bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical exercise increases plasma concentrations of nicotine during treatment with a nicotine patch.
Authors: Klemsdal TO , Gjesdal K. , Zahlsen K.
Published: July 2012

The effect of physical exercise on plasma nicotine concentrations was studied in eight healthy subjects treated with a nicotine patch releasing 14 mg 24 h‐1. After 11 h of patch application, plasma nicotine concentrations were measured before and after 20 min of moderate bicycle exercise, or 20 min of rest. Mean plasma nicotine concentration increased from 9.8 to 11.0 ng ml‐1 (P = 0.015) during physical exercise, and fell non‐significantly from 10.5 to 10.2 ng ml‐1 during rest. The increase in plasma nicotine concentration during exercise is similar to that observed for transdermal nitroglycerin, and may be related to an exercise‐induced increase in blood flow in the patch area.
The pharmacokinetics of three multiple dose regimens of chloroquine: implications for malaria chemoprophylaxis.
Authors: Wetsteyn JC , De Vries PJ , Oosterhuis B. , Van Boxtel CJ
Published: July 2012

The pharmacokinetics of chloroquine were studied in healthy volunteers who received one of three different multiple‐dose regimens for 3 weeks: once weekly 300 mg, twice weekly 200 mg and once daily 50 mg chloroquine. Plasma concentrations of chloroquine and metabolites were determined by h.p.l.c. with fluorescence detection. The concentration‐ time course was fitted to a multiple‐dose pharmacokinetic model. Volume of distribution, elimination half‐life and clearance were not different for the three regimens, ranging from 250‐302 l kg‐1, 374‐479 h and 0.44‐ 0.58 l h‐1 kg‐1 respectively. After the first week of all dosage regimens, peak and trough concentrations of chloroquine were above 16 micrograms l‐1, sufficiently suppressive for chloroquine‐sensitive P. falciparum strains. These data suggest that once daily chloroquine could be combined with proguanil in a single tablet and should improve compliance when given for malaria chemoprophylaxis.
The plasma concentrations of isosorbide 5‐mononitrate (5‐ISMN) administered in an extended‐release form to patients with acute myocardial infarction.
Authors: McClennen W. , Hornestam B. , Jonsson UE , Held P.
Published: July 2012

Eighteen patients with acute myocardial infarction (AMI) followed the same extended‐release isosorbide 5‐mononitrate dosage regimen as was used in the Fourth International Study of Infarct Survival (ISIS‐4). Plasma drug concentrations, blood pressure and heart rate were measured over 5 to 7 days following acute and repeated administrations. After the initial 30 mg dose on the first day of infarction, mean +/‐ standard deviation Cmax was 1237 +/‐ 284 nmol l‐1 with a median tmax of 4 h (range 1 to 10 h). Following the last 60 mg dose, Cmax was 2685 +/‐ 497 nmol l‐1 with a median tmax of 4 h (2 to 7 h). The plasma concentrations of this extended‐release 5‐ISMN in patients with acute myocardial infarction were similar to those seen in studies with healthy volunteers. However, drug absorption following the acute dose was protracted in some patients, possibly due to the concomitant administration of morphine. The kinetics of 5‐ISMN at steady state were similar for all patients, and none showed protracted 5‐ISMN absorption.
Enantioselective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects [see comments]
Authors: Ducharme J. , Fieger H. , Ducharme MP , Khalil SK , Wainer IW
Published: July 2012

1. Stereoselectivity in the disposition of hydroxychloroquine was investigated in 23 healthy males following a single oral dose of 200 mg racemic HCQ (rac‐HCQ) sulphate. Total concentrations (R+S) and R/S ratios of HCQ and its metabolites were measured by stereoselective h.p.l.c. 2. HCQ was detected in whole blood and urine, up to 91 and 85 days after dosing, respectively. Metabolites could not be detected in whole blood while in urine detectable concentrations were still present after 85 days. The blood concentrations of HCQ enantiomers were measurable until 168 h post‐dose. 3. R(−)−HCQ accounted for 62 +/‐ 3% (mean +/‐ s.d.) of the AUC of rac‐HCQ AUC. The elimination half‐life of S(+)‐HCQ (457 +/‐ 122 h) was significantly shorter than that of R(−)− HCQ (526 +/‐ 140 h), partly due to its faster urinary excretion and hepatic metabolism. Its renal clearance was twice that of R(−)−HCQ (4.61 +/‐ 4.01 vs 1.79 +/‐ 1.30 1 h‐1), and metabolites derived from the S‐isomer represented 80‐90% of the urinary recovery of the dose. 4. Over 85 days, 4.4 +/‐ 2.9 and 3.3 +/‐ 1.8% of the dose was recovered in urine as unchanged S(+)‐HCQ and R(−)−HCQ, respectively. For the first 2 weeks, S(+)‐HCQ excretion rate clearly surpassed that of R(−)−HCQ whereas afterwards the inverse was observed. However, since the first 2 weeks account for 95% of rac‐HCQ renal excretion, the total urinary excretion of S(+)‐HCQ clearly surpassed that of R(−)−HCQ.(ABSTRACT TRUNCATED AT 250 WORDS)
Lack of interaction between nefazodone and cimetidine: a steady state pharmacokinetic study in humans.
Authors: Barbhaiya RH , Shukla UA , Greene DS
Published: July 2012

The steady‐state pharmacokinetic interaction between nefazodone and cimetidine was evaluated in a three‐period crossover study consisting of three treatments of 1 week duration with a 1 week washout between treatments. The 18 healthy, male study subjects received: nefazodone hydrochloride 200 mg twice daily (every 12 h) for 6 days; cimetidine 300 mg four times daily for 6 days; and 200 mg nefazodone hydrochloride twice daily + 300 mg cimetidine four times daily for 6 days. On day 7 of each treatment, only the morning dose was administered. Serial blood samples were collected for pharmacokinetic analysis after drug administration on day 7 of each treatment; blood samples for trough levels (Cmin) to assess attainment of steady state, were also collected just prior to the morning doses on days 2‐7 of each study period. Plasma samples were assayed for cimetidine, and nefazodone and its metabolites hydroxynefazodone and m‐chlorophenylpiperazine by specific, validated h.p.l.c. methods. Statistical analyses of Cmin data indicated that, regardless of treatment, steady state was achieved for cimetidine by day 2 and for nefazodone and its metabolites by day 3 of multiple dosing, and that there were no significant differences in Cmin levels between treatments. When nefazodone and cimetidine were co‐administered for 1 week, no change in steady‐state pharmacokinetic parameters for cimetidine, nefazodone or hydroxynefazodone was observed compared with each drug dosed alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of diadenosine phosphates on human umbilical vessels: novel platelet‐derived vasoconstrictors.
Authors: Davies G. , MacAllister RJ , Bogle RG , Vallance P.
Published: July 2012

The responses of human isolated umbilical artery to the novel platelet‐ derived mediators, diadenosine phosphates, P1,P5‐di(adenosine‐ 5′)pentaphosphate (AP5A) and P1,P6‐di(adenosine‐5′)hexaphosphate (AP6A) were studied in vitro. AP5A (1 nM‐300 microM; n = 7) and AP6A (1 nM‐30 microM; n = 5) produced transient concentration‐dependent contractions. Responses to AP5A were unaffected by co‐incubation with indomethacin (10 microM; n = 4), NGmonomethyl‐L‐arginine (L‐NMMA; 300 microM; n = 4) and theophylline (1 microM; n = 5). These results demonstrate that diadenosine phosphates have constrictor effects on human blood vessels in vitro and are consistent with a role for these platelet‐derived mediators in the regulation of blood vessel tone.
The cardiovascular and subjective effects of thyrotropin releasing hormone (TRH) and a stable analogue, dimethyl proline‐TRH, in healthy volunteers.
Authors: Coupland NJ , Bailey JE , Glue P. , Nutt DJ
Published: July 2012

1. The cardiovascular effects of TRH 0.5 mg and 1 mg and a stable TRH analogue, dimethylproline‐TRH (RX77368) 1 mg, infused intravenously over 1 min were assessed in healthy volunteers in two randomised, double‐blind, placebo controlled crossover studies. 2. Both doses of TRH produced significant but transient increases in blood pressure (peak delta systolic: 0.5 mg = 9.2 mm Hg, 1.0 mg = 5.2 mm Hg; peak delta diastolic: 0.5 mg = 6.4 mm Hg, 1.0 mg = 5.4 mm Hg). 3. Beat‐to‐ beat Finapres monitoring demonstrated a rapid onset of effects of RX77368 1 mg, with significant blood pressure effects by 45‐60 s from the start of the infusion (delta systolic BP: 14.2 mm Hg, delta diastolic BP: 15.8 mm Hg and delta heart rate: 8.9 mm Hg at 60 s). 4. The pressor effects of RX77368 1 mg recorded by Dinamap (peak delta systolic: 14.3 mm Hg; peak delta diastolic: 11.8 mm Hg) were sustained, with diastolic pressure still elevated (delta diastolic: 8.2 mm Hg) at 60 min. Heart rate was more transiently elevated (peak delta heart rate: 9.0 beats min‐1) during the first 6 min post infusion. 5. Mild apprehension was reported for the first 6 min after RX77368 1 mg, whereas paraesthesiae were noted after TRH. Otherwise both drugs were similar in the type (flushing, nausea, acid taste, urethral sensations) and duration of subjective effects.
Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk.
Authors: Oo CY , Kuhn RJ , Desai N. , Wright CE , McNamara PJ
Published: July 2012

1. Alprazolam, a triazolobenzodiazepine, is extensively prescribed for the treatment of anxiety disorders, which predominantly affect women of child‐bearing age. The purpose of the present study was to assess the pharmacokinetics of alprazolam and its two hydroxylated metabolites: 4‐ hydroxy‐alprazolam and alpha‐hydroxy‐alprazolam in lactating human volunteers and to test the predictability of four recently reported models for drug transfer into milk based on physicochemical properties. 2. Multiple milk and serum samples in eight lactating subjects were collected up to 36 h following single oral doses of 0.5 mg alprazolam; suckling of the infant was discontinued after drug administration. 4‐ Hydroxy‐alprazolam was the predominant metabolite in serum samples while alpha‐hydroxy‐alprazolam was not detected. 3. The mean oral clearance of alprazolam was 1.15 +/‐ 0.32 ml min‐1 kg‐1. The time course of alprazolam in milk roughly paralleled the perspective plasma time profile (mean serum residence time = 16.42 +/‐ 4.69 h; mean milk residence time = 18.93 +/‐ 7.03 h). The mean terminal half‐life in serum was 12.52 +/‐ 3.53 h. 4. Observed milk/serum concentration ratios were determined in vivo as AUCmilk/AUCserum (mean M/S(obs) = 0.36 +/‐ 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of human chorionic gonadotropin (HCG) in the treatment of obesity by means of the Simeons therapy: a criteria‐based meta‐analysis.
Authors: Lijesen GK , Theeuwen I. , Assendelft WJ , Van Der Wal G.
Published: July 2012

1. A meta‐analysis was conducted to assess if there is scientific ground for the use of human chorionic gonadotropin (HCG) as adjunctive therapy in the treatment of obesity. 2. Published papers relating to eight controlled and 16 uncontrolled trials that measured the effect of HCG in the treatment of obesity were traced by computer‐aided search and citation tracking. 3. The trials were scored for the quality of the methods (based on four main categories: study population, interventions, measurement of effect, and data presentation and analysis) and the main conclusion of author(s) with regard to weight‐ loss, fat‐redistribution, hunger, and feeling of well‐being. 4. Methodological scores ranged from 16 to 73 points (maximum score 100), suggesting that most studies were of poor methodological quality. Of the 12 studies scoring 50 or more points, one reported that HCG was a useful adjunct. The studies scoring 50 or more points were all controlled. 5. We conclude that there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight‐loss of fat‐redistribution, nor does it reduce hunger or induce a feeling of well‐being.
A comparison of the contractile effects of 5‐hydroxytryptamine, sumatriptan and MK‐462 on human coronary artery in vitro.
Authors: Ferro A. , Longmore J. , Hill RG , Brown MJ
Published: July 2012

1. MK‐462 (N,N‐dimethyl‐2‐[5‐(1,2,4‐triazol‐1‐ylmethyl)‐1H‐ indol‐3‐ yl]ethylamine) is a novel selective 5‐HT1D‐receptor agonist which in clinical trials has been shown to be an effective antimigraine agent. As angiographic studies have shown that sumatriptan (an established 5‐ HT1D‐receptor agonist) can cause coronary artery vasoconstriction in patients, we compared the effects of MK‐462 with those of 5‐HT and those of sumatriptan, on isolated segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients (n = 22, 2 females, 20 males, aged 21‐60 years) undergoing cardiac transplantation. Endothelium‐denuded ring segments of coronary artery, 2mm long were mounted in organbaths for isometric tension recording. For each arterial ring segment, a cumulative concentration‐ effect curve to either 5‐HT, sumatriptan or MK‐462 was determined. After maximal response to each agonist had been obtained, ketanserin (a 5‐HT2 receptor antagonist) 0.6 microM was added to the tissue bath, followed by methiotepin (0.6 microM) and the reduction in tension produced by the addition of each antagonist was determined. 3. Out of 22 coronary arteries studied, only 10 showed any response (contraction) to 5‐HT. Not all arteries which responded to 5‐HT contracted in response to both sumatriptan and MK‐462 (one ring from each artery being exposed to a single agonist in each case).(ABSTRACT TRUNCATED AT 250 WORDS)
Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.
Authors: Bannwarth B. , Lapicque F. , Pehourcq F. , Gillet P. , Schaeverbeke T. , Laborde C. , Dehais J. , Gaucher A. , Netter P.
Published: July 2012

Since both (R)‐ and (S)‐enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve‐root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac‐ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half‐ lives of (R)‐ and (S)‐ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)‐ and (S)‐forms, respectively.
Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.
Authors: Cawello W. , Leonhardt A. , Schweer H. , Seyberth HW , Bonn R. , Lomeli AL
Published: July 2012

Prostaglandin E1 (PGE1) (30, 60, 120 micrograms) was administered by intravenous infusion over a 120 min period in an open, three way randomized, cross‐over study to 12 healthy male volunteers. For the evaluation of PGE1, PGE0 and 15‐keto‐PGE0, blood samples were drawn prior to, during and after the infusion. Analytical measurements were performed by gas chromatography/negative ion chemical ionization triple stage quadruple mass spectrometry, a highly specific and sensitive GC/MS/MS‐method. During intravenous infusion of 30, 60 and 120 micrograms PGE1, endogenous plasma PGE1 concentrations increased from 1.7 +/‐ 0.8 to 4.2 +/‐ 1.1, 6.7 +/‐ 1.0 and 11.0 +/‐ 1.9 pg ml‐1 respectively. PGE0 plasma concentrations increased from endogenous levels of 1.3 +/‐ 1.0 pg ml‐1 to 7.6 +/‐ 2.1, 14.1 +/‐ 3.7 and 28.0 +/‐ 3.0 pg ml‐1 respectively, whilst 15‐keto‐PGE0 plasma concentrations increased from endogenous levels of 10.2 +/‐ 13.9 pg ml‐1 to 99.3 +/‐ 27.9, 190.4 +/‐ 52.5 and 357.2 +/‐ 72.6 pg ml‐1 respectively. Within the dose range of 30‐120 micrograms PGE1 2 h‐1 there was a linear increase of Cmax and AUC with the dose. The results of the analysis of variance after baseline and dose‐correction show a 90% confidence interval in the bioequivalence acceptance range of 80 to 125%.
Patterns of drug treatment of schizophrenic patients in Estonia, Spain and Sweden.
Authors: Kiivet RA , Llerena A. , Dahl ML , Rootslane L. , Sanchez Vega J. , Eklundh T. , Sjoqvist F.
Published: July 2012

1. Patterns of drug treatment and the use of polypharmacy in schizophrenic in‐patients were compared and evaluated in the University Teaching Hospitals of Psychiatry in Badajoz, Spain, Huddinge, Sweden, and Tartu, Estonia. 2. The medical records of up to 100 consecutively admitted patients were retrospectively reviewed using a standardized data form. 3. The male patients were significantly younger than females in all study locations, but there were no age differences between the locations. The length of stay was equal for the two series in the same hospital, but considerably longer in Tartu than in Badajoz and Huddinge. 4. The neuroleptic drugs used most commonly in Badajoz and Tartu were similar in prescription frequency and in the doses prescribed, but different from those used in Huddinge. Haloperidol was the most frequently prescribed neuroleptic in Badajoz and Tartu, accounting for one third of all neuroleptic prescriptions. In Huddinge the choice of neuroleptics was more evenly spread over several compounds. Intramuscular injections other than depot preparations were commonly used in Tartu and Badajoz, but not in Huddinge. 5. At least two neuroleptics were prescribed simultaneously on 73% of treatment days in Badajoz and 46% in both Huddinge and Tartu. The average cumulative daily doses of concomitant multiple neuroleptic treatment, expressed in chlorpromazine equivalents, were lower in Huddinge than in the other study locations and higher for male patients in Badajoz and Tartu. 6. Anticholinergics were used together with neuroleptics in 42% of treatment days in Badajoz and 30% in Huddinge as compared with 75% in Tartu. The use of anticholinergics increased in parallel to the increase in the number and the cumulative dose of concomitant neuroleptics in all study locations. 7. About 15% of patients in Badajoz and Tartu, but only 1% in Huddinge, received concomitant treatment with antidepressant drugs. The simultaneous use of antidepressants and benzodiazepines was inversely related to the number and the cumulative dose of neuroleptics in Badajoz and Tartu. In contrast, the cumulative dose and number of neuroleptics were greater, when additional benzodiazepines were prescribed in Huddinge. 8. The study in schizophrenic in‐patients revealed that polypharmacy with concomitant multiple neuroleptics, additional anticholinergics and other psychotropics is an international phenomenon.
Plasma hydroxy‐metronidazole/metronidazole ratio in patients with liver disease and in healthy volunteers.
Authors: Muscara MN , Pedrazzoli J. , Miranda EL , Ferraz JG , Hofstatter E. , Leite G. , Magalhaes AF , Leonardi S. , De Nucci G.
Published: July 2012

Metronidazole pharmacokinetics were studied in patients with different degrees of liver cirrhosis, classified according to the Child‐Pugh algorithm (A, B or C, as liver disease severity increases) and in schistosomic patients. Metronidazole (500 mg) was administered i.v. as a slow infusion over 20 min, and blood samples were collected at set intervals after the end of the infusion. The plasma concentrations of metronidazole and its main metabolite hydroxy‐metronidazole were quantified by reversed‐phase h.p.l.c. with u.v. detection. The metronidazole and hydroxy‐metronidazole areas under the curve from 0 to 24 h (AUC0,24h), the metronidazole terminal elimination half‐life (t1/2), the total clearance (CL), the metronidazole volume of distribution (V) values and the hydroxy‐metronidazole/metronidazole concentration ratios as a function of time were calculated for each group. Comparison of the metronidazole AUC0,24h, t1/2 and CL values revealed that metronidazole metabolism is progressively impaired as the severity of liver disease increases. There were no variations in these parameters between the schistosomic and Child‐Pugh A groups. In addition, there were no differences in the V and hydroxy‐metronidazole AUC0,24h among the various groups studied. However, metronidazole metabolism was delayed in patients with hepatic disease, as illustrated by the hydroxy‐metronidazole/metronidazole ratio 10 min after the end of metronidazole infusion. These results indicate that the clinical assessment of liver disease is paralleled by an impairment of metronidazole metabolism. Of the studied variables, we propose the hydroxy‐metronidazole/metronidazole ratio 10 min after metronidazole infusion as a suitable and practical index for liver function evaluation.
The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.
Authors: Panfilov V. , Morris AD , Donnelly R. , Scemama M. , Reid JL
Published: July 2012

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double‐blind, placebo‐controlled, cross‐over study. 2. After a 4 week placebo run‐in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/‐ 15/7 mmHg) received rilmenidine 1‐2 mg day‐1, and atenolol 50‐100 mg day‐1, each for 4 weeks, with a 4 week placebo wash‐out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min‐1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min‐1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.
The effect of HN‐65021 on responses to angiotensin II in human forearm vasculature.
Authors: Cockcroft J.R. , Chowienczyk PJ , Brett SE , Mant TG , Durnin C. , Lynn F. , Stevenson P. , Ritter JM
Published: July 2012

We studied the effect of (2‐butyl‐4‐chloro‐1[[2'‐(1H‐tetrazol‐5‐yl) [1,1'‐biphenyl]methyl]‐1H‐imadazole‐5‐carboxylic acid,‐1‐ (ethoxycarbonyloxy) ethyl‐ester (HN‐65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN‐65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3‐1000 pmol min‐1) 2 h after dosing. HN‐65021 inhibited angiotensin II, causing a shift to the right of the dose‐response curve. Angiotensin II (100 pmol min‐1) decreased mean blood flow in the infused arm by 63.1 +/‐ 3.2% when infused following placebo and by 49.9 +/‐ 4.3%, 50.7 +/‐ 3.5% and 36.4 +/‐ 2.8% following HN‐65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN‐65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels.
The contribution of randomized trials to the cure of haematological disorders from Bradford Hill onwards
Authors: Hills Robert K.
Published: July 2012

It is now 75 years since the publication of Sir Austin Bradford Hill's classic textbook on Medical Statistics, and half a century since the formation of the Medical Research Council Working Party on Leukaemia. In the intervening period, trials in haematological malignancies have been at the forefront of cancer research, both in the proportion of patients recruited, and in the adoption of novel trial designs. In this paper, the principles propounded by Hill for reliable evaluation of new treatments are considered and placed in the context of the development and evaluation of novel treatments in the 21st century. Many of the original principles espoused are still highly relevant today, while the emerging heterogeneity of the conditions, both in aetiology and outcome provide their own newer challenges, which are discussed here.
TORC1 of fission yeast is rapamycin‐sensitive
Authors: Takahara Terunao , Maeda Tatsuya
Published: July 2012

The target of rapamycin (TOR) protein kinase plays central roles in the regulation of cell growth in response to nutritional availability. TOR forms two distinct multiprotein complexes termed TOR complex 1 (TORC1) and TORC2. Typically, only the activity of TORC1 is inhibited by the immunosuppressant rapamycin. Although rapamycin strongly inhibits cell growth of the budding yeast Saccharomyces cerevisiae through inhibition of TORC1, growth of the fission yeast Schizosaccharomyces pombe appears to be resistant to rapamycin. Here, we demonstrate that rapamycin inhibits the kinase activity of S. pombe TORC1 in vitro in a similar manner to TORC1 of other organisms. We furthermore show that incomplete inhibition of TORC1 by rapamycin underlies the apparent rapamycin resistance of S. pombe. In the presence of caffeine, which potentially lowers TORC1 activity, the growth of wild‐type S. pombe cells is sensitive to rapamycin in a TORC1‐dependent manner. Moreover, treatment of S. pombe cells with rapamycin plus caffeine induces starvation‐specific gene expression and autophagy, similarly to cells with reduced TORC1 activity. These results indicate that rapamycin does inhibit TORC1 in S. pombe, but the inhibition is not sufficient to cause a growth defect. These findings establish a universal action of rapamycin on TORC1 inhibition.
Pharmacokinetics and pharmacodynamics of rFVIIa and new improved bypassing agents for the treatment of haemophilia
Authors: AGERSØ HENRIK , TRANHOLM MIKAEL
Published: July 2012

Summary.  Animal models have played a critical role in developing our understanding of haemophilia and its treatment. For example, studies in mice and dogs have provided insights into the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa). Such studies have shown that antithrombin has a significant impact on clearance of rFVIIa, which explains discrepancies between the antigen and activity half‐lives of rFVIIa. Animal studies have also shown that the major clearance organs for rFVIIa are the liver and the kidneys, whereas distribution studies suggest that FVII and rFVIIa leave the circulation and enter the tissues, before returning to the circulation through the lymph. One agent that has benefited greatly from the use of animal models in its development is vatreptacog alfa, a new analogue of rFVIIa. Promising in vitro results, including increased generation of FXa, shortened clotting times and increased clot stability, were subsequently confirmed in animal models. In a severe tail‐bleed model in FVIII knock‐out mice, reduction in maximal blood loss was substantially greater with vatreptacog alfa than with rFVIIa, FVIII or plasma‐derived activated prothrombin complex concentrate. In a mouse model of joint bleeding, rFVIIa and vatreptacog alfa significantly reduced bleeding compared with vehicle‐treated haemophilic controls. More recently, a model of endothelial injury based on mouse cremaster muscle has been developed. Overall, animal models are a valuable tool in elucidating the haemostatic process and the effects of therapeutic agents, although direct extrapolation to the clinical setting should be done with caution.
From boy to man: recommendations for the transition process in haemophilia
Authors: YOUNG GUY
Published: July 2012

Summary.  Haemophilia is a life‐long genetic disorder most often diagnosed in early childhood which results in bleeding into deep tissues and can result in arthropathy and, rarely, other serious complications. As a result of the natural physical and cognitive development in children, combined with the manner in which haemophilia is treated, there is a continuous process of changes in the approach to patient management, which collectively are called transitional issues. It is important to point out that while some traditional definitions of transition are limited to the stage when an adolescent becomes an adult and how the mode and delivery of care change during this time, a broader definition incorporating all the changes that occur from birth through adulthood will be described in this article. As such, transition should be thought of as a continuous process, though for the sake of clarity and practicality, we will divide the process into several phases. The transition issues to be discussed will be divided into medical issues and psychosocial issues, though there is clearly overlap between the two. A well‐developed transition plan from birth to adulthood for patients with haemophilia facilitates the necessary change from total dependence on caregivers to complete independence by the time one reaches 18 years of age.
Antibody formation and specificity in Bethesda‐negative brother pairs with haemophilia A
Authors: Klintman J. , Hillarp A. , Donfield S. , Berntorp E. , Astermark J.
Published: July 2012

Antibodies directed towards non‐neutralizing epitopes on the factor VIII protein (FVIII) may be detected in patients with haemophilia A. We evaluated the prevalence of non‐neutralizing antibodies, in 201 inhibitor‐negative brother pairs with severe haemophilia A, enrolled in the Malmö International Brother Study and the Haemophilia Inhibitor Genetics Study. To evaluate binding specificity of the antibodies, ELISA plates were coated with two recombinant full‐length (FL) FVIII‐products and one recombinant B‐domain‐deleted (BDD) product. Seventy‐nine patients (39.3%) had a history of positive inhibitor titre measured by Bethesda assay, and FVIII antibodies were detected in 20 of them (25.3%). Additional 23 samples from subjects without a history of FVIII inhibitors were ELISA‐positive corresponding to a frequency of non‐neutralizing antibodies of 18.9%. The antibody response towards the different FVIII products was heterogenous, and was raised not only towards the non‐functional B‐domain but also towards both FL‐rFVIII and BDD‐rFVIII. In patients considered successfully treated with immune tolerance induction, 25.4% had remaining FVIII antibodies. The number of families with an antibody response in all siblings was increased when the total antibody response was taken into account, further supporting the concept of a genetic predisposition of the immune response. Further studies and careful monitoring over time are required to appreciate the immune response on the risk of inhibitor development or recurrence in the future.
Patterns of physical activity in children with haemophilia
Authors: Broderick C. R. , Herbert R. D. , Latimer J. , van Doorn N.
Published: July 2012

The current widespread use of prophylaxis in developed countries has enabled greater participation in physical activity. However, there are no data available on leisure‐time physical activity in Australian children with haemophilia. The data reported here were obtained from a case‐crossover study nested in a prospective cohort study of 104 boys with moderate and severe haemophilia followed for one year. Each child's physical activity was assessed using a modifiable physical activity questionnaire (Kriska's MAQ) administered at baseline, and a one‐week prospective activity diary at a randomly determined time. Children were aged 4–18 years. The median time spent in sport or leisure‐time physical activity in the preceding year was 7.9 h/week (IQR 4.6 to 12.9). The median time spent in vigorous physical activity was 3.8 h/week (IQR 1.6 to 6.4) and in moderate and vigorous physical activity 6.4 h/week (IQR 3.7 to 10.0). The median small‐screen time was 2.5 h/day (IQR 0.5 to 2.5). Forty‐five per cent of all children and 61% of children over the age of 10 years played at least one competitive sport. Averaged across one week, 43% of all children met the Australian government physical activity guidelines for children and 36% met the guidelines for small‐screen time. This study provides the first data regarding leisure‐time physical activity in children with haemophilia living in Australia. The majority of Australian children with haemophilia are not meeting the national physical activity and small‐screen time guidelines.
Opinions on radiosynovectomy for chronic haemophilic synovitis: point/counterpoint
Authors: Silva M. , Luck J. V. , Leissinger C.
Published: July 2012

Joint bleeding is the hallmark of severe haemophilia and the major cause of disability in patients with this coagulopathy. Repeated bleeding into the same joint can lead to chronic synovitis and progressive arthropathy. Radiosynovectomy is one option for the treatment of chronic haemophilic synovitis, but concerns about the risks of exposure to ionizing radiation have divided clinicians as to the safety and appropriate use of the procedure. This article presents two differing viewpoints, one from a pair of orthopaedic surgeons who collectively have performed more than 300 radiosynovectomies in patients with haemophilia. They maintain that radiosynovectomy is a simple, effective, safe and low‐cost technique children and adults with chronic haemophilic synovitis. The other perspective is from an experienced haemophilia treater who directs a major US haemophilia treatment centre. She believes that unresolved questions about the safety of radiation exposure in children argue against the use of radiosynovectomy in paediatric patients with haemophilia.
Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy
Authors: Puppa Giacomo , Senore Carlo , Sheahan Kieran , Vieth Michael , Lugli Alessandro , Zlobec Inti , Pecori Sara , Wang Lai Mun , Langner Cord , Mitomi Hiroyuki , Nakamura Takatoshi , Watanabe Masahiko , Ueno Hideki , Chasle Jacques , Conley Stephen A , Herlin Paulette , Lauwers Gregory Y , Risio Mauro
Published: July 2012

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M  (2012) Histopathology 61, 562–575

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy

Aims:  Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice.

Methods and results:  A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1‐3 cytokeratin‐immunostained, whole‐slide digital scans from 50 pT1–pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants’ experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding‐positive cases with all methods compared to H&E‐stained slides, but did not influence agreement levels.

Conclusions:  An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.
In vitro antioxidant and antiproliferative activity of three rosemary (Rosmarinus officinalis L.) extract formulations
Authors: Đilas Sonja , Knez Željko , Četojević‐Simin Dragana , Tumbas Vesna , Škerget Mojca , Čanadanović‐Brunet Jasna , Ćetković Gordana
Published: July 2012

Antioxidant and antiproliferative activities of three rosemary extract formulations (VivOX 20, VivOX 40 and Inolens 50) with different contents of carnosic acid, carnosol and methylcarnosol were tested in vitro. Electron spin resonance measurements revealed that Inolens 50 extract that contained highest amount of carnosic acid was the most potent scavenger of hydroxyl (concentration of extract where 50% of its maximal scavenging activity is observed, that is, EC50, 109.54 μg mL−1), superoxide anion (EC50 = 7.94 μg mL−1) and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) (EC50 = 27.4 μg mL−1)‐free radicals. Comparison of the radar charts of standard antioxidants and rosemary extracts showed similarity between antioxidant characteristics of Inolens 50 and chlorogenic and caffeic acids. Tested rosemary extracts exhibited significant (P ≤ 0.01) antiproliferative effect in cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and colon adenocarcinoma (HT‐29) cell lines. In both MCF7 and HeLa cell lines, the extracts yielded very low IC50 values (concentration of extract needed to inhibit cell growth by 50%), the most pronounced being for Inolens 50 in MCF7 (IC50 = 9.95 μg mL−1) and VivOX 20 in HeLa cell line (IC50 = 10.02 μg mL−1). The obtained results may provide support for the use of tested rosemary extracts as nutraceuticals and phytopharmaceuticals.
A two‐step inoculation of Candida etchellsii to enhance soy sauce flavour and quality
Authors: Feng Jie , Zhan Xiao‐Bei , Zheng Zhi‐Yong , Wang Dong , Zhang Li‐Min , Lin Chi‐Chung
Published: July 2012

Effects of novel two‐step inoculation to enhance soy sauce special flavour in Candida etchellsii were investigated at the cell growth phase. The first‐stage consists of a 5% culture inoculum of log phase cells at 30‐day. Subsequently, a 20% culture inoculum of stationary phase cells was added at 60‐day. The resulting amino nitrogen and soluble salt‐free solid yield reached 9.15 ± 0.12 and 269.60 ± 3.15 mg L−1 in 30 °C incubator experiments, increased by 23.1% and 17.6%, respectively, as compared to the control without culture inoculation. Maximal free amino acid yield of 58.21 ± 1.77 g L−1 was achieved, and 39 types of volatile flavour compounds content was 17.81 ± 0.45 g L−1, which were 1.76% and 178.7% higher than the control. A novel two‐step inoculation using the C. etchellsii yeast was developed and optimised. It was proven to be a feasible reproducible process for industrial application for the improvement of the flavour and quality of soy sauce production.
Reliability, availability and maintainability analysis in food production lines: a review
Authors: Tsarouhas Panagiotis
Published: July 2012

The scope of this study is to review reliability, availability and maintainability (RAM) analysis in the food industry and aims to identify the critical points of the production systems that should be improved by the operational performance and the maintenance effectiveness. RAM is an engineering tool that addresses operations and safety issues of production lines and aims to identify areas within the system or process where significant improvement can be achieved. Food production lines consist of several machines supplied with a common transfer mechanism and control system that have different failure modes. When a random failure occurs, the failed machine stops and forces most of the line upstream of the failure to operate without processing, whereas the material (raw, intermediate or end‐product) of the line downstream may have to be scrapped because of quality deterioration during the stoppage. The negative failure impact is the drop of line reliability and production rate.
Production of biogenic amines by lactic acid bacteria and bifidobacteria isolated from dairy products and beer
Authors: Lorencová Eva , Buňková Leona , Matoulková Dagmar , Dráb Vladimír , Pleva Pavel , Kubáň Vlastimil , Buňka František
Published: July 2012

The aim was to monitor production of eight biogenic amines (BAs) (histamine, tyramine (TYR), tryptamine, putrescine, cadaverine (CAD), phenylethylamine, spermine and spermidine) by selected 81 lactic acid bacteria (LAB) strains: Lactobacillus, Lactococcus, Leuconostoc, Enterococcus, Pediococcus, Tetragenococcus and Bifidobacterium. The tested LAB and bifidobacteria were isolated from dairy products and beer. The decarboxylase activity of the micro‐organisms was studied in growth medium after cultivation. The activity was monitored by HPLC after the pre‐column derivatisation with dansylchloride. Fifty LAB showed decarboxylase activity. Thirty‐one strains produced low concentrations of CAD (≤10 mg L−1). Almost 70% of beer isolates generated higher amounts of TYR (≤3000 mg L−1). Most of the tested LAB demonstrated decarboxylase activity. The above micro‐organisms can contribute to the increase of content of BAs in dairy products or beer and thereby threaten food safety and health of consumers. Production of BAs even by the representatives of some probiotic strains (Bifidobacterium and Lactobacillus rhamnosus) was detected in this research. This study has also proved that contaminating LAB can act as sources of higher amounts of CAD and TYR in beer.
Formulation optimisation of vegetable flour–loaded functional bread. Part II: effect of the flour hydration on the bread quality
Authors: Mastromatteo Marcella , Danza Alessandra , Guida Mariangela , Del Nobile Matteo Alessandro
Published: July 2012

In this work, the hydration process of durum wheat–based functional bread loaded with yellow pepper flour was optimised. In particular, the investigated vegetable flour and durum wheat semolina were mixed after they were separately hydrated. Three different amounts of water added to the yellow pepper flour were studied for assessing the effect of vegetable flour hydration level on the dough development and overall quality of bread. The bread formulation investigated in a previous work, based on 25% of yellow pepper and 2% of guar seed as structuring agent where the vegetable flour was directly added to the hydrated durum wheat semolina dough, was chosen as control sample. Results highlighted that dough samples with yellow pepper flour hydrated at highest water content showed a rheological behaviour similar to the durum wheat dough. Moreover, creep analysis showed that the sample added with no‐hydrated yellow pepper flour recorded the greatest resistance to deformation. Same results were obtained for the dough tensile and bread compression tests. The use of the hydrated yellow pepper flour also improved all sensorial attributes.
Contribution of coffee proteins to roasted coffee volatiles in a model system
Authors: Hwang Chin‐Fa , Chen Chu‐Chin , Ho Chi‐Tang
Published: July 2012

A simple roasting model using a mineral oil bath was set up to study the effects of coffee proteins on the formation of coffee volatiles during roasting. Green coffee powder was separated into four fractions, and the highest concentration of volatile compounds was observed in the roasted sample of the water extract fraction. Sugar degradation products were the dominant compounds. The addition of coffee proteins into the nonprotein water extract fraction catalysed sugar degradation and enhanced the production of selected volatiles. Higher amounts of coffee protein correlated with the concentration of pyrazines. Coffee protein also increased sucrose degradation in the roasting of sucrose with coffee protein. However, the results from colour measurements indicated that a greater amount of protein produced a lighter colour. These results demonstrated the important contribution of coffee proteins in the formation of coffee volatiles and colour.
Rheological properties of wheat flour and quality characteristics of pan bread as modified by partial additions of wheat bran or whole grain wheat flour
Authors: Schmiele Marcio , Jaekel Leandra Zafalon , Patricio Stella Maris Cardoso , Steel Caroline Joy , Chang Yoon Kil
Published: July 2012

The use of bran and whole grain flour changes dough rheology and causes difficulties in manufacturing bakery products. The aim of this study was to analyse the influence of substituting refined wheat flour (WF) by wheat bran (WB; 5%, 10%, 20%, 30% and 40%) or whole grain wheat flour (WGWF; 10%, 20%, 30%, 40% and 50%) on dough rheological properties and pan bread quality characteristics. The addition of WB and WGWF increased water absorption and resistance to extension and decreased stability, extensibility and peak viscosity. Effects with WB were more pronounced. The presence of WB or WGWF increased crumb moisture content, firmness and hardness and decreased specific volume of pan bread. It is important to set new farinographic and extensographic standards when using WB and WGWF, allowing for a correct correlation between rheology and quality characteristics of bakery products, as the same standards used for WF are not valid.
Optimising the extraction of tea polyphenols, (−)‐epigallocatechin gallate and theanine from summer green tea by using response surface methodology
Authors: Zhang Xin , Xu Fei , Gao Yuan , Wu Jing , Sun Yi , Zeng Xiaoxiong
Published: July 2012

In this study, response surface methodology was applied to determine the optimal conditions for the extraction of tea polyphenols, EGCG and theanine from summer green tea. As results, the optimal extraction conditions were determined to be temperature 96 °C, time 40 min and ratio of water to raw material 16 mL g−1. Under these optimal conditions, the experimental values for tea polyphenols, EGCG, theanine and IC50for DPPH free radical scavenging activity were 133.41 ± 3.12 mg gallic acid g−1, 30.23 ± 1.22, 3.99 ± 1.13 mg g−1and 724.95 ± 15.12 μg mL−1, respectively. There was no statistical difference at significant level of 0.05 between the experimental and predicted values. The results suggested that the regression models were accurate and adequate for the bioactives extraction from summer green tea.