bluuebunny/crossref_metadata_2025 huggingface dataset:
Light regulates attachment, exopolysaccharide production, and nodulation in
Rhizobium leguminosarum
through a LOV-histidine kinase photoreceptor
Authors: Bonomi Hernán R. , Posadas Diana M. , Paris Gastón , Carrica Mariela del Carmen , Frederickson Marcus , Pietrasanta Lía Isabel , Bogomolni Roberto A. , Zorreguieta Angeles , Goldbaum Fernando A.
Published: July 2012

Rhizobium leguminosarum
is a soil bacterium that infects root hairs and induces the formation of nitrogen-fixing nodules on leguminous plants. Light, oxygen, and voltage (LOV)-domain proteins are blue-light receptors found in higher plants and many algae, fungi, and bacteria. The genome of
R. leguminosarum
bv.
viciae
3841, a pea-nodulating endosymbiont, encodes a sensor histidine kinase containing a LOV domain at the N-terminal end (R-LOV-HK). R-LOV-HK has a typical LOV domain absorption spectrum with broad bands in the blue and UV-A regions and shows a truncated photocycle. Here we show that the R-LOV-HK protein regulates attachment to an abiotic surface and production of flagellar proteins and exopolysaccharide in response to light. Also, illumination of bacterial cultures before inoculation of pea roots increases the number of nodules per plant and the number of intranodular bacteroids. The effects of light on nodulation are dependent on a functional
lov
gene. The results presented in this work suggest that light, sensed by R-LOV-HK, is an important environmental factor that controls adaptive responses and the symbiotic efficiency of
R. leguminosarum
.
TCP transcription factor, BRANCH ANGLE DEFECTIVE 1 (BAD1), is required for normal tassel branch angle formation in maize
Authors: Bai Fang , Reinheimer Renata , Durantini Diego , Kellogg Elizabeth A. , Schmidt Robert J.
Published: July 2012

In grass inflorescences, a structure called the “pulvinus” is found between the inflorescence main stem and lateral branches. The size of the pulvinus affects the angle of the lateral branches that emerge from the main axis and therefore has a large impact on inflorescence architecture. Through EMS mutagenesis we have identified three complementation groups of recessive mutants in maize having defects in pulvinus formation. All mutants showed extremely acute tassel branch angles accompanied by a significant reduction in the size of the pulvinus compared with normal plants. Two of the complementation groups correspond to mutations in the previously identified genes,
RAMOSA2
(
RA2
) and
LIGULELESS1
(
LG1
). Mutants corresponding to a third group were cloned using mapped-based approaches and found to encode a new member of the plant-specific TCP (
TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL NUCLEAR ANTIGEN FACTOR
) family of DNA-binding proteins,

B
RANCH
A
NGLE
D
EFECTIVE 1

(
BAD1
).
BAD1
is expressed in the developing pulvinus as well as in other developing tissues, including the tassels and juvenile leaves. Both molecular and genetics studies show that
RA2
is upstream of
BAD1
, whereas
LG1
may function in a separate pathway. Our findings demonstrate that
BAD1
is a TCP class II gene that functions to promote cell proliferation in a lateral organ, the pulvinus, and influences inflorescence architecture by impacting the angle of lateral branch emergence.
HIV-1 envelope trimer elicits more potent neutralizing antibody responses than monomeric gp120
Authors: Kovacs James M. , Nkolola Joseph P. , Peng Hanqin , Cheung Ann , Perry James , Miller Caroline A. , Seaman Michael S. , Barouch Dan H. , Chen Bing
Published: July 2012

HIV-1 envelope glycoprotein is the primary target for HIV-1–specific antibodies. The native HIV-1 envelope spike on the virion surface is a trimer, but trimeric gp140 and monomeric gp120 currently are believed to induce comparable immune responses. Indeed, most studies on the immunogenicity of HIV-1 envelope oligomers have revealed only marginal improvement over monomers. We report here that suitably prepared envelope trimers have nearly all the antigenic properties expected for native viral spikes. These stable, rigorously homogenous trimers have antigenic properties markedly different from those of monomeric gp120s derived from the same sequences, and they induce potent neutralizing antibody responses for a cross-clade set of tier 1 and tier 2 viruses with titers substantially higher than those elicited by the corresponding gp120 monomers. These results, which demonstrate that there are relevant immunologic differences between monomers and high-quality envelope trimers, have important implications for HIV-1 vaccine development.
Cdk1-dependent control of membrane-trafficking dynamics
Authors: McCusker Derek , Royou Anne , Velours Christophe , Kellogg Douglas
Published: July 2012

Cyclin-dependent kinase 1 (Cdk1) is required for initiation and maintenance of polarized cell growth in budding yeast. Cdk1 activates Rho-family GTPases, which polarize the actin cytoskeleton for delivery of membrane to growth sites via the secretory pathway. Here we investigate whether Cdk1 plays additional roles in the initiation and maintenance of polarized cell growth. We find that inhibition of Cdk1 causes a cell surface growth defect that is as severe as that caused by actin depolymerization. However, unlike actin depolymerization, Cdk1 inhibition does not result in a massive accumulation of intracellular secretory vesicles or their cargoes. Analysis of post-Golgi vesicle dynamics after Cdk1 inhibition demonstrates that exocytic vesicles are rapidly mistargeted away from the growing bud, possibly to the endomembrane/vacuolar system. Inhibition of Cdk1 also causes defects in the organization of endocytic and exocytic zones at the site of growth. Cdk1 thus modulates membrane-trafficking dynamics, which is likely to play an important role in coordinating cell surface growth with cell cycle progression.
Septin ring size scaling and dynamics require the coiled-coil region of Shs1p
Authors: Meseroll Rebecca A. , Howard Louisa , Gladfelter Amy S.
Published: July 2012

Septins are conserved GTP-binding proteins that assemble into heteromeric complexes that form filaments and higher-order structures in cells. What directs filament assembly, determines the size of higher-order septin structures, and governs septin dynamics is still not well understood. We previously identified two kinases essential for septin ring assembly in the filamentous fungus Ashbya gossypii and demonstrate here that the septin Shs1p is multiphosphorylated at the C-terminus of the protein near the predicted coiled-coil domain. Expression of the nonphosphorylatable allele shs1-9A does not mimic the loss of the kinase nor does complete truncation of the Shs1p C-terminus. Surprisingly, however, loss of the C-terminus or the predicted coiled-coil domain of Shs1p generates expanded zones of septin assemblies and ectopic septin fibers, as well as aberrant cell morphology. The expanded structures form coincident with ring assembly and are heteromeric. Interestingly, while septin recruitment to convex membranes is increased, septin localization is diminished at concave membranes in these mutants. Additionally, the loss of the coiled-coil leads to increased mobility of Shs1p. These data indicate the coiled-coil of Shs1p is an important negative regulator of septin ring size and mobility, and its absence may make septin assembly sensitive to local membrane curvature.
Ultrafast genome-wide scan for SNP–SNP interactions in common complex disease
Authors: Prabhu Snehit , Pe'er Itsik
Published: July 2012

Long-range gene–gene interactions are biologically compelling models for disease genetics and can provide insights on relevant mechanisms and pathways. Despite considerable effort, rigorous interaction mapping in humans has remained prohibitively difficult due to computational and statistical limitations. We introduce a novel algorithmic approach to find long-range interactions in common diseases using a standard two-locus test that contrasts the linkage disequilibrium between SNPs in cases and controls. Our ultrafast method overcomes the computational burden of a genome × genome scan by using a novel randomization technique that requires 10× to 100× fewer tests than a brute-force approach. By sampling small groups of cases and highlighting combinations of alleles carried by all individuals in the group, this algorithm drastically trims the universe of combinations while simultaneously guaranteeing that all statistically significant pairs are reported. Our implementation can comprehensively scan large data sets (2K cases, 3K controls, 500K SNPs) to find all candidate pairwise interactions (LD-contrast) in a few hours—a task that typically took days or weeks to complete by methods running on equivalent desktop computers. We applied our method to the Wellcome Trust bipolar disorder data and found a significant interaction between SNPs located within genes encoding two calcium channel subunits:RYR2on chr1q43 andCACNA2D4on chr12p13 (LD-contrast test,). We replicated this pattern of interchromosomal LD between the genes in a separate bipolar data set from the GAIN project, demonstrating an example of gene–gene interaction that plays a role in the largely uncharted genetic landscape of bipolar disorder.
Conservation of replication timing reveals global and local regulation of replication origin activity
Authors: Müller Carolin A. , Nieduszynski Conrad A.
Published: July 2012

DNA replication initiates from defined locations called replication origins; some origins are highly active, whereas others are dormant and rarely used. Origins also differ in their activation time, resulting in particular genomic regions replicating at characteristic times and in a defined temporal order. Here we report the comparison of genome replication in four budding yeast species: Saccharomyces cerevisiae, S. paradoxus, S. arboricolus, and S. bayanus. First, we find that the locations of active origins are predominantly conserved between species, whereas dormant origins are poorly conserved. Second, we generated genome-wide replication profiles for each of these species and discovered that the temporal order of genome replication is highly conserved. Therefore, active origins are not only conserved in location, but also in activation time. Only a minority of these conserved origins show differences in activation time between these species. To gain insight as to the mechanisms by which origin activation time is regulated we generated replication profiles for a S. cerevisiae/S. bayanus hybrid strain and find that there are both local and global regulators of origin function.
Effects of G250 promoter controlled conditionally replicative adenovirus expressing Ki67‐siRNA on renal cancer cell
Authors: Liu Junjie , Fang Lin , Cheng Qian , Li Liantao , Su Changqing , Zhang Baofu , Pei Dongsheng , Yang Jie , Li Wang , Zheng Junnian
Published: July 2012

Replication‐competent adenovirus (RCAd) has been used extensively in cancer gene therapy, and tumor‐selection is critical for the use of replication‐competent adenovirus. Here we investigated the anti‐tumor characterization of oncolytic virus, whose E1A gene is under the control of a renal cell carcinoma specific promoter – the G250 promoter. The constructed oncolytic virus G250‐Ki67 is armed with transgene of Ki67‐siRNA, and G250‐ZD55‐Ki67 also with E1B‐55 KD deleted. The tumor‐specific expression of E1A and Ki67 was demonstrated by Western blot and immunohistochemistry staining, and the tumor‐specific cytotoxicity was assessed by crystal violet staining and cell viability assays. The G250‐Ki67 and G250‐ZD55‐Ki67 adenoviruses could express E1A protein in 786‐O and OSRC cell lines but not in ACHN and HK‐2 cell lines. The expression of Ki67 gene in 786‐O and OSRC cell lines were suppressed by these adenoviruses. The cytotoxic effects induced by G250‐ZD55‐Ki67 and G250‐Ki67 were more obvious on the 786‐O cell lines than on the OSRC cell lines. Each group of adenoviruses could inhibit the proliferation of the 786‐O cells and OSRC cells. However, the effects induced by G250‐ZD55‐Ki67 and G250‐Ki67 on 786‐O cells were stronger than on OSRC cells. Moreover, G250‐ZD55‐Ki67 had enhanced antitumor activities in these renal cancer cells compared with G250‐Ki67. G250 promoter‐derived CRAds carrying Ki67‐siRNA could highly amplify and express Ki67‐siRNA in renal cancer cells with expression of G250 antigen, inhibit renal cancer cells proliferation and induce apoptosis. These results demonstrated that the G250‐specific oncolytic adenovirus expressing Ki67‐siRNA is applicable for human renal clear cell cancer therapy.
Prospective effects of traumatic event re‐exposure and post‐traumatic stress disorder in syringe exchange participants
Authors: Peirce Jessica M. , Brooner Robert K. , Kolodner Ken , Schacht Rebecca L. , Kidorf Michael S.
Published: July 2012

Aim

Determine the effect of traumatic event re‐exposure and post‐traumatic stress disorder (PTSD) symptom severity on proximal drug use and drug abuse treatment‐seeking in syringe exchange participants.

Design

Prospective longitudinal 16‐month cohort study of new syringe exchange registrants enrolled in a parent study of methods to improve treatment engagement.

Setting

Data were collected in a research van next to mobile syringe exchange distribution sites in Baltimore, Maryland.

Participants

Male and female (n = 162) injecting drug users (IDUs) registered for syringe exchange.

Measurements

Traumatic event re‐exposure was identified each month with the Traumatic Life Events Questionnaire. PTSD symptoms were measured with the Modified PTSD Symptom Scale–Revised, given every 4 months. Outcome measures collected monthly were days of drug use (heroin, cocaine) and drug abuse treatment‐seeking behavior (interest, calls to obtain treatment, treatment participation).

Findings

Each traumatic event re‐exposure was associated with about 1 more day of cocaine use after accounting for the previous month's cocaine use [same month adjusted B, standard error = 1.16 (0.34); 1 month later: 0.99 (0.34)], while PTSD symptoms had no effect. Traumatic event re‐exposure increased interest in drug abuse treatment [same month adjusted odds ratios with 95% confidence intervals = 1.34 (1.11–1.63)] and calling to obtain treatment [same month 1.58 (1.24–2.01); 1 month later 1.34 (1.03–1.75)]. Each 10% increase in PTSD symptom severity was associated with persistent increased interest in treatment [same month 1.25 (1.10–1.42); 1 month later 1.16 (1.02–1.32); 2 months later 1.16 (1.02–1.32)] and calling to obtain treatment [same month 1.16 (1.02–1.32)]. Neither traumatic events nor PTSD symptoms were associated with participants receiving treatment.

Conclusions

Becoming exposed again to traumatic events among injecting drug users is associated with an increase in cocaine use up to 1 month later, but drug use is not related to post‐traumatic stress disorder symptoms. Both traumatic event re‐exposure and post‐traumatic stress disorder symptoms predict drug abuse treatment‐seeking behavior for up to 2 months.
Development of dependence following treatment with opioid analgesics for pain relief: a systematic review
Authors: Minozzi Silvia , Amato Laura , Davoli Marina
Published: July 2012

Aims

To assess the incidence or prevalence of opioid dependence syndrome in adults (with and without previous history of substance abuse) following treatment with opioid analgesics for pain relief.

Methods

Medline, Embase, CINHAL and the Cochrane Library were searched up to January 2011. Systematic reviews and primary studies were included if they reported data about incidence or prevalence of opioid dependence syndrome (as defined by DSM‐IV or ICD‐10) in patients receiving strong opioids (or opioid‐type analgesics) for treatment of acute or chronic pain due to any physical condition. The data were abstracted, and the methodological quality was assessed using validated checklists.

Results

Data were extracted from 17 studies involving a total of 88 235 participants. The studies included three systematic reviews, one randomized controlled trial, eight cross‐sectional studies and four uncontrolled case series. Most studies included adult patients with chronic non‐malignant pain; two also included patients with cancer pain; only one included patients with a previous history of dependence. Incidence ranged from 0 to 24% (median 0.5%); prevalence ranged from 0 to 31% (median 4.5%).

Conclusions

The available evidence suggests that opioid analgesics for chronic pain conditions are not associated with a major risk for developing dependence.
Neurodevelopmental investigation of the mirror neurone system in children of women receiving opioid maintenance therapy during pregnancy
Authors: Konijnenberg Carolien , Melinder Annika
Published: July 2012

Aims

Opioid maintenance therapy (OMT) is generally recommended for pregnant opioid‐dependent women. Previous studies investigating the long‐term effects of OMT on children's cognitive development found that children of women in OMT have an increased risk of developing deficits in motor and visual perceptual skills, which are important aspects of the mirror neurone system (MNS), a complex neural circuit involved in learning and social interactions. The aim of the current study was to investigate aspects of the MNS in children of women in OMT.

Design

A 2 (control group versus OMT group) × 2 (human versus mechanic) mixed factorial design.

Setting

The Cognitive Developmental Research Unit at the University of Oslo, Norway.

Participants

Fifteen children of women in OMT and 15 non‐exposed children participated.

Measurements

Goal‐directed eye movements were recorded using a Tobii 1750 eye tracker. Neurocognitive tests were employed to map children's cognitive development.

Findings

The OMT group made fewer proactive goal‐directed eye movements [mean = −37.73, standard deviation (SD) = 208.56] compared to the control group (mean = 181.47, SD = 228.65), F(1,28) = 7.53, P = 0.01, η2 = 0.21. No differences were found on tests of visual perception or goal understanding.

Conclusions

Use of opioid maintenance therapy during pregnancy appears to be associated with impaired goal‐directed eye movements in the 4‐year‐old infant which may affect later social adjustment adversely.
The persistence of the association between adolescent cannabis use and common mental disorders into young adulthood
Authors: Degenhardt Louisa , Coffey Carolyn , Romaniuk Helena , Swift Wendy , Carlin John B. , Hall Wayne D. , Patton George C.
Published: July 2012

Aims

Debate continues about whether the association between cannabis use in adolescence and common mental disorders is causal. Most reports have focused on associations in adolescence, with few studies extending into adulthood. We examine the association from adolescence until the age of 29 years in a representative prospective cohort of young Australians.

Design

Nine‐wave, 15‐year representative longitudinal cohort study, with six waves of data collection in adolescence (mean age 14.9–17.4 years) and three in young adulthood (mean age 20.7, 24.1 and 29.1 years).

Participants

Participants were a cohort of 1943 recruited in secondary school and surveyed at each wave when possible from mid‐teen age to their late 20s.

Setting

Victoria, Australia.

Measurements

Psychiatric morbidity was assessed with the Revised Clinical Interview Schedule (CIS‐R) at each adolescent wave, and as Composite International Diagnostic Interview (CIDI)‐defined ICD‐10 major depressive episode and anxiety disorder at 29 years. Frequency of cannabis use was measured in the past 6 months in adolescence. Cannabis use frequency in the last year and DSM‐IV cannabis dependence were assessed at 29 years. Cross‐sectional and prospective associations of these outcomes with cannabis use and dependence were estimated as odds ratios (OR), using multivariable logistic regression models, with the outcomes of interest, major depressive episode (MDE) and anxiety disorder (AD) at 29 years.

Findings

There were no consistent associations between adolescent cannabis use and depression at age 29 years. Daily cannabis use was associated with anxiety disorder at 29 years [adjusted OR 2.5, 95% confidence interval (CI):< 1.2–5.2], as was cannabis dependence (adjusted OR 2.2, 95% CI: 1.1–4.4). Among weekly+ adolescent cannabis users, those who continued to use cannabis use daily at 29 years remained at significantly increased odds of anxiety disorder (adjusted OR 3.2, 95% CI: 1.1–9.2).

Conclusions

Regular (particularly daily) adolescent cannabis use is associated consistently with anxiety, but not depressive disorder, in adolescence and late young adulthood, even among regular users who then cease using the drug. It is possible that early cannabis exposure causes enduring mental health risks in the general cannabis‐using adolescent population.
Screening for human immunodeficiency virus: a survey of British clinical pharmacology units
Authors: THOMSON MARGARET , HAYNES WILLIAM G. , WEBB DAVID J.
Published: July 2012

A survey of screening practices used to detect infection with the human immunodeficiency virus (HIV), covering the 12 months from June 1990 to May 1991, was carried out in 74 clinical pharmacology units performing phase I and II studies. Forty‐five units were identified from the Technomark commercial register, and 29 units were identified from the clinical academic membership of the British Pharmacological Society.

An overall response rate of 92% was obtained: 41 replies from commercial units; 27 replies from academic units. Seventeen commercial units and 26 academic units reported involvement with healthy volunteer studies; these were the 43 questionnaires analysed.

The majority of clinical pharmacology units did not believe that it was necessary to perform HIV screening by HIV antibody testing. Six commercial units (35%) and three academic units (12%) did perform HIV antibody testing in healthy volunteers.

Reasons frequently given for testing were protection of clinical and laboratory staff, and the advantages to the volunteer of prophylaxis and treatment at an early stage of HIV infection. Reasons for not testing included the perceived low risk of a positive test, a lack of benefit from treatment, and the adverse implications in relation to health insurance. Advice from an Ethics Review Committee was not generally a reason for testing.

In future, screening patterns may change, depending on prevalence of HIV positivity in the community, the benefits of diagnosis and treatment, and the perceived or real disadvantages of having an HIV antibody test. For the present, we believe that indirect methods, such as an HIV risks questionnaire, are more appropriate than direct antibody testing.
The pharmacokinetics of oxcarbazepine and its active metabolite 10‐hydroxy‐carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid
Authors: TARTARA A. , GALIMBERTI C. A. , MANNI R. , MORINI R. , LIMIDO G. , GATTI G. , BARTOLI A. , STRADA G. , PERUCCA E.
Published: July 2012

The kinetics of oxcarbazepine (OXC) and its active metabolite 10‐hydroxy‐carbazepine (10‐OH‐CZ) after a single oral OXC dose (600 mg) were compared in healthy control subjects and in epileptic patients treated with phenobarbitone or sodium valproate (n = 8 in each group). In all groups, serum 10‐OH‐CZ concentrations were much higher than those of the parent drug. In patients on valproate, the kinetics of OXC and 10‐OH‐CZ did not differ significantly from those observed in controls. In patients on phenobarbitone, AUC values of both OXC and 10‐OH‐CZ were lower than in controls (2.9 ± 0.4 vs 5.1 ± 0.7 μg ml−1 h and 89 ± 7 vs 119 ± 10 μg ml−1 h respectively, means ± s.e. mean, P < 0.05), whereas 10‐OH‐CZ half‐lives were only marginally shorter (17 ± 1 h vs 20 ± 2 h, NS). These data indicate that the biotransformation of OXC and 10‐OH‐CZ may be accelerated by concomitant treatment with phenobarbitone but that the magnitude of this effect is unlikely to be of great clinical significance.
The personality structure of ‘normal’ volunteers
Authors: BALL CHRISTOPHER J. , McLAREN PAUL M. , MORRISON P. J.
Published: July 2012

The personality structure of 65 volunteers for a Phase 1 drug trial was examined using the Eysenck Personality Questionnaire. It revealed a common pattern of high extroversion, low neuroticism and psychoticism. The reasons why the study might attract such people are examined and the structure compared with those that take drugs that might have ‘strange or dangerous effects’. The likely forms of bias that this personality structure may bring to the trial are explored.
An in vivo assessment of the tobramycin/ticarcillin interaction in cystic fibrosis patients
Authors: ROBERTS GREGORY W. , NATION ROGER L. , JARVINEN ARI O. , MARTIN A. JAMES
Published: July 2012

A non‐blinded, randomized, cross‐over investigation of the pharmacokinetic interaction between tobramycin and ticarcillin was performed in 18 healthy cystic fibrosis (CF) patients with normal renal function. On consecutive mornings the patients were given either tobramycin intravenously (i.v.) over 3–5 min (TOB phase), or tobramycin i.v. over 3–5 min followed immediately by ticarcillin infused i.v. over 20–30 min (TOB+TIC phase). Capillary blood samples were taken 30 min and 330 min after administration of the tobramycin dose in each phase. Tobramycin was measured in serum by fluorescence polarization immunoassay (TDx). There were decreases in serum tobramycin concentrations of 11% at 30 min (P < 0.001) and 330 min (P = 0.012) when measured in the presence of ticarcillin. No difference in elimination half‐life was found (TOB phase 95 ± 13 min, TOB+TIC phase 95 ± 13 min, P = 0.86). The volume of distribution and clearance of tobramycin increased by 14% (P < 0.001) and 13% (P < 0.001), respectively, in the presence of ticarcillin. This interaction appears to be of minor clinical importance but pharmacokinetic studies of tobramycin should exclude concurrent use of ticarcillin.
Computerised psychomotor performance testing: a comparative study of the single dose pharmacodynamics of minaprine and amitriptyline in young and elderly subjects
Authors: KINIRONS M. T. , JACKSON S. H. D. , KALRA L. , TREVIT R. T. , SWIFT C. G.
Published: July 2012

The psychomotor and cardiovascular effects of minaprine 100 mg, a novel antidepressant, were compared with amitriptyline 25 mg, as a positive control, and placebo in a single dose randomised double‐blind crossover trial using an automated psychomotor test battery (APT), postural sway (PS), blood pressure (BP) and pulse in nine young and nine elderly healthy subjects. Analysis of variance, taking into account baseline values, showed that continuous attention test (CAT), critical flicker fusion threshold (CFFT), decision making test (DMT) and paired word association (PWA) were significantly impaired with amitriptyline compared with minaprine and placebo. Minaprine did not differ from placebo. Amitriptyline significantly lowered supine systolic blood pressure (BP) and all treatments produced significant decreases in heart rate in young and elderly. No age effect on psychomotor performance was seen. Minaprine compared favourably with amitriptyline using the APT with the doses used. The APT is useful in the evaluation of new drugs on psychomotor performance.
Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice
Authors: RASHID J. , McKINSTRY C. , RENWICK A. G. , DIRNHUBER M. , WALLER D. G. , GEORGE C. F.
Published: July 2012

Quercetin, a flavonoid present in various fruits, is a potent in vitro inhibitor of CYP3A. Its role in the reported interaction between grapefruit juice and nifedipine has been determined in vivo in humans. Eight healthy volunteers were given in random order 10 mg nifedipine orally, either alone or with 200 ml double strength grapefruit juice, or with 400 mg quercetin. The area under the plasma concentration‐time curve (AUC) for nifedipine with grapefruit juice (mean 320 ng ml−1 h) was increased significantly (P < 0.01) compared with the AUC when nifedipine was given alone (mean 218 ng ml−1 h). The time to peak plasma concentration for nifedipine with grapefruit juice (1.5 h) was also increased (P < 0.05) compared with control (0.5 h) suggesting delayed absorption. Although quercetin delayed the time to peak nifedipine concentration (1.3 h) it did not alter the AUC of either the parent drug (mean 209 ng ml−1 h) or its first‐pass metabolite. The results suggest that quercetin does not contribute to the effects of grapefruit juice (which contains <10 mg of quercetin 200 ml−1) on the metabolism of nifedipine. Oral doses of quercetin, similar to those possible from the ingestion of other fruits such as strawberries, do not produce in vivo inhibition of CYP3A mediated metabolism of nifedipine.
Drug utilization and clinical pharmacology Report on British Pharmacological Society Symposium at Trinity College Dublin on Thursday, 9th July, 1992
Authors: FEELY JOHN
Published: July 2012

The insatiable appetite for safer more effective, but increasingly more expensive, therapy in the face of increasing government reluctance to feed this demand has put the study of drug utilization and pharmacoeconomics centre stage. Clinical pharmacologists are uniquely positioned to determine the cost benefit and utility of modern therapy and give impartial advice on safe, effective and economic patient care. To mark the Quatercentenary Celebrations of Trinity College Dublin, eight speakers addressed this theme in a symposium held in conjunction with the British Pharmacological Society Meeting in July 1992.
Vigabatrin‐induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability
Authors: GATTI G. , BARTOLI A. , MARCHISELLI R. , MICHELUCCI R. , TASSINARI C. A. , PISANI F. , ZACCARA G. , TIMMINGS P. , RICHENS A. , PERUCCA E.
Published: July 2012

The possibility that vigabatrin (VGB) decreases serum phenytoin (PHT) concentration by lowering the oral bioavailability of PHT was investigated in 21 patients with epilepsy. Each patient was switched from oral to intravenous PHT for 5 days before and after combined treatment with VGB. After VGB (2−3.5 g day−1 for at least 5 weeks), serum PHT concentrations decreased slightly from 87 ± 25 to 76 ± 31 μmol 1−1 (means ± s.d., P < 0.05), but in a subgroup of seven patients the decrease was more prominent (from 72 ± 22 to 49 ± 17 μmol 1−1 P < 0.005). At baseline (before VGB), serum PHT remained unaffected (85 ± 30 μmol 1−1) after switching PHT dosage to the intravenous route, indicating that the oral availability of the drug was virtually complete. During VGB treatment, serum PHT was also unchanged (74 ± 34 μmol 1−1) after switching from oral to intravenous therapy, and this was also true for the subgroup of patients showing a prominent interaction (48 ± 18 μmol l−1). The urinary recoveries of PHT and its metabolites pHPPH and mHPPH remained constant throughout the study. It is concluded that the oral availability of PHT is unaffected by VGB and that the VBG‐induced decrease in serum PHT is mediated by alternative mechanisms.
Frusemide causes acute increases in lipid concentrations
Authors: CAMPBELL NORMAN R. C. , WICKERT WAYNE A. , SHUMAK STEVEN L.
Published: July 2012

In a randomized double‐blind placebo controlled parallel study involving fourteen healthy male volunteers, we examined whether the acute reduction in vascular volume associated with frusemide ingestion would haemoconcentrate lipid particles. Three hours after a single 40 mg oral dose of frusemide, there were 9.6–14.4% increases in lipids and lipoproteins which were highly correlated to changes in body weight. Until further studies determine the extent of haemoconcentration in patients being treated long term with frusemide, we recommend that blood be drawn for lipid analysis prior to frusemide ingestion.
Disagreement between standard transthoracic impedance cardiography and the automated transthoracic electrical bioimpedance method in estimating the cardiovascular responses to phenylephrine and isoprenaline in healthy man.
Authors: de Mey C , Enterling D
Published: July 2012

1. Impedance cardiography is a well‐established noninvasive method to assess within‐subject changes of cardiovascular function. We compared the standard approach (ZCG) which requires tedious signal analysis with an automated approach (TEB: NCCOM 3) with its own specific equipment, algorithms and equations in order to assess agreement of the method‐ specific measurements and calculations. 2. Ten healthy men were studied on two occasions with either ZCG or TEB, at rest and at the end of 5 min i.v.‐infusions with 1 microgram min‐1 isoprenaline and 100 micrograms min‐1 phenylephrine. 3. There was good agreement for the method‐independent changes (HR, SBP/DBP), but there were large differences for method‐specific measurements: dZ/dtmax [TEB‐ZCG] = ‐ 0.68, CI: ‐0.83 to ‐0.53 ohm s‐1, PEP [TEB‐ZCG] = ‐22.1, CI: ‐35.0 to ‐ 9.2 ms and QS2c [TEB‐ZCG] = ‐16.5, CI: ‐32.4 to ‐0.6 ms and for the calculated stroke volume SV [TEB‐ZCG] = 30.3, CI: 15.5 to 45.2 ml. The responses of dZ/dtmax and SV to isoprenaline and phenylephrine, although qualitatively similar, reached no quantitative agreement either. A substantial disagreement was evident for the STI responses to isoprenaline where TEB failed to detect the expected reduction of VETc and thus grossly underestimated the shortening of QS2c. 4. It is concluded that TEB‐measurements and ‐calculations did not agree with standard ZCG, that the methods, albeit related, cannot be considered as interchangeable and that suspicion is justified that TEB might yield erroneous results under specific circumstances.
Partial mediation by nitric oxide of the relaxation of human isolated detrusor strips in response to electrical field stimulation.
Authors: James MJ , Birmingham AT , Hill SJ
Published: July 2012

1. A method for reproducing relaxation of human isolated detrusor smooth muscle in vitro in response to electrical field stimulation is described. 2. The parameters of stimulation associated with relaxation were those which would be expected to give a largely nerve‐mediated response: the relaxations were not reduced by tetrodotoxin (3 × 10(‐7) M) and were therefore not dependent on voltage sensitive sodium channels. 3. The relaxations were decreased (mean 74.1%) by nitro L‐ arginine (NOARG, 10(‐5) M). 4. Methylene blue (10(‐5) M), an inhibitor of soluble guanylate cyclase, abolished the relaxations. 5. These results indicate that there may be a relaxation mechanism in the human bladder which is at least partly mediated via the production of nitric oxide.
A comparison of the potassium and magnesium‐sparing properties of amiloride and spironolactone in diuretic‐treated normal subjects.
Authors: Murdoch DL , Forrest G , Davies DL , McInnes GT
Published: July 2012

1. The relative potencies of amiloride (5 and 20 mg) and spironolactone (25 and 100 mg) for plasma and erythrocyte electrolytes were investigated in a double‐blind, randomised, balanced, crossover study in 12 normal men treated concomitantly with hydrochlorothiazide 100 mg daily for 1 week. 2. Participants satisfied an a priori requirement for a fall in plasma potassium concentration of at least 0.5 mmol l‐1 after 7 days of treatment with hydrochlorothiazide alone. 3. After hydrochlorothiazide alone, plasma potassium and sodium concentrations fell (P < 0.001). There were associated reductions in erythrocyte sodium (P < 0.01). Plasma magnesium concentration did not change, although erythrocyte magnesium decreased (P < 0.001). 4. Both amiloride and spironolactone attenuated the thiazide‐induced fall in plasma potassium (relative potency, amiloride:spironolactone 10:1, 95% confidence interval 6.3‐16.2:1). Amiloride but not spironolactone was associated with a dose‐related increase in plasma magnesium; a relative potency estimation was precluded. There was little evidence of influences of amiloride or spironolactone on erythrocyte electrolytes. 5. On a weight basis, amiloride is ten times more potent than spironolactone as a potassium‐sparing agent in diuretic‐treated subjects but neither agent had major effects on erythrocyte potassium. The drugs may have divergent actions on magnesium handling; hydrochlorothiazide alone had no influence on plasma magnesium.
Defining small differences in efficacy between anti‐parkinsonian agents using gait analysis: a comparison of two controlled release formulations of levodopa/decarboxylase inhibitor.
Authors: Weller C , O'Neill CJ , Charlett A , Bowes SG , Purkiss A , Nicholson PW , Dobbs RJ , Dobbs SM
Published: July 2012

1. Stride length is highly relevant to mobility and is sensitive to the effects of levodopa in Parkinsonism. Its selection as the primary outcome criterion allowed comparison of two levodopa/decarboxylase inhibitor formulations using a small number of subjects. 2. It is also desirable to improve stability. An instrumental method, based on infrared telemetry, has been developed which obtains both distance/time measures of gait and broadness of base, as measured by foot separation at mid‐swing. The latter was used as a subsidiary outcome criterion. 3. Nine patients (aged 57 to 77 years) then receiving maintenance therapy for idiopathic Parkinsonism with Sinemet CR alone, but who had previously experienced end of dose effect within 4 h of receiving a dose of a conventional formulation of levodopa/decarboxylase inhibitor, were studied. 4. They received, in random order and at least 4 days apart, single doses of one tablet of Sinemet CR (200 mg levodopa/50 mg carbidopa) and of two capsules of Madopar CR (each 100 mg levodopa/25 mg benserazide), with placebo balance, at 10.00 h. Gait analysis was carried out immediately before and half‐hourly for 7 h after a challenge. No routine doses of Sinemet CR were taken between 22.00 h on the night before and 17.00 h on the day of a challenge. 5. Analysis of variance showed a highly significant difference in mean stride length (P < 0.001) and in mean foot separation (P = 0.01) between serial time points, irrespective of the nature of treatment. There appeared to be a useful therapeutic response to both challenges.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man.
Authors: Fuhr U , Klittich K , Staib AH
Published: July 2012

1. The effects of grapefruit juice and naringenin on the activity of the human cytochrome P450 isoform CYP1A2 were evaluated using caffeine as a probe substrate. 2. In vitro naringin was a potent competitive inhibitor of caffeine 3‐demethylation by human liver microsomes (Ki = 7‐ 29 microM). 3. In vivo grapefruit juice (1.2 l day‐1 containing 0.5 g l‐ 1 naringin, the glycone form of naringenin) decreased the oral clearance of caffeine by 23% (95% CI: 7%‐30%) and prolonged its half‐ life by 31% (95% CI: 20%‐44%) (n = 12). 4. We conclude that grapefruit juice and naringenin inhibit CYP1A2 activity in man. However, the small effect on caffeine clearance in vivo suggests that in general the ingestion of grapefruit juice should not cause clinically significant inhibition of the metabolism of other drugs that are substrates of CYPIA2.
The pharmacokinetics of intravenous ondansetron in patients with hepatic impairment.
Authors: Blake JC , Palmer JL , Minton NA , Burroughs AK
Published: July 2012

The pharmacokinetics of the 5‐HT3 receptor antagonist ondansetron were investigated following a single 8 mg intravenous dose given over 5 min in 19 patients with varying degrees of hepatic impairment and in six young healthy subjects. In comparison with the healthy controls, the patients with severe hepatic impairment had a lower mean plasma clearance (96 ml min‐1 vs 478 ml min‐1) and increased AUC (1383 ng ml‐1 h vs 279 ng ml‐1 h) and t1/2 (21 h vs 3.6 h). These differences were all statistically significant (P < 0.001). The corresponding values for patients with mild or moderate hepatic impairment fell between these extremes. Vss was greater in all patient groups than the control group, but the magnitude of the change was smaller than for the other parameters and did not reflect the increasing severity of hepatic impairment. There were no significant changes in Cmax. There were no drug‐related adverse events in the patients studied. It is recommended that the dosing frequency of ondansetron be limited to once daily in patients with severe hepatic impairment.
The use of proprietary medicines by patients presenting with peptic ulcer haemorrhage.
Authors: Marriott JF , Asquith PA , Shorrock CJ
Published: July 2012

1. Medication, social and symptom histories were compared in patients with severe haemorrhage from a peptic ulcer (n = 71) and matched control subjects. Self‐medication with proprietary agents was catalogued in addition to therapy prescribed by general medical practitioners. 2. Prior to the bleed, only 4% of ulcer patients had been free of symptoms normally associated with peptic ulceration, whereas 76% of the control group had been asymptomatic. 3. Gastro‐ irritant proprietary medicines were used regularly by 23% of ulcer patients compared with only 4% of controls. However, proprietary antacids were used chronically by 46% of ulcer patients compared with only 7% of controls. Bicarbonate was the antacid of choice used by 13% of ulcer patients. The odds ratio for the association between development of bleeding peptic ulcer and the use of indigestion remedies was 11.5% (95% CI 1.1, 121). 4. Fifty‐one percent of ulcer patients were prescribed agents known to cause gastro‐intestinal damage, whereas only 25% of the control group were prescribed similar agents. Only 7% of the control group were prescribed anti‐ulcer therapy compared with 37% of those with bleeding ulcer. 5. A large proportion of patients with haemorrhage from a peptic ulcer had had symptoms sufficient to warrant recourse to self‐medication with antacids without medical knowledge. Exacerbation of peptic ulcer by self‐medication with proprietary products is likely to be of lesser significance.
Plasma concentrations and ocular effects of cyclopentolate after ocular application of three formulations.
Authors: Lahdes K , Huupponen R , Kaila T , Monti D , Saettone MF , Salminen L
Published: July 2012

1. Eight volunteers received in randomized order two 30 microliters drops of either 1% w/v cyclopentolate hydrochloride or a corresponding amount of cyclopentolate polygalacturonate in saline or in acetate buffer in one eye. Cyclopentolate concentrations in plasma were measured by a radioreceptor assay. 2. Peak plasma drug concentrations of about 3 ng ml‐1 occurred within 30 min after all formulations. Occasionally, a second concentration peak in plasma, probably reflecting drug absorption from the gastrointestinal tract, was seen after 2 h. The mean elimination half‐life of cyclopentolate was 111 min when all subjects and formulations were considered together. There were no statistically significant differences between the formulations with respect to the time‐course of plasma drug concentration. 3. The maximal mydriatic effect was reached within about 15 min and was maintained for several hours, often being 1/3 of its peak value after 30 h. Similarly, an intense cycloplegic response was achieved within a few minutes, the peak changes in the near‐point of vision being 9 to 10 dioptres. The cycloplegic response was more intense after one of the polygalacturonate complexes, especially at later time points.
The effect of captopril on the superior mesenteric artery and portal venous blood flow in normal man.
Authors: Ray‐Chaudhuri K , Thomaides T , Maule S , Watson L , Lowe S , Mathias CJ
Published: July 2012

1. Measurements of superior mesenteric artery and portal venous blood flow were made non‐invasively along with systemic and other regional (cardiac index, forearm and cutaneous blood flow) vascular responses to acute ingestion of the ACE inhibitor captopril (50 mg) or placebo (50 mg vitamin C), in 12 healthy subjects while supine and during head‐up tilt. 2. After captopril, superior mesenteric artery and portal blood flow rose markedly with a reduction in superior mesenteric artery vascular resistance. Supine blood pressure was unchanged but cardiac index and forearm blood flow rose; during head‐up tilt, blood pressure fell in some subjects. 3. There was a rise in levels of plasma renin activity and a fall in levels of plasma angiotensin II after captopril. After placebo, there were no significant changes in splanchnic blood flow, systemic or other regional responses and in biochemical measurements, while supine. 4. Our studies indicate that captopril is a potent dilator of the splanchnic vascular bed and suggest that this action may contribute to its therapeutic effects. The studies indicate a role for angiotensin II in the control of this large vascular bed although other agents (bradykinin, prostacyclin) may contribute.
The treatment of heart failure—what next?
Authors: Davies RH , Sheridan DJ
Published: July 2012

1. Despite demonstrable benefits in terms of symptomatic relief and improvement in prognosis, even the best treatments of heart failure currently available fall short of being ideal. We review the basis for newer approaches to the treatment of heart failure and discuss some of the agents which capitalize on current understanding of the underlying patho‐physiology. 2. Several drugs, old and new, are presently being investigated by major clinical trials. We also consider some of the difficulties related to the design and conduct of such trials and suggest how drugs might be better assessed in the future.
Effects of terbutaline on basal thermogenesis of human skeletal muscle and Na‐K pump after 1 week of oral use—a placebo controlled comparison with propranolol.
Authors: Fagher B , Liedholm H , Sjogren A , Monti M
Published: July 2012

1. A double‐blind placebo‐controlled study was conducted on the effects of oral terbutaline (beta 2‐adrenoceptor agonist) and propranolol (beta 1 beta 2‐adrenoceptor antagonist) on basal heat production of skeletal muscle, measured ex vivo by direct microcalorimetry. Terbutaline slow‐ release 7.5 mg, propranolol 80 mg, and matching placebo were randomly administered twice daily for 1 week to 15 healthy males, using a cross‐ over design. 2. Resting heat production in biopsied vastus lateralis was lowered by median 27% (P < 0.01) after terbutaline medication as compared with placebo. The cause of this hypometabolism at the cellular level is obscure but may possibly be explained by desensitization of beta 2‐receptors. 3. Propranolol decreased the metabolic rate by 17% (P > 0.3); this might imply that the sympathetic nervous system is playing only a minor role in the regulation of basal metabolic rate in muscle, or that up‐regulation of beta‐receptors had influenced the decline. 4. The muscle utilized about 6% of its total energy for the Na‐K pump as assessed after inhibition by ouabain. 5. Serum potassium was significantly lowered by terbutaline and slightly increased by propranolol with no relationship between changes in extracellular levels and muscle content of potassium under resting conditions. Energy values for the Na‐K pump in muscle after 1 week of terbutaline or propranolol medication were similar to placebo. The results are not consistent with the hypothesis that decreased serum potassium during continuous beta 2‐adrenoceptor agonist treatment is due to a chronically activated Na‐K pump, at least not in resting muscle.