bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statin therapy and myocardial no‐reflow
Authors: Calvert J W , Lefer D J 
Published: August 2006

HMG‐CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through lipid lowering actions. However, it has now become increasingly clear that the beneficial effects of statins are not related to the lipid lowering effects, but rather to a number of pleiotropic actions. Of particular interest, statins have been shown to increase bioavailability of nitric oxide and protect against vascular inflammation and cardiac cell death in a number of cardiovascular disease states. In this present issue of the British Journal of Pharmacology, Zhao and colleagues provide a novel mechanism of action for statins with the observation that simvastatin reduces myocardial ‘no‐reflow’ after ischemia and reperfusion by activating the mitochondrial KATP channel. The findings of the present study have very profound implications for the treatment of cardiovascular disease. This commentary discusses the implications of these findings and how they relate to the established cardioprotective actions of statins.British Journal of Pharmacology (2006) 149, 229–231. doi:10.1038/sj.bjp.0706863
Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents
Authors: De Bellis M , De Luca A , Rana F , Cavalluzzi M M , Catalano A , Lentini G , Franchini C , Tortorella V , Conte Camerino D 
Published: August 2006

Background and purpose:Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites.Experimental approach:To determine their contribution to the clinical activity of Mex,p‐hydroxy‐mexiletine (PHM), hydroxy‐methyl‐mexiletine (HMM),N‐hydroxy‐mexiletine (NHM) (phase I reaction products) andN‐carbonyloxyβ‐D‐glucuronide (NMG) (phase II reaction product) were tested on sodium currents (INa) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP=−140, −100, −70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline‐gap voltage‐clamp method.Key results:All the hydroxylated derivatives blocked the sodium channel in a voltage‐ and use‐dependent manner. The PHM, HMM and NHM metabolites were up to 10‐fold less effective than the parent compound. However, HMM showed a greater use‐dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound.Conclusions and Implications:Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.British Journal of Pharmacology(2006)149, 300–310. doi:10.1038/sj.bjp.0706867
Tramadol, but not its major metabolite (mono‐O‐demethyl tramadol) depresses compound action potentials in frog sciatic nerves
Authors: Katsuki R , Fujita T , Koga A , Liu T , Nakatsuka T , Nakashima M , Kumamoto E 
Published: August 2006

Background and purpose:Although tramadol is known to exhibit a local anaesthetic effect, how tramadol exerts this effect is not understood fully.Experimental approach:The effects of tramadol and its metabolite mono‐O‐demethyl‐tramadol (M1) on compound action potentials (CAPs) were examined by applying the air‐gap method to frog sciatic nerves, and the results were compared with those of other local anaesthetics, lidocaine and ropivacaine.Key results:Tramadol reduced the peak amplitude of the CAP in a dose‐dependent manner (IC50=2.3 mM). On the other hand, M1 (1–2 mM), which exhibits a higher affinity forμ‐opioid receptors than tramadol, did not affect CAPs. These effects of tramadol were resistant to the non‐selective opioid receptor antagonist naloxone and theμ‐opioid receptor agonist, DAMGO, did not affect CAPs. This tramadol action was not affected by a combination of the noradrenaline uptake inhibitor, desipramine, and the 5‐hydroxytryptamine uptake inhibitor, fluoxetine. Lidocaine and ropivacaine also concentration‐dependently reduced CAP peak amplitudes with IC50values of 0.74 and 0.34 mM, respectively.Conclusions and implications:These results indicate that tramadol reduces the peak amplitude of CAP in peripheral nerve fibres with a potency which is less than those of lidocaine and ropivacaine, whereas M1 has much less effect on CAPs. This action of tramadol was not produced by activation ofμ‐opioid receptors nor by inhibition of noradrenaline and 5‐hydroxytryptamine uptake. It is suggested that the methyl group present in tramadol but not in M1 may play an important role in producing nerve conduction block.British Journal of Pharmacology(2006)149, 319–327. doi:10.1038/sj.bjp.0706868
Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin
Authors: Choi Y H , Lee M G 
Published: August 2006

Background and purpose:The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats.Experimental approach:Metformin at a dose of 100 mg kg−1was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3‐methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF‐525 (a non‐specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time‐averaged non‐renal clearance (CLNR) of metformin was compared with that of controls.Key results:In rats pretreated with dexamethasone, the CLNRwas significantly faster (57% increase) than for the controls. In rats pretreated with SKF‐525‐A, sulfaphenazole, quinine, and troleandomycin, the CLNRwas significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNRvalues did not significantly different in the rats pretreated with 3‐methylencholanthrene, orphenadrine, and isoniazid compared with the controls.Conclusions and implications:Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.British Journal of Pharmacology(2006)149, 424–430. doi:10.1038/sj.bjp.0706875
Identification of Thr283 as a key determinant of P2X7 receptor function
Authors: Young M T , Pelegrin P , Surprenant A 
Published: August 2006

Background and purpose:The ATP‐gated P2X7 receptor is an unusual ion channel that couples to multiple downstream signalling cascades. We noted differences in mouse cDNA sequences that may indicate polymorphisms; the aim of this study was to compare function and expression of these mouse P2X7 receptor mutations.Experimental approach:There are three differences in the sequences of P2X7 cDNA cloned from mouse NTW8 microglial cells or C57 BL/6 mice: [Phe11,Ala221,Met283]P2X7 in the former and [Leu11,Thr221,Thr283]P2X7 in the latter. We expressed these receptors and measured membrane currents, ethidium uptake, calcium influx and surface membrane expression. We also carried out these assays on the previously described polymorphism observed between C57 BL/6 and Balb/c mice ([Leu451]P2X7 vs [Pro451]P2X7).Key results:Maximum current densities at [Phe11,Ala221,Met283]P2X7 were <12% of those at [Leu11,Thr221,Thr283]P2X7 without change in the agonist concentration‐response. Replacing methionine with threonine at residue 283 yielded a receptor whose properties were the same as [Leu11,Thr221,Thr283]P2X7. Replacing T283 in the rat P2X7 receptor with methionine yielded currents that were <10% of wildtype and no ethidium uptake was associated with its activation. Maximum current densities and agonist EC50 values were the same at mouse [Thr283,Leu451]P2X7 and [Thr283,Pro451]P2X7 but ethidium uptake and Fluo4 fluorescence were significantly reduced at the [Thr283,Leu451]P2X7 receptor. There was equivalent surface membrane expression of all P2X7 receptors.Conclusions:This study has revealed a residue (Thr283) in the ectodomain that is critical for P2X7 receptor function and suggests that the intracellular residue 451 alters downstream signalling independently of ion channel activity.British Journal of Pharmacology (2006) 149, 261–268. doi:10.1038/sj.bjp.0706880
The role of area enclosures and fallow age in the restoration of plant diversity in northern Ethiopia
Authors: Abebe Muluberhan Hailu , Oba Gufu , Angassa Ayana , Weladji Robert B. 
Published: August 2006

AbstractThis study investigated the roles played by area enclosures and fallow age in the restoration of plant species richness and soil seed bank species richness in degraded mountain rangelands in northern Ethiopia. Management types (enclosures versus grazed) influenced woody and herbaceous species richness, while fallow age showed no effect on the woody species. Management, age and the doubling of fallow age influenced the herbaceous species richness and species diversity. Management showed no effect on soil seed bank species richness. Fallow age and the doubling of fallow time also showed no influence on the soil seed bank of grass species, but they were influential on the forbs species soil seed bank. The trends for restoration of plant species richness and diversity and grass seed bank in response to fallow age were positive‐linear, but they declined when the fallow ages were doubled. The exception was the forbs seed bank showed linear trends when age of restoration was doubled. The data suggest that the restoration of degraded rangelands in the high mountain zones of northern Ethiopia was still in the weedy succession stages. Long‐term monitoring will be required to gain an informed understanding of the roles played by area enclosures and fallow age in the restoration of plant biodiversity.
Influence of soil fertility on the physiognomy of the African savanna tree Colophospermum mopane
Authors: Mlambo Donald 
Published: August 2006

AbstractThis study investigated the influence of soil fertility on the physiognomy of Colophospermum mopane, one of the dominant tree or shrub species in savannas of central and southern Africa. The study was conducted in Gonarezhou National Park (GNP) in the south‐east of Zimbabwe. Mopane stands at the study site were divided into three physiognomic forms or mopane ‘types’: short mopane (SM, 1–2 m in height); medium mopane (MM, 8–12 m) and tall mopane (TM, >15 m). In each mopane type, soil samples were collected up to a depth of 15 cm to investigate the level of soil nutrient concentrations. SM stands were associated with low phosphorus and high levels of calcium and sodium relative to MM and TM. The low levels of phosphorus in SM relative to other mopane types suggest that phosphorus may be an important nutrient limiting growth in dwarf mopane. Alternatively, plant nutrients may be limiting because of interaction with factors such as the high soil sodicity present in the dwarf mopane habitats that may affect nutrient uptake or plant nutrient demand.
Platelet mass has prognostic value in patients with myelodysplastic syndromes
Authors: Bowles Kristian M. , Warner Brian A. , Baglin Trevor P. 
Published: August 2006

SummaryPlatelet mass (mean platelet volume × platelet count) can be derived from data obtained from the routine full blood count and separates patients with myelodysplastic syndromes (MDS) at diagnosis into three distinct prognostic groups: low platelet mass group – median survival 5 months and 5‐year survival 0%; intermediate platelet mass group – median survival 30 months and 5‐year survival 34%; high platelet mass group median survival – not reached at 82 months follow‐up with a 5‐year survival of 82%. These data provide a simple rapid prognostic index at the time of diagnosis in MDS.
Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell‐line HepG2 induced by thalassaemic sera
Authors: Weizer‐Stern Orly , Adamsky Konstantin , Amariglio Ninette , Levin Carina , Koren Ariel , Breuer William , Rachmilewitz Eliezer , Breda Laura , Rivella Stefano , Ioav Cabantchik Z. , Rechavi Gideon 
Published: August 2006

Summary β‐Thalassaemia represents a group of diseases, in which ineffective erythropoiesis is accompanied by iron overload. In a mouse model of β‐thalassaemia, we observed that the liver expressed relatively low levels of hepcidin, which is a key factor in the regulation of iron absorption by the gut and of iron recycling by the reticuloendothelial system. It was hypothesised that, despite the overt iron overload, a putative plasma factor found in β‐thalassaemia might suppress liver hepcidin expression. Sera from β‐thalassaemia and haemochromatosis (C282Y mutation) patients were compared with those of healthy individuals regarding their capacity to induce changes the expression of key genes of iron metabolism in human HepG2 hepatoma cells. Sera from β‐thalassaemia major patients induced a major decrease in hepcidin (HAMP) and lipocalin2 (oncogene 24p3) (LCN2) expression, as well as a moderate decrease in haemojuvelin (HFE2) expression, compared with sera from healthy individuals. A significant correlation was found between the degree of downregulation of HAMP and HFE2 induced by β‐thalassaemia major sera (r = 0·852, P < 0·0009). Decreased HAMP expression was also found in HepG2 cells treated with sera from β‐thalassaemia intermedia patients. In contrast, the majority of sera from hereditary haemochromatosis patients induced an increase in HAMP expression, which correlated with transferrin (Tf) saturation (r = 0·765, P < 0·0099). Our results suggest that, in β‐thalassaemia, serum factors might override the potential effect of iron overload on HAMP expression, thereby providing an explanation for the failure to arrest excessive intestinal iron absorption in these patients.
Denis Burkitt and his contribution to haematology/oncology
Authors: Coakley Davis 
Published: August 2006

SummaryDenis Burkitt was motivated by Christian Evangelism from his early years. It was a critical factor not only in his personal development and decision to work in Uganda, but also in his medical achievements. The events in his life which led to his description of Burkitt lymphoma in 1958 are described together with his discovery of the endemic nature of the condition and its treatment. His research on the aetiology of the condition is also described. The endemic form of the lymphoma is still a major cause of childhood mortality in Africa due to a lack of basic resources to treat the condition. Burkitt Lymphoma has been used as a model to advance research and treatment on a wide range of conditions in haematology and oncology. Burkitt's work in later life on dietary fibre and its implications are summarised.
α+‐Thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea
Authors: O'Donnell A. , Raiko A. , Clegg J.B. , Weatherall D.J. , Allen S.J. 
Published: August 2006

SummaryThe effect of maternal α+‐thalassaemia on pregnancy was assessed in the north coastal region of Papua New Guinea (PNG), where malaria is hyperendemic and α+‐thalassaemia is extremely common. In a prospective study of 987 singleton hospital deliveries, we correlated maternal α‐globin genotype with markers of reproductive fitness (age in primigravidae, gravidity, pregnancy interval and the number of miscarriages and stillbirths), Plasmodium falciparum(P. falciparum) infection of the mother and placenta, maternal haemoglobin, preterm delivery and birthweight. The frequency of the −α genotype in mothers was 0·61. Markers of reproductive fitness were similar in women with and without α+‐thalassaemia. Median haemoglobin concentration during pregnancy and after delivery was about 1·0 g/dl lower in homozygous α+‐thalassaemia than in women with a normal α‐ globin genotype (P ≤ 0·001). The frequency of placental P. falciparum infection and systemic malaria infection after delivery showed no consistent relationship to α‐globin genotype. The frequency of preterm delivery and low birthweight did not vary significantly according to maternal α‐globin genotype. Maternal α+‐thalassaemia does not affect reproductive fitness or susceptibility to malaria during pregnancy. Although median haemoglobin concentration was significantly lower in mothers homozygous for α+‐thalassaemia than those with a normal α‐globin genotype, this did not result in an adverse outcome of pregnancy.
P‐12 A RETROSPECTIVE AUDIT OF FINE NEEDLE ASPIRATION CYTOLOGY OF PANCREAS
Authors: Lynch M. A. , Rana D. N. , Charan V. , Desai M. 
Published: August 2006

Background:  Fine needle aspiration cytology (FNAC) of pancreas is a widely accepted method of diagnosis of pancreatic mass lesions. We have performed a retrospective analysis of all radiological (CT/ultrasound) and endoscopic ultrasound guided procedures at our institution.Aim:  (1) To review the results of FNAC of pancreas from January 2000 to April 2006. (2) To calculate the inadequate rate. (3) To account for discrepancies between the cytological and histological diagnoses. (4) To identify any false positive cases if present.Method:  The results of all pancreatic FNAC reported at our institute from January 2000 to April 2006 were identified from the laboratory system. All results were classified as follows: Inadequate, inconclusive, benign, suspicious and malignant. The results were further categorised depending on whether they were CT/ultrasound guided or EUS guided. The histological diagnosis where available was used as the gold standard and where discrepancies were present the cytological preparations were reviewed.Results:  Seventy‐three patients underwent pancreatic FNAC during the study period. Table 1 illustrates our results.

Number
Inadequate
Inconclusive
Benign
Suspicious
Malignant

CT/US
53
8 (11%)
1(1%)
17(23%)
6(8%)
21(29%)

Endoscopic ultrasound
20
1 (1%)
2(3%)
14(19%)
1(1%)
2(3%)

Total
73
9 (12%)
3(4%)
31(42%)
7(10%)
23(32%)

Three false negative cases where a later histological diagnosis of malignancy was present contained no diagnostic cellular material. To date no false positive diagnosis has occurred and all patients with malignant diagnosis have died except those diagnosed in the last 6 months.Conclusion:  Pancreatic FNAC is a useful procedure in the majority of cases at our institute. Our inadequate/inconclusive rate is low. In fact our analysis shows that the inadequate rate for EUS guided FNAC pancreas is only 5% despite the fact that on site assessment of adequacy is not yet carried out. This is in a small group of patients however. No false positive diagnosis was identified. Discrepancies between cytological and histological diagnosis have been due to unrepresentative samples. We intend to proceed with on site assessment of adequacy in future cases. We will continue to review all cases where pancreatic FNA is carried out at our weekly pancreatic/hepatobiliary clinicopathological multidisciplinary team meeting and within our department at peer review meetings.
P‐13 CERVICAL SMEAR REPORTING IN NORTHERN IRELAND SLE PATIENTS
Authors: McHenry M. T. , Clarke R. , Anderson N. , Bell A. L. 
Published: August 2006

Introduction:  SLE is an autoimmune disease with the potential for multi‐organ involvement. It has been suggested that SLE patients may be at increased risk of cervical dysplasia. We studied a cohort of Northern Ireland Lupus patients and compared them to controls within the same geographical location assessing their cervical smear histories and performing an up‐to‐date cervical smear.Methods:  A total of 141 SLE patients fulfilling the ACR criteria for lupus were enrolled into the study. They were compared to 138 control patients who were due to attend for a routine cervical smear within the same geographical location. Each patient gave written consent to be involved in the study including access to medical records and pathology data.Results:

Cervical Smear report
SLE n = 141
Controls n = 138

Unsuitable
5.7% (8/141)
9.4% (13/138)

Low grade
15.6% (22/141)
10.9% (15/138)

High grade
4.3% (6/141)
2.2% (3/138)

Life time occurrence of any abnormal cervical smear
41.8% (59/141)
29% (40/138)

Discussion:  Latest cervical smear reports between the two groups showed an increase in low‐grade and high‐grade cervical smear abnormalities in the SLE group. SLE patients appear to have an increased rate of lifetime occurrence of abnormal smear. The control group of patients were younger than SLE patients and when this was taken into consideration using logistic binary regression to correct for co‐variates the risk of lupus patients having an abnormal smear history compared to controls became highly significant RR 2.53 (1.44–4.43) P = 0.001.
P‐16 DEFAULT FROM CYTOLOGICAL SURVEILLANCE OF LOW‐GRADE SMEARS: LEVELS OF DEFAULT AND CHARACTERISTICS OF DEFAULTERS IN THE TRIAL OF MANAGEMENT OF BORDERLINE AND OTHER LOW‐GRADE ABNORMAL SMEARS (TOMBOLA)
Authors: Thornton A. J. , Cotton S. C. , Sharp L. , Gray N. M. , Smart L. M. 
Published: August 2006

Introduction:  We report levels of default in women with low‐grade cytological abnormalities managed by cytological surveillance and identify factors associated with default.Method:  TOMBOLA is an RCT comparing cytological surveillance (repeat smears every 6 months in primary care) with hospital‐based colposcopy in women with a low‐grade smear. TOMBOLA recruits were aged 20–59, with a recent mild or borderline smear, plus up to one previous borderline smear, detected within the NHS‐CSPs. This analysis includes 2224 women randomised to cytological surveillance. Default was defined as non‐attendance within 6 months of each surveillance smear being due.Results:  11% (95% CI 9.3–12.0) of women defaulted from the first surveillance smear. 13% (11.0–14.1) of those having a first surveillance smear defaulted from the second. 14% (12.1–15.5) of those having a second surveillance smear defaulted from the third. The median time from the recruitment smear to the first surveillance smear was 7 months (interquartile range 6–8 months). In univariate analyses, at each surveillance smear, younger women were more likely to default (first smear: 16% aged 20–29 versus 2% aged 50–59). Default was slightly higher among women with a mild (12% for first smear) than a borderline (10%) recruitment smear. For the first surveillance smear, women with a college/university degree were less likely (7%) than those without a degree (11%) to default, but this difference was not apparent for subsequent smears. For the first and second surveillance smears, default was higher among smokers than non‐smokers. Multivariate analyses of these and other sociodemographic factors will be presented.Conclusions:  Default was 11% from the first surveillance smear and increased slightly with subsequent smears. Some sub‐groups of women are more likely to default (eg younger women, smokers). Analyses such as these may help inform strategies to ensure maximum attendance by women for cytological follow‐up of low‐grade abnormal smears.