bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential settlement by nesting male and female Baya weaverbirds Ploceus philippinus: the role of monsoon winds
Authors: Quader Suhel
Published: June 2006

Theory predicts that females should track resources while making decisions about where to reproduce, and males should track females. However, when males create the resource that females require, female settlement follows that of males. In this situation, how do individuals make settling decisions and what are the fitness consequences of these decisions? Here, I test the hypothesis that environmental factors (wind direction and velocity) affect optimal nest placement and orientation, and thus male and female settlement, in Baya weaver Ploceus philippinus colonies. Nests experimentally placed in windward locations with entrance tubes oriented toward the wind were more likely to lose clutches of artificial eggs than were nests placed in other combinations of placement and orientation. Correspondingly, males built their nests strongly clustered on the leeward side of colony trees, with entrance tubes oriented away from the wind. However, females did not discriminate amongst natural nests on the basis of nest placement or orientation. This may be because the effect of wind on the success of natural nests was small and was overwhelmed by other causes of nest loss. I suggest that, in some situations, female preference may remain undetected because the options available to females are constrained by preceding settlement decisions by males. In these cases, it is necessary to manipulate male distribution outside the range of natural variation to gain a better understanding of selective pressures imposed by female preferences.
Omeprazole‐amoxycillin versus omeprazole‐amoxycillin‐clarithromycin in the eradication of Helicobacter pylori.
Authors: Delchier JC , Elamine I , Goldfain D , Chaussade S , Barthelemy P , Idstrom JP
Published: June 2006

AIM: To assess the effect of adding clarithromycin to the combination of omeprazole and amoxycillin for the eradication of H. pylori infection. PATIENTS AND METHODS: In an open, randomized, three‐centre study 120 patients (69 men, mean age 47 years, caucasians 74%) with symptoms of dyspepsia had normal gastroscopic examination and a positive urease test. They underwent a 13C‐urea breath test and received, for 14 days, either omeprazole 40 mg b.d. plus amoxycillin 750 mg b.d., or the same regimen plus clarithromycin 250 mg b.d. Compliance was assessed by returned tablet counts. H. pylori clearance at the end of treatment and eradication 4 weeks after finishing treatment were assessed by 13C‐urea breath test. RESULTS: Results are expressed according to 'all patients treated analysis', excluding patients who did not receive treatment and patients who had no final 13C‐urea breath test assessment. In the groups treated with omeprazole‐ amoxycillin or omeprazole‐amoxycillin‐clarithromycin good compliance (> or = 90%) was observed in 85% vs. 76% (N.S.) of patients but 25% vs. 34% (N.S.) experienced at least one adverse event. Adverse events were minor, and no patient reported a metallic taste. Four weeks after finishing treatment eradication rates were 26% (95% CI: 15‐37%) vs. 93% (95% CI: 86‐99%) (P < 0.001). CONCLUSION: These results show that dual therapy with omeprazole plus amoxycillin achieves an unacceptably low H. pylori eradication rate. Addition of clarithromycin at low dosage (250 mg b.d.) proved to be useful, achieving a high eradication rate without increasing side‐effects.
A seven‐day Helicobacter pylori treatment regimen using clarithromycin, omeprazole and tripotassium dicitrato bismuthate.
Authors: Weldon MJ , Broadbent A , Chambers S , Mistry R , Ranganath L , Gould SR
Published: June 2006

AIM: To evaluate clarithromycin 500 mg t.d.s., tripotassium dicitrato bismuthate 240 mg b.d. and omeprazole 20 mg b.d. for 7 days as a Helicobacter pylori treatment regimen. METHODS: The H. pylori status of dyspeptic patients undergoing endoscopy was assessed by histology, culture and rapid urease testing of biopsies and by 13C‐urea breath test. Fifty patients who were H. pylori‐positive were treated with the above treatment regimen for 7 days. Those patients with active duodenal ulcers present at endoscopy were given omeprazole 20 mg nocte for a further 21 days. Not less than 28 days after completing treatment, all tests were repeated to reassess H. pylori status. Bacterial sensitivity of H. pylori cultures was determined and patients recorded any side‐ effects. RESULTS: On an intention‐to‐treat basis, H. pylori infection was cured in 90% (95% CI: 78‐96%) of patients. Taste disturbance was experienced by 35% patients. Compliance was excellent, with 96% patients taking more than 95% of tablets. Metronidazole resistance was 41% but all cultures were sensitive to clarithromycin. CONCLUSIONS: This 7‐day treatment achieved a high level of cure of H. pylori infection with relatively minor side‐effects. It may have a role to play, particularly where there is a high level of metronidazole resistance.
Dose‐response of omeprazole combined with amoxycillin on duodenal ulcer healing and eradication of Helicobacter pylori.
Authors: Pommerien W , Schultze V , Braden B , Lembcke B , Wrangstadh M , Londong W
Published: June 2006

BACKGROUND: Combination therapy using omeprazole and amoxycillin can cure Helicobacter pylori infection, but data are controversial concerning the efficacy of this regimen. The present study investigated varying doses of omeprazole combined with a standard amoxycillin dose on duodenal ulcer healing and eradication of H. pylori, in order to find an optimal dose regimen. METHODS: H. pylori‐positive out‐patients (n = 231) with duodenal ulcers were treated randomly and double‐blind with either omeprazole 20, 40 or 80 mg b.d. plus amoxycillin 1 g b.d. for 14 days. Patients with an unhealed ulcer after this therapy took omeprazole 20 mg o.m. for another month. RESULTS: After 2 weeks, ulcer healing rates in the three treatment groups were not statistically different (85, 82 and 93%, respectively). Treatment with omeprazole 80 mg b.d. was significantly better in curing H. pylori infection (eradication rate 69%) than treatment with omeprazole 20 and 40 mg b.d. (47 and 53%). CONCLUSIONS: Combination of either omeprazole 20 or 40 mg b.d. plus amoxycillin 1 g b.d., is not sufficiently effective to be recommended as an anti‐H. pylori therapy. Omeprazole 80 mg b.d. combined with amoxycillin is more efficient and well tolerated, but better treatment options now exist to cure H. pylori infection.
Methotrexate for the treatment of refractory Crohn's disease.
Authors: Lemann M , Chamiot‐Prieur C , Mesnard B , Halphen M , Messing B , Rambaud JC , Gendre JP , Colombel JF , Modigliani R
Published: June 2006

BACKGROUND: Previous studies suggested that methotrexate has beneficial effects in patients with Crohn's disease. We report our experience with this agent in patients with chronic active Crohn's disease who previously failed to improve with conventional treatment, including azathioprine in most cases. METHODS: Between June 1988 and June 1992, 39 patients with refractory Crohn's disease were treated with methotrexate. In patients with active disease, clinical remission was defined by a Harvey‐Bradshaw index of less than 4. For patients also taking corticosteroids, the dates of remission and complete steroid withdrawal were recorded. For patients who achieved clinical remission, and those in clinical remission when methotrexate was started, the relapse rate on methotrexate therapy was noted. RESULTS: In the 37 patients with active disease at methotrexate initiation, the probability of remission was 72% at 3 months. The probability of remission and steroid withdrawal was 42% at 12 months. In patients on clinical remission, the probability of relapse on methotrexate was 58% at 12 months. Twenty‐two patients experienced side‐effects, but these only warranted methotrexate discontinuation in four cases. CONCLUSIONS: Methotrexate appears effective in most patients with refractory Crohn's disease and its short‐term toxicity is acceptable, but the long‐term benefit seems more limited.
Distribution of mesalazine enemas in active and quiescent ulcerative colitis.
Authors: Van Bodegraven AA , Boer RO , Lourens J , Tuynman HA , Sindram JW
Published: June 2006

BACKGROUND: The efficacy of mesalazine enemas depends on intraluminal concentration of the drug and is therefore limited by the enema distribution in the colon. Active ulcerative colitis changes colon motility and this leads to uncertainty about enema spread. AIM: To assess the influence of disease activity on enema distribution, we conducted a physician‐blinded, longitudinal study of the retrograde spread of three mesalazine enemas. METHODS: Thirty‐one patients with mild to moderate ulcerative colitis were subdivided into three groups, and treated with 2 g mesalazine in 30 mL (group I, n = 10), 4 g mesalazine in 60 mL (group II, n = 12) or 1 g mesalazine in 100 mL (group III, n = 9). All patients received oral mesalazine 500 mg t.d.s. Enemas were labelled by adding 10 MBq (99mTc)technetium‐sulphur colloid. Anterior scintigraphic images were taken at the start of the study and after 12 weeks of therapy; retrograde spread was assessed by calculating the percentage of the enema in each colonic segment. RESULTS: The activity score of ulcerative colitis diminished significantly after 12 weeks of treatment, but five patients dropped out of the study. At the start of treatment enema activity in group I was mainly concentrated in the sigmoid (99%); in group II activity was found in the rectum (9%), the sigmoid (61%) and the descending colon (15%); in group III activity was distributed between the sigmoid (66%) and descending colon (25%). The colonic distribution of mesalazine enemas was not influenced by disease activity. CONCLUSION: Volume, but not disease activity, is the important determinant of retrograde colonic spread of mesalazine enemas in ulcerative colitis.
Diagnostic interpretation of 24‐hour intragastric pH‐metry using a pattern recognition method.
Authors: Hunyady B , Juricskay I , Pakodi F , Horvath C , Mozsik G
Published: June 2006

BACKGROUND: Intragastric pH‐metry is a widely used method in the evaluation of gastric acidity, but the interpretation of these data is not standardized. METHODS: The pH‐metry data of 60 patients were sorted retrospectively into three groups according to the maximal acid output (MAO) values measured after stimulation by pentagastrin: hypoacid group (MAO < 5 mmol/h, n = 17), normacid group (MAO 10‐15 mmol/h, n = 18) and superacid group (MAO > 25 mmol/h, n = 25). Statistical effectiveness of several descriptive statistical values and predefined time‐intervals in differentiation between the study groups was analysed by the pattern recognition by independent multicategory analysis (PRIMA) method. RESULTS: The mean pH, the integrated pH and the time‐interval of pH > or = 3 values were the most effective parameters for discriminating between each pair of groups. Hypoacid‐normacid‐superacid: mean pH 6.1 +/‐ 0.2‐4.2 +/‐ 0.23‐1.5 +/‐ 0.07; integrated pH 8898 +/‐ 208‐5987 +/‐ 339‐2224 +/‐ 98 pH.min; and pH > or = 3 1440 +/‐ 0‐392 +/‐ 44‐80 +/‐ 11 min, respectively (+/‐ SEM). More than a 99.9% separation of the study groups was achieved using these three parameters concomitantly by the PRIMA method, even when comparing 6‐h daytime periods of measurements. A relative disagreement was found when reclassifying the hypoacid and normacid patients on the basis of pH records, compared with the primary classification based on the MAO data (11 out of 35 patients, 31%). CONCLUSIONS: The analysis of the mean pH data (instead of medians or [H+]), the AUC‐pH and the pH > or = 3 duration, either separately or most beneficially concomitantly, are recommended for the diagnostic interpretation of intragastric pH‐metry data. The duration of the diagnostic intragastric pH‐metry measurements might be decreased to 6 h by using the PRIMA method.
Twenty‐four‐hour intragastric pH profiles and pharmacokinetics following single and repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole.
Authors: Hartmann M , Theiss U , Huber R , Luhmann R , Bliesath H , Wurst W , Lucker PW
Published: June 2006

BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzyme system in man. Its effect on intragastric pH following single and repeated oral intake was investigated in comparison to omeprazole by continuous intragastric pH‐metry at doses recommended for treatment of peptic ulcer disease. METHODS: Sixteen healthy male subjects underwent two dosing periods. From day 1 to day 7, they were given once daily by mouth 40 mg pantoprazole in one period and 20 mg omeprazole in the other period, according to a double‐blind randomized crossover design. Twenty‐four‐hour intragastric pH was recorded and frequent blood samples for pharmacokinetic analysis were taken on day 1 and day 7. A placebo pH profile was obtained prior to each treatment period. RESULTS: Pantoprazole was significantly more effective than omeprazole with regard to increase in 24‐h and daytime pH, following both single (median 24‐h pH: 1.45 vs. 1.3, P < 0.05; median daytime pH: 1.6 vs. 1.3, P < 0.01) and repeated (median 24‐h pH: 3.15 vs. 2.05, P < 0.01; median daytime pH: 3.8 vs. 2.65, P < 0.05) oral intake. As compared to the first dose, repeated administration of both drugs markedly increased the effect on intragastric pH. With pantoprazole, steady‐ state serum concentrations were obtained after the first dose, but not with omeprazole. Both drugs were well tolerated without relevant changes in vital signs of clinical laboratory parameters. CONCLUSION: Pantoprazole 40 mg is significantly more effective than omeprazole 20 mg in raising intragastric pH.
Ranitidine 300 mg twice daily and 150 mg four‐times daily are effective in healing erosive oesophagitis.
Authors: Silver MT , Murdock RH , Morrill BB , Sue SO
Published: June 2006

BACKGROUND: Ranitidine 150 mg q.d.s. is the currently recommended dosage in the United States for the treatment of erosive oesophagitis. To determine whether a higher dose of ranitidine administered less frequently would also be effective in healing erosive oesophagitis, we compared ranitidine 300 mg b.d. with ranitidine 150 mg q.d.s. in the treatment of erosive oesophagitis. METHODS: This multicentre, double‐ blind, randomized, placebo‐controlled study conducted in the United States compared two dosages of ranitidine in 772 patients with endoscopically diagnosed erosive oesophagitis. Patients were treated with ranitidine 300 mg b.d., ranitidine 150 mg q.d.s. or placebo for up to 12 weeks. Endoscopies were repeated after 4, 8 and 12 weeks of treatment. RESULTS: Ranitidine 300 mg b.d. was significantly more effective than placebo in healing erosive oesophagitis at weeks 8 and 12 (51 vs. 36% and 66 vs. 52%, respectively; P < or = 0.004). Significantly higher healing rates were also achieved with ranitidine 150 mg q.d.s. compared with placebo at 4, 8 and 12 weeks (37 vs. 21%, 62 vs. 36% and 77 vs. 52%, respectively; P < 0.001). Healing rates were significantly higher with ranitidine 150 mg q.d.s. than with ranitidine 300 mg b.d. at all scheduled endoscopies (P < or = 0.041). CONCLUSIONS: Ranitidine 300 mg b.d. is effective in healing erosive oesophagitis and may be appropriate as an alternative dosage regimen to ranitidine 150 mg q.d.s. in some patients with erosive oesophagitis.
The management of refractory gastric ulcer using H2‐receptor antagonists.
Authors: Raju GS , Bardhan KD , Royston C , Beresford J
Published: June 2006

BACKGROUND: There is little information on the natural history of refractory gastric ulcer, defined as non‐healing on cimetidine > or = 1 g daily given for at least 3 months. SETTING: A district general hospital serving an industrial population. METHODS: Patients with refractory gastric ulcer had their treatment extended and/or the dose increased, and upon healing the majority were put on maintenance treatment with cimetidine 400 mg nightly or 1 g daily and their progress was followed. RESULTS: Of 536 patients with gastric ulcer, 74 (14%) were refractory. Fifty of the 74 (68%) refractory gastric ulcer patients were refractory on their very first course of cimetidine. They had no distinguishing demographic features. Healing occurred in 62 patients (84%) after a mean treatment period of 11.1 months; 28 patients required cimetidine > or = 2 g daily. Eleven of 23 (48%) patients relapsed on maintenance with cimetidine 400 mg compared with seven of 24 (29%) on 1 g daily. A total of 22 out of 62 (35%) relapsed; nine had a second refractory recurrence but none thereafter. Eleven patients were operated upon, seven for failed medical treatment. Only two patients eventually proved to have malignant disease. CONCLUSIONS: Refractory gastric ulcer is uncommon, transient and rarely malignant. Most patients can be satisfactorily managed medically.
Efficacy and tolerability of pantoprazole 40 mg versus 80 mg in patients with reflux oesophagitis.
Authors: Van Rensburg CJ , Honiball PJ , Grundling HD , Van Zyl JH , Spies SK , Eloff FP , Simjee AE , Segal I , Botha JF , Cariem AK , Marks IN , Theron I , Bethke TD
Published: June 2006

BACKGROUND: Pantoprazole is a substituted benzimidazole which is a potent inhibitor of gastric acid secretion by its action upon H+, K+‐ ATPase. METHODS: Pantoprazole 40 mg and 80 mg were compared in a randomized double‐blind study in 192 out‐patients with stage II or III (Savary‐Miller classification) reflux oesophagitis. Patients received either pantoprazole 40 mg (n = 97) or pantoprazole 80 mg (n = 95), once daily before breakfast for 4 weeks. Treatment was extended for a further 4 weeks if the oesophagitis had not healed. RESULTS: After 4 weeks complete healing of the reflux oesophagitis was seen in 78% of protocol‐correct patients given pantoprazole 40 mg daily (n = 86), and in 72% in the 80 mg (n = 87) group. The cumulative healing rates after 8 weeks were 95 and 94%, respectively (P > 0.05, Cochran‐Mantel‐ Haenszel), and time until healing of oesophagitis comparable in both groups. Differences between doses were also not significant in an intention‐to‐treat analysis. Both dosing schedules were well tolerated and the patients experienced remarkable symptom relief. No adverse event or changes in laboratory values of clinical significance could definitely be ascribed to the trial medication. CONCLUSION: The 40 mg pantoprazole dosage is comparable to 80 mg in reflux oesophagitis, both in efficacy and tolerability.
Effect of dexloxiglumide and spiroglumide, two new CCK‐receptor antagonists, on gastric emptying and secretion in the rat: evaluation of their receptor selectivity in vivo.
Authors: Scarpignato C , Kisfalvi I , D'Amato M , Varga G
Published: June 2006

BACKGROUND: Clear definition of the role of CCK in the physiology of gastric motor activity has been long hampered by the lack of specific and potent nonpeptide antagonists of CCK‐receptors. The availability of such compounds has stimulated a broad array of investigations into the physiological actions of this hormone and to examine its putative role in certain diseases. AIMS: The effect of two recently developed CCK‐ receptor antagonists, namely dexloxiglumide and spiroglumide, on gastric emptying and secretion as well as their selectivity towards CCKA‐ and CCKB‐receptors in vivo was studied in the rat. METHODS: Gastric emptying was quantified by using a liquid noncaloric meal labelled with phenol red. Acid secretion was measured by titration in conscious rats. RESULTS: The putative CCKA‐antagonist, dexloxiglumide, administered by intravenous route, was able to inhibit CCK‐8‐induced delay of gastric emptying in a dose‐dependent fashion, with an ID50 (95% CL) of 1.14 (0.84‐1.53) mg/kg. Similarly, the putative CCKB‐ gastrin‐antagonist, spiroglumide, proved to be capable of inhibiting dose‐dependently pentagastrin‐induced acid hypersecretion, its ID50 being 20.1 (8.67‐46.4) mg/kg. On the other hand, dexloxiglumide, at doses able to almost completely block CCKA mediated effects (i.e. delay of gastric emptying), was ineffective against pentagastrin‐induced acid hypersecretion. Similarly, spiroglumide, at doses which inhibit by 55% CCKB‐gastrin mediated effects (i.e. acid secretion) was inactive when tested against CCK‐8 induced delay of gastric emptying. CONCLUSIONS: These results demonstrate in vivo that dexloxiglumide is a selective antagonist for CCKA‐receptors whereas spiroglumide is selective for CCKB‐gastrin‐receptors. These compounds are therefore useful tools for discriminating between different subclasses of CCK‐receptors in vivo and might have a therapeutic potential in motility or acid‐related disorders.
Sucralfate gel versus placebo in patients with non‐erosive gastro‐ oesophageal reflux disease.
Authors: Simon B , Ravelli GP , Goffin H
Published: June 2006

BACKGROUND: Gastro‐oesophageal reflux disease, a term used to refer to chest symptoms that result from reflux of gastric acid into the oesophagus, occur at least daily in 7% and every 3 days in 33% of the population. METHODS: One hundred and forty‐one patients with moderate to severe gastro‐oesophageal reflux symptoms occurring at least three times per week (but no oesophageal erosions or ulcers at endoscopy) were treated in this randomized, double‐blind, placebo‐controlled study at six trial centres. Treatment was given for 6 weeks and consisted of daily doses of either 1 g sucralfate gel b.d. or placebo. The evaluation of efficacy was based on data of 139 patients. RESULTS: The responder rate at Day 42 was statistically significantly higher for the patients treated with sucralfate (71%) than for the placebo patients (29%) (P < 0.0001, Fisher's exact test). The overall response of the non‐ulcer dyspepsia and gastro‐oesophageal reflux disease symptoms was better for sucralfate gel than for placebo with 45% of patients treated with sucralfate gel being considered as having a 'good' or 'excellent' overall response compared with 22% of the patients who received placebo (P < 0.0001, Wilcoxon test). Only a few adverse experiences were reported by 10% of sucralfate patients and 7% of placebo patients. CONCLUSION: In this trial, we demonstrated a statistically significant superiority of sucralfate gel at a dosage of 1 g b.d. compared to placebo in the treatment of patients with gastro‐oesophageal reflux disease. Sucralfate gel was well tolerated.
Effect of dietary antioxidants and risk of oral, pharyngeal and laryngeal squamous cell carcinoma according to smoking and drinking habits
Authors: Suzuki Takeshi , Wakai Kenji , Matsuo Keitaro , Hirose Kaoru , Ito Hidemi , Kuriki Kiyonori , Sato Shigeki , Ueda Ryuzo , Hasegawa Yasuhisa , Tajima Kazuo
Published: June 2006

Several intervention trials and prospective studies have reported that β‐carotene supplementation is not associated with a decreased risk of several cancers among smokers and drinkers, and that it may even have adverse effects in these groups. The relationship between dietary antioxidant intake and the risk of head and neck squamous cell carcinoma (HNSCC) has been examined intensively, but little is known about the effects of antioxidants on HNSCC with respect to smoking and drinking habits. Here, we conducted a case‐control study of 385 histologically confirmed cases of HNSCC (193 oral, 132 pharyngeal and 60 laryngeal), excluding nasal and paranasal cancer, and 1925 age‐matched and sex‐matched cancer‐free outpatient controls using data from the Hospital‐based Epidemiologic Research Program at Aichi Cancer Center, Japan. The intake of nutrients and food groups was assessed with a food frequency questionnaire, and multivariate‐adjusted odds ratios for cancer were estimated for smoking and drinking habits using logistic models. The results showed an overall inverse association between the intake of dietary antioxidants, including carotene, and vitamins C and E, and risk of HNSCC. The protective effect of these antioxidants was seen in both men and women. High consumption of antioxidants was associated with a decreased risk of HNSCC among smokers, drinkers and those with both smoking and drinking habits. These findings suggest that dietary antioxidant intake prevents HNSCC in smokers and drinkers. (Cancer Sci 2006; 97: 760–767)
Two‐step transcriptional amplification–lipid‐based nanoparticles using PSMA or midkine promoter for suicide gene therapy in prostate cancer
Authors: Hattori Yoshiyuki , Maitani Yoshie
Published: June 2006

A two‐step transcriptional amplification system (TSTA) was used to enhance the efficacy of suicide gene therapy for treatment of prostate cancer. We designed a TSTA system and constructed two types of plasmid: one containing GAL4–VP16 fusion protein under the control of a tumor‐specific promoter, the other containing luciferase or herpes simplex virus thymidine kinase (HSV‐tk) under the control of a synthetic promoter. The TSTA systems using nanoparticles based on lipids were evaluated by measuring the amount of induced luciferase activity as a function of prostate‐specific membrane antigen (PSMA) and midkine (Mk) promoters, specific for LNCaP and PC‐3 prostate cancer cells, respectively. In LNCaP cells that were PSMA‐positive, the TSTA system featuring the PSMA enhancer and promoter exhibited activity that was 640‐fold greater than a system consisting of one‐step transcription with the PSMA promoter. In contrast, this difference in activity did not occur in PSMA‐negative PC‐3 cells. In Mk‐positive PC‐3 cells, the TSTA system with the Mk promoter exhibited a five‐fold increase in activity over one‐step transcription, but such activity was not induced in Mk‐negative LNCaP cells. When using HSV‐tk for suicide gene therapy, TSTA systems featuring the PSMA or Mk promoter inhibited in vitro cell growth in the presence of ganciclovir. Furthermore, the TSTA system featuring the Mk promoter suppressed in vivo growth of PC‐3 tumor xenografts to a greater extent than one‐step transcription. These findings show that TSTA systems can enhance PSMA and Mk promoter activities and selectively inhibit PC‐3 cell growth in tumors. This suggests that TSTA systems featuring tumor‐specific promoters are suitable for cancer treatment by gene therapy. (Cancer Sci 2006; 97: 787–798)
The impact of new insights and revised practice guidelines on prescribing drugs in the treatment of Type 2 diabetes mellitus
Authors: Lub René , Denig Petra , Van Den Berg Paul B. , Hoogenberg Klaas , De Jong‐van den Berg Lolkje T. W.
Published: June 2006

Aims

The aim of this study was to investigate the impact of new insights and revised guidelines on initial and follow‐up treatment with antihyperglycaemic drugs over the period 1998–2003.

Methods

The InterAction Database (IADB), which contains pharmacy dispensing data from 53 community pharmacies in the Northern and Eastern part of the Netherlands, was used in this study. Prevalence and incidence rates of oral antihyperglycaemic drug use were calculated for each year. Follow‐up treatment was compared for two cohorts of initial users of oral antihyperglycaemic drugs, starting treatment either 1 year before or 1 year after guideline revision.

Results

The prevalence and incidence rate of oral antihyperglycaemic drug use increased over the study period from 1.8% to 2.4% (P < 0.001) and 0.3% to 0.4% (P = 0.04). The proportion of metformin as initial treatment increased rapidly in the observation period from 14% to 50% (P < 0.001). Initial users of metformin in 2000 received additional treatment with a sulphonylurea in the follow‐up period less often compared with those who started metformin in 1998 (46%vs. 60%, P < 0.004). In contrast, initial users of sulphonylurea in 2000 received additional treatment with metformin more often compared with those who started a sulphonylurea in 1998 (42%vs. 36%, P < 0.008). The new drugs, thiazolidinediones and meglitinides, were seldom used as initial treatment

Conclusions

New insights and the revision of the practice guideline were followed by a significant increase in both initial and follow‐up treatment with metformin among patients with Type 2 diabetes mellitus.
Population pharmacokinetics of imatinib and the role of α1‐acid glycoprotein
Authors: Widmer N. , Decosterd L. A. , Csajka C. , Leyvraz S. , Duchosal M. A. , Rosselet A. , Rochat B. , Eap C. B. , Henry H. , Biollaz J. , Buclin T.
Published: June 2006

Aims

The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma α1‐acid glycoprotein concentrations.

Methods

A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients.

Results

A one‐compartment model with first‐order absorption appropriately described the data, giving a mean (± SEM) oral clearance of 14.3 l h−1 (± 1.0) and a volume of distribution of 347 l (± 62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma α1‐acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells.

Conclusion

Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating α1‐acid glycoprotein concentrations or free imatinib concentrations.
New targets and challenges in the molecular therapeutics of cancer
Authors: Eastman Alan , Perez Raymond P.
Published: June 2006

The past 20 years have seen an explosion of information on the molecular changes that lead to cancer. The pathways that have been uncovered include many targets for the development of novel therapeutics. Several such drugs have been approved for clinical use and many additional drugs and targets are now being evaluated in preclinical studies. These new drugs may exhibit impressive therapeutic activity, but this is often restricted to a subpopulation of cancers with a particular molecular change. Moreover, toxicity or even antagonism may result from off‐target effects of the drugs. Accordingly, it will be critical to stratify patients for treatment based on the propensity of their tumours to respond. In addition, defining the appropriate dose of targeted agents to administer is challenging; early clinical trial designs must include assays to define the effective biological dose, in addition to more traditional end‐points such as the maximum tolerable dose. These and many other challenges exist in the preclinical and clinical development of these drugs.
Immunoglobulins and complement factor C4 in adult rhinosinusitis
Authors: Seppänen M , Suvilehto J , Lokki M-L , Notkola I-L , Järvinen A , Jarva H , Seppälä I , Tahkokallio O , Malmberg H , Meri S , Valtonen V
Published: June 2006

We assessed whether complement and its factor C4 or abnormal immunoglobulin levels are associated with chronic or recurrent rhinosinusitis. We used multiple patient and control groups to obtain clinically meaningful data. Adult chronic or recurrent rhinosinusitis and acute purulent rhinosinusitis patients were compared with unselected adults and controls without previous rhinosinusitis. Associated clinical factors were reviewed. Levels of immunoglobulins, plasma C3, C4 and classical pathway haemolytic activity were analysed. C4 immunophenotyping was used to detect C4A and C4B deficiencies as null alleles. Complement was up-regulated in rhinosinusitis. C4A nulls and low IgA, IgG, IgG1, IgG2, IgG3 and IgG4 levels were all more common in chronic or recurrent rhinosinusitis patients than in unselected and healthy controls. We searched for relevant differences between the patient groups. According to stepwise logistic regression analysis, nasal polyposis [odds ratio (OR) 10·64, 95% confidence interval (CI) 2·5–45·7, P = 0·001], bronchial asthma (OR 8.87, 95% CI 2·3–34·9, P = 0·002), C4A null alleles (OR 5·84, 95% CI 1·4–24·9, P = 0·017) and low levels of IgG4 together with either IgG1 or IgG2 (OR 15·25, 95% CI 1·4–166·8, P = 0·026) were more common in chronic or recurrent rhinosinusitis than in acute rhinosinusitis patients. Isolated low IgG subclasses had limited value in patient assessment. C4A null alleles are associated with chronic or recurrent rhinosinusitis, potentially through their effect on immune defence and inflammation control. Multiple clinical and immunological parameters may need to be evaluated when searching for prognostic variables.
Changes in leucocyte and lymphocyte subsets during tuberculosis treatment; prominence of CD3dimCD56+ natural killer T cells in fast treatment responders
Authors: Veenstra H , Baumann R , Carroll N M , Lukey P T , Kidd M , Beyers N , Bolliger C T , Van Helden P D , Walzl G
Published: June 2006

The immune responses against pulmonary tuberculosis are still poorly defined. This study describes changes in leucocyte and lymphocyte subsets during treatment to find reliable immunological markers for the disease and treatment response. Flow cytometric peripheral blood immune phenotyping, routine haematology and sputum microbiology were performed on 21 HIV-negative adult tuberculosis (TB) patients with positive sputum cultures during therapy in comparison with 14 healthy purified protein derivative (PPD)-positive volunteers. Patients at diagnosis showed high absolute neutrophil and monocyte counts which fell during treatment but low lymphocyte subset counts which increased [except natural killer (NK) and NK T cells]. High counts of a population of CD3dim/CD56+ NK T cells at diagnosis correlated significantly with negative sputum culture after 8 weeks of treatment. A multivariate classification technique showed improved correlation when NK cells were taken into account. In conclusion, peripheral blood white cell counts change significantly during treatment and counts at diagnosis, especially CD3dim/CD56+ NK T cells, hold promise in predictive models of TB treatment response.
Treatment of monocytes with interleukin (IL)-12 plus IL-18 stimulates survival, differentiation and the production of CXC chemokine ligands (CXCL)8, CXCL9 and CXCL10
Authors: Coma G , Peña R , Blanco J , Rosell A , Borras F E , Esté J A , Clotet B , Ruiz L , Parkhouse R M E , Bofill M
Published: June 2006

During inflammation, interleukin (IL)-12 and IL-18 are produced by macrophages and other cell types such as neutrophils (IL-12), keratinocytes and damaged endothelial cells (IL-18). To explore the role of IL-12 and IL-18 in inflammatory innate immune responses we investigated their impact on human peripheral blood monocytes and mature bronchoalveolar lavage (BAL) macrophages. IL-12 and IL-18 together, but not alone, prevented spontaneous apoptosis of cultured monocytes, promoted monocyte clustering and subsequent differentiation into macrophages. These morphological changes were accompanied by increased secretion of CXC chemokine ligands (CXCL)9, CXCL10 (up to 100-fold, P < 0·001) and CXCL8 (up to 10-fold, P < 0·001) but not CCL3, CCL4 or CCL5. Mature macrophages (from BALs) expressed high basal levels of CXCL8, that were no modified upon stimulation with IL-12 and IL-18. In contrast, the basal production of CXCL9 and CXCL10 by BALs was increased by 10-fold (P < 0·001) in the presence of either IL-12 or IL-18 alone and by 50-fold in the presence of both cytokines. In conclusion, our results indicate a relevant role for IL-12 and IL-18 in the activation and resolution of inflammatory immune responses, by increasing the survival of monocytes and by inducing the production of chemokines. In particular, those that may regulate angiogenesis and promote the recruitment of monocytes, activated T cells (CXCL9 and CXCL10) and granulocytes (CXCL8).
Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes
Authors: Mäkelä M , Öling V , Marttila J , Waris M , Knip M , Simell O , Ilonen J
Published: June 2006

Rotavirus infections have been implicated as a possible trigger of type 1 diabetes. We elucidated this connection by comparing peripheral blood T cell responses to rotavirus between children with newly diagnosed type 1 diabetes (n = 43), healthy children with multiple diabetes-associated autoantibodies (n = 36) and control children carrying human leukocyte antigen (HLA)-conferred susceptibility to type 1 diabetes but without autoantibodies (n = 104). Lymphocyte proliferation assays based on stimulation with an antigen were performed using freshly isolated peripheral blood mononuclear cells (PBMC) and IgG and IgA class rotavirus antibodies were measured using plasma samples collected from the children. The expression of interferon (IFN)-γ, interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-β in PBMC was studied with real-time polymerase chain reaction (PCR) in a subgroup of 38 children. No differences were observed in the strength or frequency of positive T cell responses to rotavirus between children with overt diabetes, children with multiple autoantibodies and control children. Children with diabetes-associated autoantibodies had, instead, stronger T cell responses to purified coxsackie B4 virus than control children. Rotavirus-stimulated lymphocytes from autoantibody-positive children produced more IL-4 and phytohaemagglutinin (PHA)-stimulated lymphocytes more IL-4 and IFN-γ than lymphocytes from control children. PHA-stimulated lymphocytes from children with diabetes also produced more IL-4 and purified protein derivative (PPD)-stimulated lymphocytes less TGF-β than lymphocytes from autoantibody-negative control children. In conclusion, our lymphocyte proliferation studies did not provide evidence supporting an association between rotavirus infections and the development of type 1 diabetes or diabetes-associated autoantibodies in young children.
Pneumococcal surface protein A (PspA) is effective at eliciting T cell-mediated responses during invasive pneumococcal disease in adults
Authors: Baril L , Dietemann J , Essevaz-Roulet M , Béniguel L , Coan P , Briles D E , Guy B , Cozon G
Published: June 2006

Humoral immune response is essential for protection against invasive pneumococcal disease and this property is the basis of the polysaccharide-based anti-pneumococcal vaccines. Pneumococcal surface protein A (PspA), a cell-wall-associated surface protein, is a promising component for the next generation of pneumococcal vaccines. This PspA antigen has been shown to stimulate an antibody-based immunity. In the present study, we evaluated the capacity of PspA to stimulate CD4+ T cells which are needed for the correct development of a B cell based immune response in humans. Cellular immunity to PspA was evaluated by whole-blood culture with different pneumococcal antigens, followed by flow cytometric detection of activated CD4+CD25+ T cells. T cell-mediated immune responses to recombinant PspA proteins were assessed in acute-phase and convalescent blood from adults with invasive pneumococcal disease and in blood from healthy subjects. All cases had detectable antibodies against PspA on admission. We found that invasive pneumococcal disease induced transient T cell depletion but adaptive immune responses strengthened markedly during convalescence. The increased production of both interleukin (IL)-10 and interferon (IFN)-γ during convalescence suggests that these cytokines may be involved in modulating antibody-based immunity to pneumococcal disease. We demonstrated that PspA is efficient at eliciting T cell immune responses and antibodies to PspA. This study broadens the applicability of recombinant PspA as potent pneumococcal antigen for vaccination against S. pneumoniae.
Anti-oxidant enzyme activities and expression and oxidative damage in patients with non-immediate reactions to drugs
Authors: Cornejo-Garcia J A , Mayorga C , Torres M J , Fernandez T D , R-Pena R , Bravo I , Mates J M , Blanca M
Published: June 2006

Adverse drug reactions with an immunological basis (ADRIB) may involve activation of other concomitant, non-specific mechanisms, amplifying the specific response and contributing to the severity and duration. One concomitant mechanism could be the generation of reactive oxygen species (ROS) and/or their detoxification by anti-oxidants, including anti-oxidant enzymes. We analysed the activity of the anti-oxidant enzymes Cu/Zn-superoxide dismutase (SOD), catalase (CAT) and cellular glutathione peroxidase (GPX), as well as certain markers of oxidative damage (thiobarbituric acid reactive substances (TBARS) and carbonyl content) in peripheral blood mononuclear cells from patients with non-immediate ADRIB using spectrophotometric methods and the anti-oxidant enzymes expression by quantitative real-time reverse transcription–polymerase chain reaction. SOD activity and expression were increased in all types of non-immediate reactions (urticaria, maculopapular exanthema and toxic epidermal necrolysis). Regarding oxidative damage, TBARS were increased in urticaria and maculopapular exanthema, and carbonyl groups in all types of reactions. Our observations indicate that oxidative damage occurs in non-immediate reactions. Carbonyl stress and the inadequacy of the anti-oxidant defences are probable causes.
Metabolic effects of caffeine ingestion and physical work in 75‐year old citizens. A randomized, double‐blind, placebo‐controlled, cross‐over study
Authors: Norager C. B. , Jensen M. B. , Weimann A. , Madsen M. R.
Published: June 2006

Objective  Whereas caffeine has been demonstrated to impact substantially on the metabolic response to exercise in healthy young subjects, this issue remains to be addressed in healthy elderly subjects.

Design and participants  The metabolic response to caffeine ingestion (6 mg/kg) and exercise in healthy elderly citizens at 70 years was examined in a randomized, double‐blind, placebo‐controlled, cross‐over study. We included 30 subjects attending for driver license renewal at their general practitioner. Participants abstained from caffeinated drinks and food for 48 h and were randomized to receive placebo‐caffeine or caffeine‐placebo with 1 week between sessions.

Measurements  A cycling endurance test at 65% of the expected maximal heart rate was performed 1 h after intervention. Blood samples were taken before intervention, before cycling, after 5 min of cycling, and at exhaustion. Analysis was by intention‐to‐treat and P < 0·05 was regarded as significant.

Results  Caffeine significantly increased the concentration of plasma epinephrine (by 42%, 39%, and 49%), serum‐free fatty acids (by 53%, 44%, and 50%), and plasma lactate (by 46%, 36%, and 48%), and insulin resistance (homeostasis model assessment‐IR) (by 21%, 26%, and 23%) during rest, after 5 min of cycling, and at exhaustion. At exhaustion, the concentration plasma norepinephrine was elevated by 29%. A decrease was seen with caffeine treatment in blood potassium after 5 min of cycling and at exhaustion (by 3% and 2%, respectively).

Conclusions  Caffeine treatment increased epinephrine, fatty acids, lactate and norepinephrine at different times during test session and led to insulin‐resistance.

Hence, caffeine ingestion elicits a similar metabolic response in elderly participants at 70 years old to that seen in younger subjects.
Use of factor VIII replacement during open heart surgery in a patient with haemophilia A
Authors: STINE K. C. , BECTON D. L.
Published: June 2006

Summary.  We present a patient with haemophilia undergoing cardiac surgery treated with continuous infusion factor VIII.
Pregnancy in women with congenital factor VII deficiency
Authors: KULKARNI A. A. , LEE C. A. , KADIR R. A.
Published: June 2006

Summary.  The aim was to review the pregnancy and obstetric outcome in women with factor VII (FVII) deficiency. The study group contained women with FVII deficiency, registered with Haemophilia centre and Haemostasis Unit at the Royal Free Hospital, London. The women were interviewed and case notes were reviewed. The main outcome measures were changes in FVII levels in pregnancy, maternal and perinatal outcome. The FVII levels ranged from 7–36 IU dL−1 in the 13 women included in the study. There were a total of 14 pregnancies in seven women. Ten pregnancies in four women were prior to the diagnosis of FVII deficiency. Following the diagnosis of FVII deficiency, there were four pregnancies in three women. There was an increase in the FVII level during pregnancy in these women from a mean baseline level of 33 IU dL−1 to a mean of 73 IU dL−1. These women received recombinant FVIIa replacement during labour and delivery. There were two early pregnancy losses, both associated with excessive haemorrhage. There was only one postpartum haemorrhage in the study. There is a significant increase in FVII levels in pregnancy in women with heterozygous FVII deficiency. The risk of bleeding in early pregnancy might be higher than that at term, due to inadequate rise in the FVII level in early pregnancy.
Non‐invasive biomarkers of liver fibrosis in haemophilia patients with hepatitis C: can you avoid liver biopsy?
Authors: MAOR Y. , BASHARI D. , KENET G. , LUBETSKY A. , LUBOSHITZ J. , SCHAPIRO J. M. , PÉNARANDA G. , BAR‐MEIR S. , MARTINOWITZ U. , HALFON P.
Published: June 2006

Summary.  Introduction:  Liver biopsy remains the gold standard for the evaluation of fibrosis despite its risks and limitations, especially in haemophilia patients. Recently, non‐invasive biomarkers have been used to assess histological features. The most thoroughly evaluated biomarker is the FibroTest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs. F0F1).

Aim:  To estimate liver fibrosis in haemophilia patients infected with hepatitis C (HCV) using non‐invasive biomarkers without liver biopsy.

Methods:  One hundred and thirty‐two haemophilia patients (124 male, mean age 38 ± 14 years) with anti‐HCV antibodies were evaluated. These patients were stratified into several groups: patients with features of advanced liver disease – seven, persistently HCV RNA‐negative – 21, persistently normal liver function tests (LFTs)– 24, HCV/HIV co‐infected – 27. The following biomarkers of fibrosis were used: FT, AST‐to‐platelet ratio index (APRI), Forns index, age‐platelet index and hyaluronic acid. The obtained scores were correlated with the clinical features of the patients.

Results:  Estimated by the FT, the distribution of the stage of fibrosis in the 132 patients was F0F1 = 65% (86/132), F2 = 5% (7/132), F3 = 13% (17/132) and F4 = 17% (22/132). Using FT, all patients with clinical suspicion of advanced liver disease were classified as F3F4, whereas patients with persistently HCV RNA‐negative were all classified as F0F1. Twenty‐one per cent (5/24) of the patients with persistently normal LFTs had fibrosis stage F3F4. The proportion of F3F4 among HCV/HIV co‐infected patients was significantly higher than among HCV mono‐infected (52% vs. 33%; P = 0.05). Concordance of three or more biomarkers was present in 43% (57/132) of the patients. Liver biopsy could be avoided in 70% (92/132) using a practical assumption that if FT is in concordance with APRI and/or Forns, then we may confidently rely on the biomarker. Concordance rate for patients with presumably advanced or minimal liver disease was excellent (100% and 95% respectively).

Conclusions:  In our HCV‐infected haemophilia patients, FT correctly identified clinically advanced or minimal liver disease. Discordance among the various biomarkers of fibrosis was considerate; nevertheless, practical combination of FT, APRI, and Forns may predict stage of fibrosis with accuracy, potentially avoiding liver biopsy in the majority of the patients.