Efficiency of hit generation and structural characterization in fragment-based ligand discovery.

Fragment-based ligand discovery constitutes a useful strategy for the generation of high affinity ligands with suitable physico-chemical properties to serve as drug leads. There is an increasing number of generic biophysical screening strategies established with the potential for accelerating the generation of useful fragment hits. Crystal structures of these hits can subsequently be used as starting points for fragment evolution to high affinity ligands.

The discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS).

By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.

Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.

Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket.

A simplified oral glucose tolerance test in pregnancy: compliance and results.

Background: To describe a reliable method for a general oral glucose tolerance test (OGTT) during pregnancy, to evaluate adherence to the method, and to compare the frequency of reported gestational diabetes mellitus (GDM) and perinatal outcome in affected pregnancies in Skåne, using direct diagnostic OGTT, with those from a comparable area, Halmstad-Ljungby-Växjö (HLV), using random glucose measurements (RGM) to identify women for the OGTT.

Methods: The OGTT program and quality assurance in Skåne is described. Antenatal records on deliveries in May 2003 were scrutinised to ascertain if OGTT had been performed.

Abnormal fetal growth is associated with gestational diabetes mellitus later in life: population-based register study.

Background: Increasing evidence has been collected that intrauterine growth restriction is associated with development of type-2 diabetes mellitus in adult life. The present study was designed to test the hypothesis that abnormal intrauterine growth of female fetuses correlates with their future risk of developing gestational diabetes mellitus (GDM).

Methods: Population-based register study of the data from the Swedish Medical Birth Registry; perinatal data from 1973 to 1983 were linked with the diagnosis of GDM during 1987-2001.

Presence of GAD antibodies during gestational diabetes mellitus predicts type 1 diabetes.

Objective: We sought to study the frequency of beta-cell-specific autoantibody markers in women with gestational diabetes mellitus (GDM) and to follow these women to estimate the risk of later development of type 1 diabetes.

Research Design And Methods: Of 385 pregnant women with GDM during 1995-2005 in the district of Lund, 24 (6%) women were found positive for at least one of the following: islet cell antibody (ICA), GAD antibody (GADA), or tyrosine phosphatase antibody (IA-2A). The women were followed and autoantibodies reanalyzed.

Beliefs about health and illness in women managed for gestational diabetes in two organisations.

Objective: to explore beliefs about health, illness and health care in women with gestational diabetes mellitus (GDM) managed in two different organisations based on diabetology or obstetrics.

Design: an explorative qualitative study using semi-structured interviews.

Setting: clinic A: a specialist diabetes clinic with regular contact with a diabetologist and antenatal care provided by a midwife; clinic B: a specialist maternity clinic providing regular contact with a midwife, a structured programme for self-monitoring of blood glucose and insulin treatment, and a 1-day diabetes class by an obstetrician, a diabetologist, a midwife and a dietician.

Pregnancy outcome after maternal organ transplantation in Sweden.

Objective: To study pregnancy outcome before and after organ transplantation.

Design: Registry study.

Setting: Swedish Health Registers.

Different HLA-DR-DQ and MHC class I chain-related gene A (MICA) genotypes in autoimmune and nonautoimmune gestational diabetes in a Swedish population.

The genetic susceptibility for gestational diabetes (GDM) was estimated by comparisons of genotypes within human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related gene A (MICA) in 199 women with GDM and 213 healthy women. At least one of ICA, glutamic acid decarboxylase antibodies, or islet cell antigen-2 antibodies/tyrosine phosphatase antibodies was found in 6.0% (12/199) of women with GDM and were considered as autoimmune GDM, whereas the remaining 187 were considered as nonautoimmune GDM.

2-aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution.

4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.

Acupuncture relieves pelvic and low-back pain in late pregnancy.

Background: The study was designed to evaluate the analgesic effect and possible adverse effects of acupuncture for pelvic and low-back pain during the last trimester of pregnancy.

Methods: Following individual informed consent, 72 pregnant women reporting pelvic or low-back pain were randomized during pregnancy weeks 24-37 to an acupuncture group (n = 37) or to a control group (n = 35) at three maternity wards in southern Sweden. Traditional acupuncture points and local tender points (TP) were chosen according to individual pain patterns and stimulated once or twice a week until delivery or complete recovery in acupuncture patients.

Relationship between vitamin use, smoking, and nausea and vomiting of pregnancy.

Background: Nausea and vomiting in pregnancy (NVP) is a common complaint but risk factors for NVP are not well characterized.

Methods: Occurrence of NVP was studied by questionnaires given to pregnant women at their first visit to the antenatal care unit and were returned around gestational week 28.

Results: Analysis of 3675 completed questionnaires was made.

Low-dose hormone therapy and carbohydrate metabolism.

Objective: To evaluate the influence by two low doses of oral continuous-combined formulations of 17 beta-estradiol (E(2)) and norethisterone acetate (NETA) on carbohydrate metabolism in healthy postmenopausal women.

Design: A double-blind, randomized, placebo-controlled trial.

Setting: Volunteers at a university hospital.

Conformational changes in nitric oxide synthases induced by chlorzoxazone and nitroindazoles: crystallographic and computational analyses of inhibitor potency.

Nitric oxide is a key signaling molecule in many biological processes, making regulation of nitric oxide levels highly desirable for human medicine and for advancing our understanding of basic physiology. Designing inhibitors to specifically target one of the three nitric oxide synthase (NOS) isozymes that form nitric oxide from the L-Arg substrate poses a significant challenge due to the overwhelmingly conserved active sites. We report here 10 new X-ray crystallographic structures of inducible and endothelial NOS oxygenase domains cocrystallized with chlorzoxazone and four nitroindazoles: 5-nitroindazole, 6-nitroindazole, 7-nitroindazole, and 3-bromo-7-nitroindazole.

Changes in lipid and lipoprotein profile in postmenopausal women receiving low-dose combinations of 17beta-estradiol and norethisterone acetate.

Objective: To evaluate the modification of lipid and lipoprotein by use of low doses of continuous-combined formulations of 17beta-estradiol (E ) and norethisterone acetate (NETA) in healthy postmenopausal women.

Design: The study was designed as a double-blind, randomized, placebo-controlled trial. A total of 120 healthy postmenopausal women were randomized to one of three treatment arms: (1) placebo group ( = 40); (2) E /NETA 0.

Predictive factors of developing diabetes mellitus in women with gestational diabetes.

Background: To investigate which factors during gestational diabetes pregnancies correlate with the risk of developing impaired glucose tolerance or diabetes 1 year postpartum and to compare this risk in women with gestational diabetes and women with a normal oral glucose tolerance test during pregnancy.

Methods: Of 315 women with gestational diabetes, defined as a 2-hr blood glucose value of at least 9.0 mmol/l at a 75-g oral glucose tolerance test, who delivered in Lund 1991-99, 229 (73%) performed a new test 1 year postpartum.

Screening for MODY mutations, GAD antibodies, and type 1 diabetes--associated HLA genotypes in women with gestational diabetes mellitus.

Objective: To investigate whether genetic susceptibility to type 1 diabetes or maturity-onset diabetes of the young (MODY) increases susceptibility to gestational diabetes mellitus (GDM).

Research Design And Methods: We studied mutations in MODY1-4 genes, the presence of GAD antibodies, and HLA DQB1 risk genotypes in 66 Swedish women with GDM and a family history of diabetes. An oral glucose tolerance test was repeated in 46 women at 1 year postpartum.