The impact of obesity on outcomes of midwife-led pregnancy and childbirth in a primary care population: a prospective cohort study.

OBJECTIVE: To assess the impact of obesity on the likelihood of remaining in midwife-led care throughout pregnancy and childbirth. DESIGN: Secondary analysis of data from a prospective cohort study. SETTING: Dutch midwife-led practices. POPULATION: A cohort of 1369 women eligible for midwife-led care after their first antenatal visit. METHODS: First-trimester body mass index (BMI) was calculated as weight measured at booking divided by height squared. Obstetric data were retrieved from medical records. Multiple logistic regressions were performed to examine the effects of BMI classification on midwife-led pregnancies and childbirths. MAIN OUTCOME MEASURES: Percentages of women remaining in midwife-led care throughout pregnancy and throughout childbirth. RESULTS: Of women in obesity classes II and III, 55% remained in midwife-led care throughout pregnancy and 30% remained in midwife-led care throughout birth. Compared with women of normal weight, women in obesity classes II and III had fewer midwife-led pregnancies (OR 0.38, 95% CI 0.21-0.69), and women who were overweight or in obesity class I had fewer midwife-led childbirths (OR 0.63, 95% CI 0.44-0.90; OR 0.49, 95% CI 0.29-0.84, respectively). Compared with women of normal weight, women who were obese had higher referral rates for hypertensive disorders (4 versus 14%), prolonged labour (4.6 versus 10.4%), and intrapartum pain relief (4 versus 10.4%). The women who were eligible for midwife-led birth and who were overweight or obese, had no more urgent referrals than women of normal weight. Women who were obese and who completed a midwife-led birth had no more adverse outcomes than women of normal weight, with the exception of higher rates of large for gestational age (LGA) babies (>97.7 centile; 12.1%, versus 1.9% in normal weight and versus 3.3% in overweight women). CONCLUSIONS: Although fewer women who were obese remain in midwife-led care during pregnancy and childbirth, there was no increased risk of unfavourable birth outcomes for women who were obese and eligible for a midwife-led birth when compared with women of normal weight. This indicates that when primary care midwives use a risk assessment tool throughout pregnancy and childbirth they are able to safely assign women who are obese to either midwife-led or obstetrician-led care.

Tailoring bioanalysis for PK studies supporting drug discovery.

Over the last years, there has been an exponentially growing need and interest to bring pharmacokinetic expertise into discovery. In order to allow a multidisciplinary selection and a higher attrition rate, both the in vivo and in vitro pharmacokinetic parameters of an ever increasing number of tentative new chemical entities are evaluated in an earlier phase of Drug Discovery. A higher attrition rate at the beginning of the pipeline should result in a lower attrition rate at a later stage in development. In this process, the bioanalytical laboratory has become increasingly important. Analytical strategies needed to be adapted to cope with novel experimental designs such as cassette dosing, cassette analysis or 96-well techniques. At the same time, HT-synthesis programs surfaced a broader variety of chemical classes to be investigated, disfavoring further generalization of analytical approaches. Progress in lab automation, improved chromatographic techniques and the proliferation of LC-MS/MS enabled the analyst to deal with these challenges much faster and with a higher level of confidence. Quality standards regarding method development and method validation, setting the boundaries for more than a decade, needed to be titrated to reach an optimal balance between speed and quality. This review will give an illustrative overview of the bioanalytical techniques and strategies used to support Drug Discovery, together with some pitfalls related to the overzealous use of new techniques.

The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan.

The mechanistically novel benzopyran derivative SB-220453, which is undergoing clinical evaluation in migraine, exhibits a high affinity for a selective, but not yet characterized, binding site in the human brain. It inhibits nitric oxide release and cerebral vasodilatation following cortical spreading depression as well as carotid vasodilatation induced by trigeminal nerve stimulation in the cat. The aim of our study was to investigate the contractile properties of SB-220453 on a number of human isolated blood vessels (coronary artery, saphenous vein and middle meningeal artery) as well as atrial and ventricular cardiac trabeculae. While sumatriptan induced marked contractions in three blood vessels investigated, SB-220453 was devoid of any effect. In atrial and ventricular cardiac trabeculae, neither SB-220453 nor sumatriptan displayed a positive or negative inotropic effect. Since SB-220453 did not contract the middle meningeal artery, we conclude that potential anti-migraine effects are not mediated via a direct cerebral vasoconstriction. The lack of activity of SB-220453 in coronary artery, saphenous vein and cardiac trabeculae demonstrates that the compound is unlikely to cause adverse cardiac side-effects.

Synergy between enzymes from Aspergillus involved in the degradation of plant cell wall polysaccharides.

Synergy in the degradation of two plant cell wall polysaccharides, water insoluble pentosan from wheat flour (an arabinoxylan) and sugar beet pectin, was studied using several main-chain cleaving and accessory enzymes. Synergy was observed between most enzymes tested, although not always to the same extent. Degradation of the xylan backbone by endo-xylanase and beta-xylosidase was influenced most strongly by the action of alpha-L-arabinofuranosidase and arabinoxylan arabinofuranohydrolase resulting in a 2.5-fold and twofold increase in release of xylose, respectively. Ferulic acid release by feruloyl esterase A and 4-O-methyl glucuronic acid release by alpha-glucuronidase depended largely on the degradation of the xylan backbone by endo-xylanase but were also influenced by other enzymes. Degradation of the backbone of the pectin hairy regions resulted in a twofold increase in the release of galactose by beta-galactosidase and endo-galactanase but did not significantly influence the arabinose release by arabinofuranosidase and endo-arabinase. Ferulic acid release from sugar beet pectin by feruloyl esterase A was affected most strongly by the presence of other accessory enzymes.

Monotherapy with nifedipine GITS compared with atenolol in stable angina pectoris. The Working Group on Cardiovascular Research (WCN).

This double-blind, randomised multicentre study compares nifedipine gastrointestinal therapeutic system (GITS) with atenolol in 129 male patients, with exercise-induced angina pectoris. At 4 weeks, there was no significant difference between nifedipine GITS 60 mg o.d. and atenolol 100 mg o.d., in respect of improved time to onset of 0.1 mV ST-segment depression, time to onset of pain, and total exercise time. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise. There were significantly more vasodilator-related side effects with nifedipine. Nifedipine GITS and atenolol as once-daily monotherapy are equally effective and safe, but have different effects on exercise parameters.

Nifedipine gastrointestinal therapeutic system versus atenolol in stable angina pectoris. The Netherlands Working Group on Cardiovascular Research (WCN).

The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the beta-blocker atenolol, we conducted a double-blind, randomised, multi-centre study in 129 male patients with documented exercise induced angina pectoris. After 4 weeks' treatment, nifedipine (60 mg), improved time to onset of 0.1 mV ST-segment depression from 536 s by 72 +/- 117s, time to onset of pain from 619 s by 56 +/- 120 s, and total exercise time from 685 s by 40 +/- 88 s. Atenolol 100 mg, had a comparable effect, time to onset of 0.1 mV ST-segment depression improved from 496 s by 53 +/- 129 s, time to onset of pain from 572 s by 57 +/- 118 s, and total exercise time from 653 s by 33 +/- 99 s. Between group analysis revealed no statistically significant differences for these exercise parameters. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise (P < 0.001 between groups), indicating different modes of action of the drugs. With regard to safety, both drugs were generally well tolerated. There were significantly (P = 0.01) more vasodilation related side effects with nifedipine. These data demonstrate that gastrointestinal therapeutic system formulation of nifedipine and atenolol as once-daily monotherapy are equally effective and safe, but with different effects on exercise parameters.

Effect of isradipine and nifedipine on diastolic function in patients with left ventricular dysfunction due to coronary artery disease: a randomized, double-blind, nuclear, stethoscope study.

To elucidate the effect of isradipine and nifedipine on left ventricular (LV) systolic and diastolic function, each drug was given intravenously (i.v.) in equihypotensive doses to 10 patients accepted for coronary arteriography for stable angina pectoris. All 20 patients had LV ejection fraction (LVEF) of < 40% owing to previous myocardial infarction (MI). Systolic and diastolic function was assessed by standard hemodynamic parameters and pressure-volume relations measured by nuclear stethoscope. All measurements were taken at rest and during ischemia caused by right atrial pacing. Both systolic and diastolic parameters improved equally with isradipine and nifedipine. LVEF and cardiac output (CO) increased owing to peripheral vasodilatation. A decrease in P/Vmax, indicating a negative inotropic effect, was noted in patients at rest with both medications, but not during pacing-induced ischemia. With either medication, the time constant of relaxation and the end-diastolic elasticity constant decreased during pacing, indicating improvement in diastolic function, probably owing to relief of myocardial ischemia.

HLA-DR3 molecules can bind peptides carrying two alternative specific submotifs.

Three different HLA-DR3-specific peptide binding motifs have been proposed. These motifs shared a major hydrophobic anchor at the N-terminus, but differed in the C-terminal anchor residues. In the present study, the structural requirements for peptide binding to HLA-DR3 were examined in further detail by using quantitative HLA-DR3-specific binding assays and sets of single substitution analogues of DR3 binding peptides (Lol pollen amino acids 171-190 and sperm whale myoglobin amino acids 132-151). We found that the requirements for binding to HLA-DR3 vary among different DR3 binding peptides; the absence of an anchor or the presence of only a weak anchor residue at either position n or n + 3 can be compensated for by the presence of a strong, positively charged anchor residue at position n + 5. These results explain several of the previously reported differences between DR3-specific peptide binding motifs. To evaluate the predictive value of the thus-refined motif, the DR3 binding capacity of an overlapping set of peptides, spanning the entire sequence of the 65-kDa heat shock protein of Mycobacterium tuberculosis was investigated and correlated with the occurrence of the different DR3 motifs. A strong correlation was found between the presence of the refined DR3 motif and peptide binding to purified HLA-DR3 molecules.