Pharmacological and molecular evidence for kinin B1 receptor expression in urinary bladder of cyclophosphamide-treated rats.

1. In the present study, we developed an experimental model of cystitis induced by cyclophosphamide (CYP). In order to characterize des-Arg9-BK-induced contraction on the urinary bladder (UB) during the development of inflammation and to quantify kinin B1 receptor gene expression using a quantitative RT - PCR technique. 2. In the presence of peptidase inhibitors captopril (10 microM), DL-thiorphan (1 microM) and DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MERGEPTA 5 microM), bradykinin (BK) (0.3 - 3,000 nM) evoked a concentration-dependent contraction of rat UB which was not different between the CYP- and vehicle-treated groups. Unlike BK, des-Arg9-BK (0.3 - 100,000 nM) did not contract UB from vehicle-treated rats but contracted vigorously bladder strips from CYP-treated rats 14, 24 and 168 h after treatment. In UB of 24 h treated rat, the pD2 value of des-Arg9-BK was 7.3+/-0.1. 3. The cyclo-oxygenase inhibitor indomethacin (3 microM) reduced by 30% the maximal response of des-Arg9-BK. Both the kinin B1 receptor antagonists des-Arg9-[Leu8]BK (10 microM) and des-Arg10-Hoe 140 (10 microM) produced a rightward shift of the concentration-response curve to des-Arg9-BK yielding pKB values of 6.8+/-0.2 and 7.2+/-0.1, respectively, whilst the kinin B2 receptor antagonist Hoe 140 (1 microM) had no effect. 4. After CYP treatment, mRNA coding for the kinin B1 receptor appeared predominantly in UB. In this organ, the induction was progressive, reaching a maximum 48 h after CYP treatment. 5. In conclusion, the present study provides strong evidence for an induction of kinin B1 receptors in UB of CYP-treated rats. This was associated at a molecular level with an increase in mRNA expression of the gene coding for the kinin B1 receptor. This kinin receptor displayed the whole features of a classical rat kinin B1 receptor.     

Sequential electrodiagnostic evaluation of diabetic neuropathy after combined pancreatic and renal transplantation

To asses the long-term evolution of diabetic polyneuropathy after a combined kidney-pancreas transplant, an electrophysiological study was performed in 20 diabetic patients before transplant, and 1 (n=18), 2 (n=16), 3 (n=10) and 4 years (n=5) at a later date. Motor and sensory scores were calculated for conduction velocity and amplitude to determine the physiopathological process. During evolution the scores were not found to be decreasing. Motor and sensory velocity scores were significantly improved (p<0.05) 1=" and=" 2=" years=" after=" the=" graft,=" when=" score=" values=" tended=" to=" stabilize.=" motor=" and=" sensory=" amplitude=" scores,=" which=" are=" more=" sensitive=" for=" axonal=" loss=" assessment=" were=" slightly=" but=" not=" significantly=">     

Voxel-based analysis of confounding effects of age and dementia severity on cerebral metabolism in Alzheimer's disease

Alzheimer's disease is characterized by early hippocampal lesions, but neuropathological and functional imaging studies have also demonstrated involvement of associative cortices in patients suffering from this illness. New image-processing technologies have led to demonstration of predominant posteromedial cortical metabolic impairment in the disease. Confounding effects of both age and dementia severity on brain metabolism were assessed using categorical and correlational analyses performed with Statistical Parametric Mapping. Posterior cingulate and precuneus metabolism, assessed by positron emission tomography, was significantly correlated with age in a population of 46 patients with probable Alzheimer's disease. Metabolism in posterior cingulate and precuneus was higher in elderly than in younger patients with a diagnosis of Alzheimer's disease, even when dementia severity was taken as a confounding covariate. The data suggest that the sensitivity of positron emission tomography for the diagnosis of Alzheimer's disease is reduced in elderly cases, where less severe pathology is sufficient to induce clinical symptoms of dementia. Conversely, higher posteromedial metabolic impairment in early onset cases may reflect greater density of regional cerebral lesions or major decrease of functional afferences in a richly connected multimodal associative area. Posterior cingulate metabolism was also correlated to dementia severity, even when age was taken as a confounding covariate, whereas metabolism in the hippocampal formation was not shown to correlate with global cognitive deficit. Functional correlation was maintained between posterior cingulate and middle frontal cortex in demented patients as in elderly controls. The key role of posteromedial cortex in cognitive dysfunction assessed in Alzheimer's disease is probably related to its highly integrated position within attentional, visuospatial and memory neuronal networks.     

Striatum forever, despite sequence learning variability: a random effect analysis of PET data

This PET study is concerned with the what, where, and how of implicit sequence learning. In contrast with previous studies imaging the serial reaction time (SRT) task, the sequence of successive locations was determined by a probabilistic finite-state grammar. The implicit acquisition of statistical relationships between serially ordered elements (i.e., what) was studied scan by scan, aiming to evidence the brain areas (i.e., where) specifically involved in the implicit processing of this core component of sequential higher-order knowledge. As behavioural results demonstrate between- and within-subjects variability in the implicit acquisition of sequential knowledge through practice, functional PET data were modelled using a random-effect model analysis (i.e., how) to account for both sources of behavioural variability. First, two mean condition images were created per subject depending on the presence or not of implicit sequential knowledge at the time of each of the 12 scans. Next, direct comparison of these mean condition images provided the brain areas involved in sequential knowledge processing. Using this approach, we have shown that the striatum is involved in more than simple pairwise associations and that it has the capacity to process higher-order knowledge. We suggest that the striatum is not only involved in the implicit automatization of serial information through prefrontal cortex-caudate nucleus networks, but also that it plays a significant role for the selection of the most appropriate responses in the context created by both the current and previous stimuli, thus contributing to better efficiency and faster response preparation in the SRT task.     

Predictive factors of acute urinary morbidity after iodine-125 brachytherapy for localised prostate cancer: a phase 2 study.

PURPOSE: To analyse predictive factors of acute urinary morbidity after transperineal permanent prostate brachytherapy. METHODS AND MATERIALS: Sixty patients treated in a phase 2 study with iodine-125 brachytherapy (9/1998 to 2/2000) for localised prostate adenocarcinoma were analysed after at least 1-year follow-up. Prescribed dose was 144 Gy and all patients had a pre-planning and a post-implant dosimetry. Urinary morbidity was evaluated prospectively using the Radiation Therapy Oncology Group (RTOG) scale. We examined the relationship between pre-implant ultrasound prostate volume, post-implant CT-scan prostate volume, neoadjuvant hormonotherapy, total number of needles and seeds, post-implant dosimetry variables, first 30 vs. last 30 treated patients and post-implant urinary morbidity. RESULTS: All patients experienced some degree of urinary distress symptoms after treatment. Symptoms were generally mild grade 1 in 56% and grade 2 in 10% lasting less than 6 months. Eight patients (13%) required bladder catheter for acute urinary obstruction. At 1-year follow-up, nine patients (15%) complained from persistent dysuria requiring in three cases endoscopic prostate resection. The percentage of urethra volume receiving 216 Gy (cut-off 40%) and the pre-implant prostate volume (cut-off 31 ml) were the only statistically significant predictor of grade 2-3 or persistent urinary morbidity on multivariate analysis. CONCLUSION: Our short-term data suggest that both pre-implant prostate volume value and post-implant V.U. 150 value might be predictors for urinary morbidity after prostate brachytherapy.     

The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation

In order to examine whether changes in the bispectral index (BIS) may be an adequate monitor for the analgesic component of anesthesia, we evaluated the effect of remifentanil on the BIS change and hemodynamic responses to laryngoscopy and tracheal intubation. Fifty ASA physical status I patients were randomly assigned, in a double-blinded fashion, to one of five groups (n = 10/group) according to the remifentanil target effect compartment site concentration (0, 2, 4, 8, or 16 ng/mL). The target-controlled infusion (TCI) of remifentanil was initiated 3 min after the TCI of propofol that was maintained at the effect-site concentration of 4 microg/mL throughout the study. After the loss of consciousness and before the administration of vecuronium 0.1 mg/kg, a tourniquet was applied to one arm and inflated above the systolic blood pressure in order to detect any gross movement within the first minute after tracheal intubation, which was performed 3 min after remifentanil TCI began. A BIS value was generated every 10 s. Arterial blood pressure and heart rate (HR) were measured every minute, noninvasively. Measures of mean arterial pressure (MAP), HR, and BIS were obtained before the induction, before the start of remifentanil TCI, before laryngoscopy, and 5 min after intubation. The relationships between remifentanil effect-site concentrations and BIS change or hemodynamic responses (changes in MAP and HR) to intubation were determined by logarithmic regression. BIS values were not affected by remifentanil before laryngoscopy. During this period, MAP and HR decreased significantly (P < 0.01) in the remifentanil 8 and 16 ng/mL groups. Changes in BIS, MAP, and HR were negatively correlated with remifentanil effect-site concentration (P < 0.0001). The number of movers in the remifentanil 0-, 2-, 4-, 8-, and 16-ng/mL groups was, respectively, 10, 9, 7, 1, and 0. Hypotensive episodes (MAP < 60 mm Hg) were noted in 1, 2, and 5 patients in the remifentanil 4-, 8-, and 16-ng/mL groups, respectively. We conclude that the addition of remifentanil to propofol affects BIS only when a painful stimulus is applied. Moreover, remifentanil attenuated or abolished increases in BIS and MAP after tracheal intubation in a comparable dose-dependent fashion. IMPLICATIONS: Bispectral index change is as sensitive as hemodynamic responses after a painful stimulus for detecting deficits in the analgesic component of anesthesia. It may, therefore, be a useful monitor of the depth of anesthesia in patients who are incapable of HR and MAP responses to noxious stimuli because of medications or cardiovascular disease.     

Better preservation of endothelial function and decreased activation of the fetal renin-angiotensin pathway with the use of pulsatile flow during experimental fetal bypass

OBJECTIVE: Pulsatile flow was shown to overcome the progressive rise in peripheral and placental vascular resistances observed during steady-flow bypass, this rise being counteracted by inhibition of nitric oxide synthase. This study quantifies the release of endothelial vasoactive substances during a 60-minute in utero model of fetal bypass. METHODS: Fetuses were randomly allocated into 1 of 2 groups (steady flow, n = 8, or pulsatile flow, n = 13) and subjected to bypass through central cannulation and perfusion with either a centrifugal or pulsatile (125 beats x min(-1)) blood pump. RESULTS: Lactate concentration was high, starting at fetal exteriorization and increasing during fetal preparation in the 2 groups. Once bypass was established, the rise was significant only in the steady-flow group. Plasma nitric oxide metabolites, similar before bypass, reached higher levels during pulsatile flow at the end of bypass (99+/-9 vs. 82+/-23 micromol x L(-1); P =.037). Levels of urinary nitric oxide metabolites were significantly higher in the pulsatile-flow than in the steady-flow group (764+/-143 vs. 508+/-240 micromol x L(-1); P =.005). Plasma cyclic guanosine monophosphate levels increased after 30 minutes of bypass in the pulsatile-flow group (25+/-18 vs. 12+/-8 pmol x mL(-1); P =.004), and urinary cyclic guanosine monophosphate excretion was higher in the pulsatile-flow group (517+/-450 vs. 118+/-78 pmol x mL(-1); P =.024). Plasma endothelin-1 levels increased in the 2 groups and were higher in the steady-flow group at 30 minutes (27+/-5 vs. 23+/-2 pg x mL(-1); P =.04) and 60 minutes of bypass (39+/-7 vs 32 +/- 6 pg x mL(-1); P =.04). Plasma renin concentration increased significantly during bypass only in the steady-flow group (26+/-10 vs. 57+/-42 in ng A1 x mL(-1) x h(-1); P =.04). CONCLUSIONS: Improved placental and peripheral perfusion during fetal pulsatile-flow bypass may be mediated by preservation of fetal/maternal endothelial nitric oxide biosynthetic mechanisms and/or decreased activation of the fetal renin-angiotensin pathway.     

Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.