a total of 215 biopsies, 143 in fluorescent and 72 in nonfluorescent areas, all visible tumors on white light cytoscopy appeared in a bright red fluorescence with the photodetection technique. In addition, this method permitted to discover 47 unsuspected carcinomatous lesions on white light observation, among which 40% were carcinoma in situ. CONCLUSION: PpIX fluorescence induced by instillation into the bladder of 5-ALA is an efficient method of mapping the mucosa in bladder carcinoma.