bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days
Authors: Yamada Yasuhide , Yamamoto Noboru , Shimoyama Tatsu , Horiike Atsushi , Fujisaka Yasuhito , Takayama Kyoko , Sakamoto Terumi , Nishioka Yuki , Yasuda Sanae , Tamura Tomohide 
Published: October 2005

E7070 is a novel sulfonamide anticancer agent that disrupts the G1/S phase of the cell cycle. The objectives of this phase I study of E7070 were to estismate the maximal tolerated dose (MTD), to determine the recommended dose for phase II, and to clarify the pharmacokinetic profile of E7070 and its relation to polymorphisms of CYP2C9 (*2, *3) and CYP2C19 (*2, *3) in Japanese patients. Patients received 1–2‐h i.v. infusions of E7070 (400, 600, 700, 800 or 900 mg/m2) on day 1 of a 21‐day cycle. Twenty‐one patients received between one and eight cycles of E7070. The dose‐limiting toxicities (DLT) comprised leukopenia, neutropenia, thrombocytopenia, elevation of aspartate aminotransferase, colitis, and ileus. The mean area under the plasma concentration–time curve (AUC) for successive dose levels increased in a non‐dose‐proportional manner. Two patients were heterozygous for the CYP2C9 mutation. For CYP2C19, eight patients were wild type and the remainder had heterozygous (n = 8) or homozygous mutations (n = 5). Regarding the CYP2C19 genotype, the AUC of patients with mutant alleles were higher than those of patients with wild type at a dose of 600 mg/m2 or more. The severity of toxic effects, such as myelosuppression, seemed to depend on the AUC. No partial responses were observed. One patient treated at a dose of 700 mg/m2 experienced a maximum tumor volume reduction of 22.5%. The MTD was estimated to be 900 mg/m2. A dose of 800 mg/m2 is recommended for further phase II studies. The pharmacokinetic/pharmacodynamic properties of E7070 seemed to be influenced by CYP2C19 genotype. The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in monotherapy or in combination chemotherapy. (Cancer Sci 2005; 96: 721 –728)
Nrf2‐deficient mice are highly susceptible to cigarette smoke‐induced emphysema
Authors: Iizuka Takashi , Ishii Yukio , Itoh Ken , Kiwamoto Takumi , Kimura Toru , Matsuno Yosuke , Morishima Yuko , Hegab Ahmed E. , Homma Shinsuke , Nomura Akihiro , Sakamoto Tohru , Shimura Masako , Yoshida Aruto , Yamamoto Masayuki , Sekizawa Kiyohisa 
Published: October 2005

Inflammation, protease/anti‐protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti‐oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2‐knockout mice to cigarette smoke (CS)‐induced emphysema was examined. In Nrf2‐knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS‐exposure, whereas no pathological abnormalities were observed in wild‐type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2‐knockout mice 8 weeks after CS‐exposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2‐knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild‐type, but not in Nrf2‐knockout mice. This protease/anti‐protease imbalance, together with the lack of inducible expression of ARE‐regulated anti‐oxidant/anti‐inflammatory genes, may explain the predisposition of Nrf2‐knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti‐oxidant balance, but also inflammation and the protease/anti‐protease balance.
Environmental warming increases invasion potential of alpine lake communities by imported species
Authors: Holzapfel Angela M. , Vinebrooke Rolf D. 
Published: October 2005

AbstractGlobal warming increasingly pressures species to show adaptive migratory responses. We hypothesized that warming increases invasion of alpine lakes by low‐elevation montane zooplankton by suppressing native competitors and predators. This hypothesis was tested by conducting a two‐factor experiment, consisting of a warming treatment (13 vs. 20°C) crossed with three invasion levels (alpine only, alpine+montane, montane only), in growth chambers over a 28‐day period. Warming significantly reduced total consumer biomass owing to the decline of large alpine species, resulting in greater autotrophic abundance. Significant temperature‐invasion interactions occurred as warming suppressed alpine zooplankton, while stimulating certain imported species. Herbivorous invaders suppressed functionally similar alpine species while larger native omnivores reduced invasion by smaller taxa. Warming did not affect total invader biomass because imported species thrived under ambient and warmed alpine conditions. Our findings suggest that the adaptability of remote alpine lake communities to global warming is limited by species dispersal from lower valleys, or possibly nearby warmer alpine ponds.
Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69 kDa target antigen of neutrophil granules
Authors: CHEN MIN , ZHAO MING‐HUI , ZHANG YOU‐KANG , WANG HAI‐YAN 
Published: October 2005

SUMMARY:Objective:  Antineutrophil cytoplasmic autoantibodies (ANCA) were found in patients with systemic lupus erythematosus (SLE). Cathepsin G and lactoferrin were the major target antigens. However, some ANCA‐positive sera did not recognize either of them. The present study was to investigate the unknown target antigens of ANCA in patients with SLE and their clinical significance.Methods:  Sera were collected from 72 patients with SLE. ANCA were detected in both indirect immunofluorescence and antigen‐specific enzyme‐linked immunosorbent assay (ELISA). Mixed neutrophil granules were separated from normal human peripheral neutrophils; soluble acid extracts in non‐reducing conditions were used as antigens in western blot analysis to detect ANCA.Results:  SLE sera could blot a few bands. Interestingly, 14/72 (19.4%) sera recognized a novel 69 kDa protein band and 10/72 (13.9%) sera recognized the 55 kDa protein band, which might be bactericidal/permeability‐increasing protein (BPI). The 69 kDa target antigen was different from the known target ANCA antigens such as cathepsin G and lactoferrin. Further study revealed that the percentages of patients with photosensitivity and oral ulcer in the anti‐69 kDa autoantibodies‐positive group were significantly higher than those in the anti‐69 kDa autoantibodies‐negative group (57.1%vs 10.3%, P < 0.005 and 50.0%vs 12.1%, P < 0.05, respectively).Conclusions:  A 69 kDa protein in human neutrophil granules was identified as a novel target antigen of ANCA in patients with SLE. The anti‐69 kDa autoantibodies might be associated with photosensitivity and oral ulcer in patients with SLE.
Renal plasma flow, filtration fraction and microalbuminuria in hypertensive patients: Effects of chronic smoking
Authors: ANDRONICO GIUSEPPE , ROMÉ MARIA , LO CICERO ANTONINA , PARSI RENATO , SEDDIO GIOVANNA , FERRARO‐MORTELLARO ROSELLA , BUSCEMI SILVIO , CERASOLA GIOVANNI 
Published: October 2005

SUMMARY:Introduction:  Albumin excretion rate is usually increased in people who smoke, but the physiological basis of this phenomenon is not fully understood.Methods:  The effect of chronic smoking on renal haemodynamics was studied in a cohort of 66 men. Twenty‐seven were smokers and 36 were hypertensive. In all subjects, the albumin excretion rate was evaluated; in hypertensive patients, a renoscintigraphic evaluation of renal plasma flow and glomerular filtration were carried out and the filtration fraction was calculated.Results:  The hypertensive smoking population presented an increased urinary albumin excretion rate in comparison with hypertensive non‐smoking patients. No significant differences were found for the mean values of renal plasma flow, the glomerular filtration rate and the filtration fraction between hypertensive smokers and hypertensive non‐smoking patients.Conclusions:  In hypertensive patients, smoking does not modify typical renal haemodynamic changes of arterial hypertension; however, it significantly increases the albumin excretion rate.
Plasma and urinary adrenomedullin levels in children with acute pyelonephritis
Authors: KALMAN SÜLEYMAN , BUYAN NECLA , YÜREKLI MUHITTIN , ÖZKAYA OZAN , BAKKALOĞLU SEVCAN , SÖYLEMEZOĞLU OĞUZ 
Published: October 2005

SUMMARY:Aim:  Adrenomedullin (AM), a novel peptide recently isolated from pheochromocytoma, eliciting vasorelaxing activity, is the strongest among all known peptides. AM has been detected in the adrenal medulla, cardiac tissue, lung and kidney. Immunohistochemical studies have demonstrated the localization of AM in glomeruli, tubules and collecting cells of the kidney. Clinically, plasma and urinary AM levels are altered in patients with different renal disease. The present study aims to determine plasma and urinary AM levels in children with acute pyelonephritis (APN) and compare the results with a control group.Materials and Methods:  The study group was comprised of 19 patients with APN aged 11.6 ± 3.7 months (range, 6–18 months) and the control group consisted of 16 cases aged 11.5 ± 3.2 months (range, 7–16 months). Acute pyelonephritis was diagnosed by clinical, laboratory and imaging methods. Plasma and urinary AM levels were measured by high performance liquid chromotography (HPLC).Results:  The plasma AM levels were lower in APN patients (33.40 ± 2.27 pmol/mL) than in the control group (43.76 ± 4.27 pmol/mL) (P < 0.001), whereas the urinary AM levels were higher in APN patients (248.58 ± 140.63 pmol/mg urinary creatinine) than in the control group (49.42 ± 45.23 pmol/mg) (P < 0.001). Coefficients of correlation between urinary AM levels and C‐reactive protein and white blood cells were statistically significant (r = 0.472, P = 0.041; r = 0.555, P = 0.014, respectively).Conclusion:  Adrenomedullin, a smooth muscle relaxant peptide that is synthesized in urinary tract tissue might have a role in acute pyelonephritis. However, the importance of AM in the pathogenesis of acute pyelonephritis remains to be determined by further detailed studies.
‘Flexible’ or ‘lifestyle’ dialysis: Is this the way forward?
Authors: AGAR JOHN WM , MAHADEVAN KUMAR , KNIGHT RICHARD , ANTONIS MICHELLE L , SOMERVILLE CHRISTINE A 
Published: October 2005

SUMMARY:Background:  Despite the advent of two new dialysis options, nocturnal home haemodialysis and short daily haemodialysis, many units are yet to build them into the modalities on offer to end‐stage renal failure patients. The reasons behind this inertia are complex but primarily include anxieties about workload, budgetary implications and outcome data.Method:  The Geelong dialysis programme, where both nocturnal home haemodialysis and short daily haemodialysis are offered, is compared with Australian and New Zealand national profiles.Results:  Significant profile differences emerge when comparing sessions/week and h/week between the three groups. Most Australian (92.93%) and New Zealand (95.07%) haemodialysis patients dialyse for three sessions/week. This contrasts to Geelong where only 73.6% dialyse for three sessions/week. 18.8% of Geelong haemodialysis patients versus 1.8% (Australia) and 0.9% (New Zealand) dialyse for five or more sessions/week. Australia and New Zealand follow similar h/session patterns although more Australians (44.2%) dialyse for 4 h and fewer (24.2%) for 5 h than their New Zealand counterparts (39.6% and 29.8%, respectively), and few dialyse outside the 3.5–5 h window. In contrast, 6.7% of Geelong patients dialyse for 2–2.5 h/session versus Australia (0.9%) and New Zealand (0.2%). This represents the Geelong short daily dialysis programme. More Geelong patients (>15%) dialyse ≥8 h/week and represent the Geelong nocturnal home haemodialysis programme.Conclusion:  The flexible Geelong programme has been supported without exceeding the budget applied to a conventional dialysis programme with the same patient numbers.
Pharmacodynamic effects of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers
Authors: Kay Gary G. , Wesnes Keith A. 
Published: October 2005

OBJECTIVETo evaluate the pharmacodynamic effects of darifenacin (a muscarinic M3 selective receptor antagonist) and dicyclomine (an M1 selective receptor antagonist) in healthy male volunteers.SUBJECTS AND METHODSIn this double‐blind, four‐way crossover study, 27 healthy men (aged 19–44 years) were randomized to receive darifenacin 7.5 mg or 15 mg once daily, dicyclomine 20 mg four times daily or matching placebo. Each 7‐day treatment period was separated by a 7‐day washout. Multiple assessments of cognitive function, quantitative electroencephalogram (EEG) recordings, salivation, visual nearpoint, heart rate and heart rate variability were made on day 7 in each treatment period.RESULTSCompared with placebo, neither dose of darifenacin affected cognitive function, whereas dicyclomine impaired performance on five of the 12 variables 2 h after dosing; simple reaction time (P = 0.009), speed of numeric (P = 0.012) and spatial (P = 0.048) working memory, and speed (P = 0.04) and sensitivity (P = 0.03) of picture recognition. These cognitive changes were accompanied by slowing of the EEG for dicyclomine. Darifenacin showed no clinically relevant effect on EEG. Darifenacin 7.5 and 15 mg once daily did not differ from placebo in effects on visual nearpoint, heart rate or heart rate variability. By contrast, dicyclomine significantly increased the maximum visual nearpoint, decreased heart rate and increased heart rate variability, relative to placebo. Both agents decreased salivary flow rate vs placebo. Treatment‐related adverse events were comparable in all groups, the most common being dry mouth; none led to treatment discontinuation.CONCLUSIONSDarifenacin did not affect cognitive, cardiac or visual function in healthy volunteers, a profile that may reflect its relative M3 receptor selectivity and M1/M2 sparing properties.
Intra‐operative prostate examination: predictive value and effect on margin status
Authors: Rapp David E. , Orvieto Marcelo A. , Lucioni Alvaro , Gong Edward M. , Shalhav Arieh L. , Brendler Charles B. 
Published: October 2005

OBJECTIVETo evaluate the ability of intra‐operative prostate examination (IOPE) to predict extraprostatic extension (EPE) and its effect on margin status in the region of the neurovascular bundle (NVB) when combined with wide excision.PATIENTS AND METHODSWe retrospectively reviewed 403 patients with clinical stage T1c prostate adenocarcinoma undergoing radical retropubic prostatectomy (RRP). All patients had IOPE during RRP, and those with palpable abnormalities in the region of the NVB underwent wide excision. Pathological outcomes were analysed.RESULTSOf 403 patients, 49 (12%) had a palpable abnormality in the region of the NVB. After wide excision, 18 (37%) of these 49 patients were found to have EPE at the site of the palpable abnormality; with wide excision of the NVB, only one of these 18 patients (6%) had a corresponding positive surgical margin (PSM). In 354 patients with a normal IOPE and who underwent bilateral NVB preservation, 30 were found to have EPE in the region of the NVB. The PSM rate in this subset was 23% (seven of 30). The positive predictive value of IOPE for detecting EPE was 37%.CONCLUSIONIOPE detects abnormalities in 12% of patients with preoperative stage T1c prostate cancer. Although the predictive value of this test is limited, IOPE may decrease PSMs in a subset of patients with EPE in the region of the NVB. The present study reaffirms the value of IOPE for assessing the risk of extraprostatic disease, and for guiding surgical management.
What surgical resection margins are required to achieve oncological control in men with primary penile cancer?
Authors: Minhas Suks , Kayes Oliver , Hegarty Paul , Kumar Pardeep , Freeman Alex , Ralph David 
Published: October 2005

OBJECTIVETo evaluate the surgical excision margin required for local oncological control in primary penile cancers, as patients with penile cancer who undergo radical amputation suffer marked psychological, functional and cosmetic sequelae, and although organ‐sparing surgery has improved the quality of life of these men, the optimum surgical excision margin to achieve oncological control is unknown.PATIENTS AND METHODSIn all, 51 patients (mean age 61 years) diagnosed with squamous cell carcinoma of the penis between May 2000 and December 2004 were selected for treatment with conservative surgical techniques. All patients were staged before surgery using magnetic resonance imaging. Histopathological features of the tumours, including type, grade, stage and distance from the surgical excision margin, were evaluated. All patients were followed in the outpatient department according to European Association of Urology guidelines.RESULTSThe median (range) follow‐up of the men was 26 (2–55) months. Patients were treated by wide localized excision (nine), glans excision (26) and partial penectomy (16). The histopathological review included the analysis of 102 surgical margins (deep and skin) with 49 (48%) measured within 10 mm of the tumour edge and 92 (90%) within a <20‐mm resection margin. Three patients (6%) had tumour involvement at the surgical margin and had further surgery. During follow‐up two patients (4%) developed local tumour recurrence and were treated successfully with partial penectomy.CONCLUSIONA traditional 2‐cm excision margin is unnecessary for treating squamous cell carcinoma of the penis. Conservative techniques, involving excision margins of only a few millimetres, appear to offer excellent oncological control.
A magnetic resonance imaging‐based study of retropubic haematoma after sling procedures: preliminary findings
Authors: Giri Subhasis K. , Wallis Fintan , Drumm John , Saunders Jean A. , Flood Hugh D. 
Published: October 2005

OBJECTIVETo determine, using magnetic resonance imaging (MRI), the incidence of retropubic haematoma and any associated clinically significant effects after a xenograft (porcine dermis) sling (XS) or the tension‐free vaginal tape (TVT) procedure.PATIENTS AND METHODSBetween October 2003 and March 2004, 24 consecutive patients presenting with stress urinary incontinence (SUI) were enrolled in this prospective study; 12 each underwent an XS or TVT procedure. A vaginal balloon pack was used for only 3 h after XS and not after TVT. All patients had pelvic MRI 6–8 h after surgery. The primary outcome measure was the incidence and distribution of retropubic haematoma after each sling technique. Secondary outcome measures included the interval to the first three spontaneous voids, the bladder emptying efficiency of the first three voids, a visual analogue scale pain score at 24 h after surgery, and the short‐term (6‐month) cure rate for SUI.RESULTSOverall, six (25%) patients (four XS and two TVT) developed a retropubic haematoma. Most commonly, they spread along the right paravesico‐urethral space between the right half of the levator ani and the bladder neck. Patients with large haematomas took significantly longer to void (median 14.5 vs 6.0 h, P = 0.048). There was no difference in pain score in patients with or with no haematoma. None of the patients had clinically detectable haematomas in the suprapubic wound. All six patients with haematomas were cured or improved at the 6‐month follow‐up.CONCLUSIONSMRI is a useful noninvasive method for detecting retropubic haematomas soon after surgery. There was a surprisingly high incidence of retropubic haematomas, especially after the XS procedure. Retropubic haematomas may influence postoperative voiding efficiency.
Venous thromboembolism in radical prostatectomy: is heparinoid prophylaxis warranted?
Authors: Koya Madhusudan P. , Manoharan Murugesan , Kim Sandy S. , Soloway Mark S. 
Published: October 2005

OBJECTIVETo review the incidence of venous thromboembolism (VTE) after radical retropubic prostatectomy (RRP) and evaluate the need for heparinoid prophylaxis as opposed to mechanical compression devices after RRP.PATIENTS AND METHODSRRP is classified as a category 1 (high risk) procedure for VTE by the American College of Chest Physicians and several international guidelines recommend subcutaneous heparinoids as the preferred prophylaxis. However, this regimen may be associated with a greater risk of bleeding. We have not used heparinoid prophylaxis but place a mechanical compression device for prophylaxis of VTE, and report our clinical experience over a 12‐year period. Between 1992 and 2004, all RRPs carried out by one surgeon (M.S.S.) at our centre were retrospectively reviewed after obtaining institutional review board approval. The protocol for prophylaxis of VTE consisted of compression stockings and a sequential compression device from the time of entry into the operating room until complete ambulation (we encourage early ambulation). Patients were evaluated for VTE if they developed any clinical signs or symptoms. Patients were followed at 7 days, 6 weeks and 3 months after RRP in the first year and 6‐monthly thereafter. All relevant clinical data and complications were entered in a database.RESULTSIn all there were 1364 RRPs; the mean (sd) age of the patients was 61 (7) years and the mean follow‐up 44 (38) months. All patients had a mechanical compression device and ambulated on the first day after surgery. None received heparinoid prophylaxis. Three VTE events were identified (0.21%); two patients had a lower limb VTE and one an upper limb VTE. All were successfully treated with anticoagulation. No patient had a documented pulmonary embolus and none died from VTE. There was one death after RRP, from myocardial infarction.CONCLUSIONThe incidence of VTE after RRP is low, possibly related to the use of a mechanical compression device and early aggressive mobilization. Despite the recommendations by some, we feel that routine heparinoid prophylaxis is questionable.
Lidocaine suppositories for prostate biopsy
Authors: Fink Klaus G. , Gnad Andrea , Meissner Phillip , Götschl Robert , Schmeller Nikolaus T. 
Published: October 2005

OBJECTIVESTo evaluate, in a randomized prospective study, the efficiency of transrectal lidocaine suppositories to reduce pain during transrectal prostate biopsy, as suppositories allow longer for the agent to be effective.PATIENTS AND METHODSIn all, 100 patients were randomized to receive either a placebo suppository or 10 mL of 2% (200 mg) lidocaine gel rectally 10 min before biopsy, or a suppository containing 60 mg lidocaine 1 or 2 h before biopsy. Costs (in euros) per application were 0.82 for gel and 0.63 for suppositories. In all patients the same 10‐core biopsy technique was used. Pain was evaluated using a visual linear pain scale ranging from 0 to 100 points; the patient's side of the scale did not show the number of points.RESULTSThe mean pain scores in the placebo, lidocaine gel, and lidocaine suppositories applied 1 h and 2 h before biopsy were 36.2, 40.9, 29.2 and 21.2, respectively. Thus patients with no anaesthesia reported 25% more pain than those receiving lidocaine suppositories 1 h before and 71% more pain than those receiving lidocaine suppositories 2 h before biopsy (P = 0.002).CONCLUSIONSLidocaine suppositories at a lower dose and with longer to take effect can be used to reduce pain significantly more effectively than the commonly used gel. As suppositories are easy to use and cheap, they are recommended in daily routine prostate biopsy.