bluuebunny/crossref_metadata_2025_split huggingface dataset:
Candidate mechanisms for capecitabine‐related hand–foot syndrome
Authors: Milano Gérard , Etienne‐Grimaldi Marie‐Christine , Mari Mireille , Lassalle Sandra , Formento Jean‐Louis , Francoual Mireille , Lacour Jean‐Philippe , Hofman Paul 
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Hand–foot syndrome (HFS) is a limiting toxicity of the widely used fluorouracil (5FU) prodrug capecitabine.• The pharmacological origin of HFS has not been elucidated.• The expression of capecitabine‐metabolizing enzymes thymidine phosphorylase (TP, activating pathway) and dihydropyrimidine dehydrogenase (DPD, catabolic pathway) in the skin of the palm (target tissue for HFS) is unknown. WHAT THIS STUDY ADDS • This pilot study, conducted in healthy volunteers, clearly demonstrated that TP expression is significantly greater in the palm compared with the lower back (control area).• This suggests TP‐facilitated enhanced production of 5FU in the palm that could explain the occurrence of HFS.• This result may support strategies to prevent HFS.AIMSThe oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand–foot syndrome (HFS) is a limiting toxicity of capecitabine. A pilot study on healthy volunteers was conducted in order to test the hypothesis that the occurrence of HFS could be related to tissue‐specific expression of drug‐metabolizing enzymes in the skin of the palm and sole. To this end, the expression of TP (activating pathway), dihydropyrimidine dehydrogenase (DPD, catabolic pathway) and cell proliferation (Ki67) were measured in the skin of the palm (target tissue for HFS) and of the lower back (control area).METHODSTwo paired 4‐mm diameter punch biopsy specimens (palm and back) were taken in 12 healthy volunteers. Immunohistochemical analyses were performed on frozen tissues.RESULTSProliferation rate (Ki67 staining) was significantly higher in epidermal basal cells of the palm compared with the back (P = 0.008). Also, TP and DPD expression were significantly greater in the palm relative to the back (P = 0.039 and 0.012, respectively). TP and Ki67 expression were positively and significantly correlated in the palm.CONCLUSIONSThe high proliferation rate of epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs. TP‐facilitated local production of 5FU in the palm during capecitabine treatment could explain the occurrence of HFS. This observation may support future strategies to limit the occurrence of HFS during capecitabine therapy.
Absence of respiratory effects with ivabradine in patients with asthma
Authors: Babu K. Suresh , Gadzik Frantisek , Holgate Stephen T. 
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ivabradine is a new heart rate‐lowering agent that acts specifically on the sinoatrial node via the If pacemaker channels.• Ivabradine has demonstrated similar efficacy to β‐blockers.• As β‐blockers are contraindicated in patients with obstructive airway disease, this study was conducted to assess the safety of ivabradine in patients with asthma. WHAT THIS STUDY ADDS • This study demonstrates that ivabradine has no effect on the pulmonary functions in patients with asthma and can be safely used a heart rate‐lowering agent in patients with angina and coexistent airflow obstruction.AIMβ‐Blockers are commonly prescribed for stable angina and are recommended as initial therapy. However, β‐blockers are contraindicated in patients with obstructive airway disease because of a risk of bronchoconstriction. Ivabradine is a specific heart rate‐lowering agent that acts via If pacemaker channels in the sinoatrial node with no β‐adrenoreceptor activity. Ivabradine has been recently approved for the treatment of stable angina. This study assessed the effects of repeated administration of ivabradine on lung function in patients with asthma.METHODSIn this double‐blind, placebo‐controlled, crossover study, 20 subjects with asthma received either oral ivabradine 10 mg b.i.d. or placebo for 4.5 days. Forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate (PEFR) were designated as the main outcome variable. Diary cards were used to monitor asthma symptoms on a five‐point scale, rescue medication usage, and adverse events.RESULTSThere were no significant differences in mean variation of FEV1 (ivabradine P = 0.664; placebo P = 0.652) or PEFR (ivabradine P = 0.153; placebo P = 0.356) from baseline following administration of ivabradine. There was also no significant difference in maximum percent variation in FEV1 or PEF between treatment groups (P = 0.994; FEV1 and P = 0.704; PEF). On a similar note, there was no significant difference in asthma symptoms or rescue medication usage reported between the two groups. Adverse events were generally mild‐to‐moderate in intensity and no cardiovascular or serious adverse events were recorded.CONCLUSIONSThis study confirms that ivabradine does not affect respiratory function or symptoms in patients with asthma and therefore represents a valuable therapeutic alternative to β‐blockers for treating patients with stable angina and asthma.
Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients
Authors: Nath Christa E. , Earl John W. , Pati Nalini , Stephen Katherine , Shaw Peter J. 
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetics of oral busulphan given four times daily has been extensively studied.• Large inter‐ and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring.• However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6‐h dosing interval, due to late absorption in some patients.• Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose. WHAT THIS STUDY ADDS • Inter‐ and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable.• Children with immune deficiencies, in particular, have widely variable exposure.AIMTo examine inter‐ and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease.METHODSBusulphan (120 mg m−2, 130 mg m−2 or 3.2 mg kg−1) was administered over median 2.1 h. Blood samples (4–10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration–time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m−2 dose in 13 children who had busulphan pharmacokinetic monitoring.RESULTSClearance of i.v. busulphan in 40 children was 4.78 ± 2.93 l h−1 (% CV 61%), 0.23 ± 0.08 l h−1 kg−1 (% CV 35%) and 5.79 ± 1.59 l h−1 m−2 (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h−1) and CL (l h−1 kg−1), but not with CL (l h−1 m−2). AUC normalized to the 130 mg m−2 dose ranged from 14.1 to 56.3 mg l−1.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h−1 m−2) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children.CONCLUSIONSThere is considerable inter‐ and intrapatient variability in i.v. busulphan CL (l h−1 m−2) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.
The effect of anti‐CD40 ligand in immune thrombocytopenic purpura
Authors: Patel Vivek L. , Schwartz Joseph , Bussel James B. 
Published: March 2008

SummaryImmune thrombocytopenic purpura (ITP) is mediated by antiplatelet autoantibodies possibly involving CD40:CD40L co‐stimulation. Two humanized anti‐CD40L monoclonal antibodies, hu5c8 and IDEC‐131, were evaluated in 46 patients with chronic refractory ITP. Fifteen patients were treated with 20 mg/kg of hu5c8: four (27%) had complete responses (CR) and two (13%) had partial responses (PR). Three responders to hu5c8 were successfully retreated with IDEC‐131, demonstrating its efficacy. Thirty‐one subsequent patients were treated with 5–20 mg/kg per infusion of IDEC‐131: five (16%) responded (one CR and four PR). The 24% (11/46) overall response rate demonstrates the potential role of CD40‐CD40L in the pathogenesis of ITP.
Mutated and non‐mutated TP53 as targets in the treatment of leukaemia
Authors: Nahi H. , Selivanova G. , Lehmann S. , Möllgård L. , Bengtzen S. , Concha H. , Svensson A. , Wiman K. G. , Merup M. , Paul C. 
Published: March 2008

Summary TP53 is mutated in 10–20% of cases of chronic lymphocytic leukaemia (CLL) and 3–8% of cases of acute myeloid leukaemia (AML). Recently, two classes of compounds that restore the function of p53 in tumours have been described. PRIMA‐1 (p53‐dependent reactivation and induction of massive apoptosis) restores the wild‐type conformation of mutant TP53, whereas RITA (reactivation of p53 and induction of tumour cell apoptosis) increases intracellular levels of p53. We evaluated the effects of RITA alone and in combination with PRIMA‐1 or conventional cytostatics on leukaemic cells isolated from AML and CLL patients. AML samples with −17, which are more resistant to daunorubicin and cytarabine compared with samples without −17, were effectively killed by PRIMA‐1. RITA, which stabilizes the function of wild‐type p53, induced apoptosis in AML cells. In contrast to that seen with PRIMA‐1, AML patient samples without −17 were significantly more sensitive to RITA. Similarly, RITA exerted dose‐dependent apoptosis and cytotoxicity in CLL cells, which was significantly more pronounced in samples without hemizygous TP53 deletion. Notably, a synergistic effect was observed in all CLL samples with RITA and fludarabine in combination. In both AML and CLL cells exposure to RITA resulted in induction of intracellular p53. We conclude that small molecules targeting p53 might be of clinical importance in the future for treating drug‐resistant leukaemia.
The insulin‐like growth factor‐I receptor inhibitor NVP‐AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells
Authors: Maiso Patricia , Ocio Enrique M. , Garayoa Mercedes , Montero Juan C. , Hofmann Francesco , García‐Echeverría Carlos , Zimmermann Johann , Pandiella Atanasio , San Miguel Jesús F. 
Published: March 2008

SummaryMultiple myeloma (MM) is a B‐cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP‐AEW541, a small molecule that belongs to the pyrrolo[2,3‐d]pyrimidine class, identified as a selective inhibitor of the insulin‐like growth factor‐I receptor (IGF‐IR) in vitro kinase activity. NVP‐AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP‐AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP‐AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP‐AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP‐AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP‐AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP‐AEW541 induced cell death through caspase‐dependent and ‐independent mechanisms. All these data, suggest the potential effect of IGF‐IR kinase inhibitors as therapeutic agents for MM patients.
Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis
Authors: Ricart José M. , Ramón Luis A. , Vayá Amparo , España Francisco , Santaolaria Maria‐Luisa , Todolí José , Castelló Remedios , Fontcuberta Jordi , Estellés Amparo 
Published: March 2008

SummaryThis study aimed to assess the fibrinolytic inhibitors and their association with thrombosis in Behçet disease. Thrombin activatable fibrinolysis inhibitor (TAFI) (P < 0·001) and plasminogen activator inhibitor‐1 (PAI‐1) levels (P = 0·022) were significantly higher in 79 patients than in 84 controls. No significant differences were observed in CPB2 (TAFI) Thr325Ile and SERPINE1 (PAI1) 4G/5G polymorphism distribution between patients and controls. TAFI activity levels were significantly higher in patients with thrombosis than in those without thrombosis (P = 0·024). In conclusion, the increased TAFI levels in Behçet disease could contribute to the increased risk of thrombosis observed in these patients.
Disorders of red cell membrane
Authors: An Xiuli , Mohandas Narla 
Published: March 2008

SummaryStudies during the last three decades have enabled the development of detailed molecular insights into the structural basis of altered function in various inherited red cell membrane disorders. This review highlights our current understanding of molecular and mechanistic insights into various inherited red cell membrane disorders involving either altered membrane structural organization (hereditary spherocytosis, hereditary elliptocytosis and hereditary ovalocytosis) or altered membrane transport function (hereditary stomatocytosis). The molecular basis for the vast majority of cases of hereditary spherocytosis, elliptocytosis and ovalocytosis have been fully defined while little progress has been made in defining the molecular basis for hereditary stomatocytosis. Mutations in a number of distinct genes account for hereditary spherocytosis and elliptocytosis, while a single genetic defect accounts for all cases of hereditary ovalocytosis. Based on these molecular insights, a comprehensive understanding of the structural basis for altered membrane function has been developed. Loss of vertical linkage between membrane skeleton and lipid bilayer leads to membrane loss in hereditary spherocytosis, while weakening of lateral linkages between skeletal proteins leads to membrane fragmentation and surface area loss in hereditary elliptocytosis. Importantly, the severity of anaemia in both these disorders is directly related to extent of membrane surface area loss. Splenectomy results in amelioration of anaemia.
Novel melanocortin 4 receptor gene mutations in severely obese children
Authors: Lee Yung Seng , Poh Larry Kok Seng , Kek Betty Lay Kee , Loke Kah Yin 
Published: March 2008

SummaryObjective  Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children.Design  We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing.Results  We identified three mutations in three subjects: 4 bp deletion from nucleotides 631–634 (c.631–634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1·32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non‐obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early‐onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity.Conclusion  MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.
Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo–pituitary–adrenal axis
Authors: Finucane Francis M. , Liew Aaron , Thornton Evan , Rogers Barbara , Tormey William , Agha Amar 
Published: March 2008

SummaryObjective  The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol production in pituitary disease. However, areas of uncertainty remain regarding its safety in older people, the optimal duration of the test and its performance in insulin resistant states. Whether basal cortisol concentration can reliably predict an adequate adrenal response to hypoglycaemia remains to be determined.Patients and design  We performed a cross‐sectional retrospective examination of 197 consecutive patients (mean age 41·8 ± 16·4, range 13–76 years) with pituitary disease who underwent the ITT over 18 months. The standard intravenous insulin dose administered was 0·15 units/kg body weight. Patients with acromegaly or with type 2 diabetes received 0·2 units/kg; those with basal cortisol < 100 nmol/l received 0·1 units/kg.Results  Adequate hypoglycaemia (nadir glucose < 2·2 mmol/l) was achieved in 87% of patients, amongst whom 17% did not achieve peak cortisol until 120 min. There were no significant adverse events, even in those ≥ 65 years. Of the 18 patients who had basal cortisol < 100 nmol/l, 78% achieved adequate hypoglycaemia; 29% of those had an adequate peak cortisol response ≥ 500 nmol/l. A receiver operating characteristics curve identified a basal cortisol of ≥ 393 nmol/l to predict a normal peak cortisol response to hypoglycaemia.Conclusions  In specialized units, the ITT is safe even in elderly patients and those with hypocortisolaemia. The standard 90‐min. cut‐off for the ITT misses one in six peak cortisol responses. Some patients with basal cortisol < 100 nmol/l had a normal cortisol response to hypoglycaemia.
Glucose turnover and intima media thickness of internal carotid artery in type 2 diabetes offspring
Authors: Anderwald C. , Pfeiler G. , Nowotny P. , Anderwald‐Stadler M. , Krebs M. , Bischof M. G. , Kozakova M. , Luger A. , Pacini G. , Roden M. , Waldhäusl W. 
Published: March 2008

ABSTRACTBackground  First‐degree offspring (OFF) of type 2 diabetic (T2DM) patients bear a ~40% lifetime risk of developing T2DM. They are insulin resistant and carry a risk of premature atherosclerosis, the extent of which can be estimated by intima media thickness (IMT) of the carotid artery (CA). Thus, this study examines parameters of glucose and lipid metabolism, insulin sensitivity, beta cell function (BCF) and IMT with their interrelationships in middle‐aged OFF.Materials and methods  T2DM‐OFF (n = 18, 14f/4m, 45·6 ± 2·1 years, BMI: 26 ± 1 kg m−2) were compared with 18 matching humans without a family history of diabetes (CON; 14f/4m, 44·5 ± 2·1 years, BMI: 24 ± 1 kg m−2; each P > 0·30), all with normal glucose tolerance as tested by three‐hour (75 g) oral glucose tolerance tests (OGTT). Two‐hour hyperinsulinaemic (40 mU min−1·m−2)isoglycaemic clamp tests were performed with simultaneous measurement of endogenous glucose (D‐[6,6‐2H2]glucose) production (EGP). IMT [internal (ICA), common CA, and bulb] were measured sonographically. BCF was assessed by Adaptation Index (AI).Results  Before and during OGTT, both groups were similar in plasma glucose, insulin, C‐peptide and free fatty acids (FFA), whereas OFF showed ~30% lower (P < 0·03) fasting plasma triglycerides before OGTT. During hyperinsulinaemic clamps, insulin sensitivity was ~38% lower (P < 0·03) in OFF who showed higher plasma FFA (44 ± 9 µmol L−1) than CON (26 ± 3 µmol L−1, P < 0·05) after 90 min. EGP was similar in both groups. OFF had 38% (P < 0·007) reduced AI. ICA‐IMT was ~18% higher in OFF (P < 0·002), but did not correlate with insulin sensitivity.Conclusion  The data obtained show middle‐aged T2DM‐OFF with normal glucose tolerance displaying reduced total insulin sensitivity and impaired beta cell function, which relates to impaired insulin‐dependent suppression of plasma FFA and increased ICA‐IMT.
Secretory type II phospholipase A2 in culprit coronary lesions is associated with myocardial infarction
Authors: Nijmeijer R. , Meuwissen M. , Krijnen P. A. J. , Van Der Wal A. , Piek J. J. , Visser C. A. , Hack C. E. , Niessen H. W. M. 
Published: March 2008

ABSTRACTBackground  Secretory type‐II phospholipase A2 (sPLA2‐II) is a cardiovascular risk marker since higher levels of this acute phase protein imply an increased risk for coronary artery disease. Moreover, it is hypothesized that local activity of sPLA2‐II in the atherosclerotic plaque facilitates an inflammatory response to induce plaque instability or rupture. We have studied the presence of sPLA2‐II in culprit lesions in the coronary arteries of patients with acute myocardial infarction (AMI) or angina pectoris.Materials and methods  We performed a histological examination of culprit lesions in 41 patients with stable (SAP) or unstable angina pectoris (UAP), or AMI using directed coronary atherectomy (DCA). Frozen slides were analysed immuno‐histochemically for the presence of sPLA2‐II, macrophages and smooth muscle cells. Immunopositive areas were calculated as a percentage of the total tissue area using image analysis software.Results  Intracellular sPLA2‐II was found in atherosclerotic lesions in the macrophages of the intima as well as in vascular smooth muscle cells. Next to this, extracellular sPLA2‐II depositions were also found. These depositions were significantly more extensive in patients with AMI, i.e. 26%median[6%25th(percentile)–44%75th(percentile)] of the intima area, than in patients with SAP 0%median (0%25th–10%75th; P = 0·013) or UAP 0%median (0%25th–0%75th; P = 0·04).Conclusions  Extracellular sPLA2‐II is more abundantly present in atherosclerotic culprit lesions that have led to myocardial infarction. This suggests a role for extracellular sPLA2‐II in the development of complications of atherosclerotic lesions in coronary arteries.