Syntheses and catalytic oxotransfer activities of oxo molybdenum(vi) complexes of a new aminoalcohol phenolate ligand.

The new aminoalcohol phenol 2,4-di-tert-butyl-6-(((2-hydroxy-2-phenylethyl)amino)methyl)phenol (H2L) was prepared by a facile solvent-free synthesis and used as a tridentate ligand for new cis-dioxomolybdenum(vi)(L) complexes. In the presence of a coordinating solvent (DMSO, MeOH, pyridine), the complexes crystallise as monomeric solvent adducts while in the absence of such molecules, a trimer with asymmetric Mo[double bond, length as m-dash]O→Mo bridges crystallises. The complexes can catalyse epoxidation of cis-cyclooctene and sulfoxidation of methyl-p-tolylsulfide, using tert-butyl hydroperoxide as oxidant.

Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus.

OBJECTIVE: To compare the efficacy and safety of preprandial administration of rapid-acting lispro analogue with regular short-acting insulin to pregnant women with type 1 diabetes. STUDY DESIGN: Open randomised multicentre study. Women were treated with multiple insulin injections aiming at normoglycaemia. Blood glucose was determined six times daily, HbA(1c) every 4 weeks. Diurnal profiles of blood glucose were analysed at gestational week 14 and during the study period at weeks 21, 28 and 34. PARTICIPANTS: 33 pregnant women with type 1 DM were randomised to treatment with lispro insulin (n=16) or regular insulin (n=17). RESULTS: Blood glucose was significantly lower (P<0.01) after breakfast in the lispro group, while there were no significant group differences in glycemic control during the rest of the day. Severe hypoglycaemia occurred in two patients in the regular group but biochemical hypoglycaemia (blood glucose <3.0 mmol/l) was more frequent in the lispro than in the regular group (5.5 vs. 3.9%, respectively). HbA(1c) values at inclusion were 6.5 and 6.6% in the lispro and regular group respectively. HbA(1c) values declined during the study period and were similar in both groups. There was no perinatal mortality. Complications during pregnancy, route of delivery and foetal outcome did not differ between the groups. Retinopathy progressed in both groups, one patient in the regular group developed proliferative retinopathy. CONCLUSION: The results suggest that it is possible to achieve at least as adequate glycemic control with lispro as with regular insulin therapy in type 1 diabetic pregnancies.

Design and synthesis of new models for diiron biosites.

In order to mimic dinuclear active sites of some non-heme diiron proteins, ten new polydentate and potentially dinucleating ligands have been synthesized. Each ligand contains a carboxylate moiety designed to bridge two metal atoms. These central carboxylate moieties are derived from substituted benzoic acids that in turn are linked to terminal nitrogen or oxygen donors by spacers so that framework-type polydentate ligands similar to the polypeptide frames in diiron metallobiosites are formed. Reaction of these ligands with Fe(ClO4)3 x 9H2O leads to ferric mu-oxo-mu-carboxylato iron complexes of the general formulas [Fe2O(L)2(H2O)2](ClO4)2 and [Fe2O(L)(BzO)](ClO4)2 (L = ligand), containing one or two immobilized bridging carboxylates, respectively. While X-ray crystallography shows that some of these complexes are dimers or network polymers in the solid state, electrospray ionization mass spectrometry (ESMS) and spectroscopic data (UV-Vis, NMR, Móssbauer) indicate that they dissociate to monomeric Fe2O units in dilute CH3CN solutions.

Synthesis and reactivity studies of model complexes for molybdopterin-dependent enzymes.

The molybdenum cofactor (Moco)-containing enzymes are divided into three classes that are named after prototypical members of each family, viz. sulfite oxidase, DMSO reductase and xanthine oxidase. Functional or structural models have been prepared for these three prototypical enzymes: (i) The complex [MoO2(mnt)2]2- (mnt2- = 1,2-dicyanoethylenedithiolate) has been found to be able to oxidize hydrogen sulfite to HSO4- and is thus a functional model of sulfite oxidase. Kinetic and computational studies indicate that the reaction proceeds via attack of the substrate at one of the oxo ligands of the complex, rather than at the metal. (ii) The coordination geometries of the mono-oxo [Mo(VI)(O-Ser)(S2)2] entity (S2 = dithiolene moiety of molybdopterin) found in the crystal structure of R. sphaeroides DMSO reductase and the corresponding des-oxo Mo(IV) unit have been reproduced in the complexes [M(VI)O(OSiR3)(bdt)2] and [M(VI)O(OSiR3)(bdt)2] (M = Mo,W; bdt = benzene dithiolate). (iii) A facile route has been developed for the preparation of complexes containing a cis-Mo(VI)OS molybdenum oxo, sulfido moiety similar to that detected in the oxidized form of xanthine oxidase.

Premature rupture of the membranes (PROM) at term in nulliparous women with a ripe cervix. A randomized trial of 12 or 24 hours of expectant management.

OBJECTIVE: To compare maternal and neonatal outcomes after 12 or 24 hours of expectant management in healthy nulliparous women with a ripe cervix and PROM at term. DESIGN: A prospective, randomized study. LOCATION: Karolinska Hospital, Stockholm, Sweden. SUBJECTS: Two hundred and five healthy nulliparous women with singleton pregnancies, cephalic presentation, gestational duration 36 to 42 weeks, randomized to 12 or 24 hours of expectant management after evaluation of the cervical score (> 5). If spontaneous labor did not occur, induction was performed with oxytocin after 12 or 24 hours, respectively. MAIN PARAMETERS: Maternal early morbidity and neonatal infections, obstetric intervention rate (cesarean section or instrumental delivery). RESULTS: The cesarean section rate was 4% in each group. The vacuum extraction rate was 21% in each group. Induction of labor was performed in 47% of the women allocated to 12 hours of expectant management vs 17% of the women allocated to 24 hours of expectant management (p < 0.05). The maternal morbidity rate was almost negligible. Only a few fetal infections occurred and no difference was noted between the groups. CONCLUSIONS: In healthy nulliparous women at term with a ripe cervix, expectant management over 24 hours vs 12 hours resulted in fewer inductions of labor and no increase in instrumental deliveries, without any increase in neonatal or maternal morbidity.

Comparison of two mefloquine regimens for treatment of Plasmodium falciparum malaria on the northeastern Thai-Cambodian border.

In 1991 and 1992, a prospective randomized trial was conducted on the northern Thai-Cambodian border. That trial compared the efficacy and tolerance of two mefloquine regimens for the treatment of uncomplicated Plasmodium falciparum malaria in an area with multi-drug-resistant P. falciparum. The resolution of fever and other symptoms was faster with high-dose mefloquine (25 mg/kg of body weight [M25 group; n = 68]) than with the conventional 15-mg/kg dose (M15 group; n = 71). There were no early treatment failures (days 7 to 9) in the M25 group, but there were 5 (7%) treatment failures in the M15 group (P = 0.03). The incidences of treatment failures by day 28 were 40% with the M15 group and 11% with the M25 group (P = 0.0004). By day 42, these values had risen to 50 and 27%, respectively (P = 0.01). The risk of treatment failure was highest in children (relative risk, 2.1; 95% confidence interval, 1.3 to 3.4) and patients with posttreatment diarrhea (relative risk, 2.0; 95% confidence interval, 1.3 to 3.1). Over half of the recrudescences in the M25 group occurred between days 28 and 42, whereas 17% of the recrudescences in the M15 group occurred between days 28 and 42 (P = 0.02). Thus, the sensitivity of assessment was significantly increased with longer follow-up. Treatment failure was associated with a delayed parasite clearance and an inadequate hematological recovery. Upper gastrointestinal side effects and dizziness were significantly more common in the M25 group, but overall, the high dose was relatively well tolerated, in particular by children. An increase in the dose to 25 mg/kg can prolong the therapeutic use of mefloquine in areas with multi-drug-resistant P.falciparum malaria where high-grade resistance to mefloquine is still rare.

Microscopic examination of stools and a latex slide agglutination test for the rapid identification of bacterial enteric infections in Khmer children.

Eighty-five stools collected from 50 children with diarrhea at an evacuation site on the Thai-Kampuchean border were (1) examined microscopically for fecal leukocytes, (2) tested after 24 hr enrichment in brain/heart infusion broth by a latex slide agglutination test for detection of Salmonella and Shigella, and (3) examined with microbiological techniques to identify bacterial, viral, and parasitic pathogens. If the 65 specimens in which one or no pathogens are considered, 6 or more fecal leukocytes/hpf were found on microscopic examination of stools in both children infected with Shigella spp., the one child infected with Salmonella spp., and three of eight children infected with Campylobacter spp. Less than or equal to 5 leukocytes/hpf were found in 70% (7/10) of children infected with rotavirus, 100% (2/2) infected with Cryptosporidium, 100% (2/2) infected with Giardia, 89% (8/9) infected with enterotoxigenic Escherichia coli, and 77% (24/31) with diarrhea in whom no etiologic agent was identified. The Salmonella slide latex test had a sensitivity of 50%, a specificity of 92%, and a positive predictive value of 12%. The Shigella slide latex test had a sensitivity of 0%, a specificity of 95%, and a positive predictive value of 0%. Forty-five percent of the latex slide agglutination tests from enrichment cultures were nonspecific. Microscopic examination of diarrheal stools for fecal leukocytes, though nonspecific, appears to be the best way to differentiate Shigella spp. from rotavirus and parasitic infections. Examining stools for fecal leukocytes was less helpful in differentiating Shigella from other bacterial infections.

Factors influencing neonatal morbidity in gestational diabetic pregnancy.

The influence of obstetric factors and indices of maternal blood glucose control on neonatal morbidity was examined in 261 women with gestational diabetes. A reference group of 218 women, matched for age and day of delivery, within 1 week, was used for comparison. Perinatal morbidity was significantly more frequent in the gestational diabetic pregnancies (23%) than in the reference group (13%), whereas the occurrence of large-for-gestational-age infants was not different between the groups. Infants born to women with gestational diabetes were categorized to a no-morbidity group (n = 200) and a morbidity group (n = 61). The group with morbidity had significantly shorter gestational age at delivery, higher frequency of caesarean section, higher maternal pre-pregnancy weight and higher area under the glucose tolerance curve. There was no significant difference in third-trimester blood glucose between the groups. Discriminant analysis revealed that the most significant influence on neonatal morbidity was gestational age at delivery. After correction for this factor the only factor with added significance for neonatal morbidity was maternal pre-pregnancy weight. The present study clearly illustrates that other factors beside blood glucose control are of importance for neonatal outcome in gestational diabetic pregnancy.

Twenty-four hour excretion of urinary C-peptide in gestational diabetic women before and after treatment with diet or diet and insulin.

24-h urinary C-peptide excretion was studied in 119 women with gestational diabetes before and after treatment with diet or diet and insulin. The 24-h urinary C-peptide excretion in normal-weight gestational diabetic women at diagnosis was also compared to that of a healthy reference group. There was a wide variation in urinary C-peptide values which tended to be higher in normal-weight women with gestational diabetes at diagnosis compared to the reference group, but it did not reach statistical significance. Post partum gestational diabetic women had significantly higher urinary C-peptide excretion (p less than 0.002) than the reference group, indicating insulin resistance in women with gestational diabetes at this time. In 29 overweight women with gestational diabetes 24-h urinary C-peptide excretion did not significantly differ from that in normal-weight women with gestational diabetes. In 32 women with a more marked deviation in glucose tolerance (area greater than or equal to 46 mmol/l) 24-h urinary C-peptide values were significantly (p less than 0.05) higher than in 58 women with gestational diabetes with an area between 42 and 45.9 mmol/l. Both treatment alternatives, diet and diet plus insulin, significantly reduced postprandial blood glucose values (p less than 0.05) and urinary C-peptide excretion was significantly decreased (p less than 0.05).

Pancreatic B-cell function during normal pregnancy.

24-h urinary C-peptide excretion was studied in 19 healthy normal weight women with normal glucose tolerance, and related to weight gain and skinfold thickness at 12, 20, 30, 36 weeks of gestation and 6-8 weeks post partum. The urinary C-peptide values (total nmoles or nmoles per kg body weight) showed a significant and progressive increase with gestation. The average C-peptide value was already at 12 weeks of gestation 4 times higher than under non-pregnant conditions. The urinary C-peptide excretion was neither related to maternal weight, weight gain or skinfold thickness at any of the observation periods during pregnancy, nor to the plasma C-peptide response to an oral glucose load at 32 weeks of gestation. A significant correlation was found between urinary C-peptide excretion and body weight determined post partum (r = 0.54, p less than 0.05). The increment in urinary C-peptide excretions at 12 weeks of gestation was unrelated to body mass, suggesting that insulin resistance is present already at this early stage of normal gestation.

Treatment of falciparum malaria with quinne and tetracycline or combined mefloquine/sulfadoxine/pyrimethamine on the Thai-Kampuchean border.

Three different regimens were compared for treatment of falciparum malaria in displaced Kampucheans living in encampments on the Thai-Kampuchean border in 1983: single dose 750 mg mefloquine, 1.5 g sulfadoxine, 75 mg pyrimethamine (MSP); 600 mg quinine 8-hourly for 3 days and 500 mg tetracycline 8-hourly for 7 days (Q3T7); or 600 mg quinine 8-hourly for 7 days and 500 mg tetracycline 8-hourly for 7 days (Q7T7). Radical cure rates were 98% (40/41) for MSP, 76% (32/42) for Q3T7 and 92% (33/36) for Q7T7. The criterion for treatment failure was reappearance of parasites by 35 days after commencement of treatment or no parasite clearance. Treatment failures comprised one case of reduction but no clearance of parasites (RII resistance) for MSP, 10 recrudescences (RI) for Q3T7 and 3 recrudescences (RI) for Q7T7. The radical cure rate for Q3T7 was significantly lower than that for MSP (P less than 0.01), whilst Q7T7 significantly from the other groups. Parasite clearance time was shorter (2.4 days) with MSP than with Q3T7 (3.5 days) and Q7T7 (3.3 days). There was little difference in side effects between the regimens, and tolerance was good. The MSP and Q7T7 regimens are both effective for treatment, but the single dose of MSP is much easier to manage than 7 days of quinine and tetracycline.

Gestational diabetes mellitus (GDM). Comparative evaluation of two treatment regimens, diet versus insulin and diet.

Two-hundred and two pregnant women with impaired glucose tolerance were randomized to treatment with diet or diet and insulin by stratified selection. Self-monitoring of blood glucose was performed six times a day, 3 days/wk. Dietary treatment was considered inappropriate if fasting and postprandial blood glucose values exceeded 7 and 9 mmol/L, respectively, in which case insulin therapy was instituted. Insulin doses were adjusted according to blood glucose values, aiming at fasting and postprandial values below 5 and 6.5 mmol/L, respectively. There were no perinatal deaths. The two treatment regimens disclosed no differences regarding achieved degree of maternal blood glucose control, hemoglobin A1c at delivery, obstetric or neonatal complications, infant's size at birth including skin-fold thickness, or C-peptide concentration in cord serum. Routine treatment of pregnant women with mild carbohydrate intolerance with insulin seems unnecessary. However, 15 patients (14%) in the diet group needed insulin to achieve acceptable blood glucose control, underlining the importance of monitoring blood glucose to detect those who are at risk of developing overt diabetes.

Random capillary blood glucose and conventional selection criteria for glucose tolerance testing during pregnancy.

The normal variation of random capillary blood glucose values and the usefulness of elevated (greater than or equal to 6.5 mmol/l) blood glucose values as a selection criterion for oral glucose tolerance testing (OGTT) during pregnancy were investigated. A consecutive series of 1,500 pregnant women without signs or symptoms of diabetes and 81 pregnant women with conventional selection criteria for OGTT were studied. The mean blood glucose value was 4.66 mmol/l and the 95% tolerance interval of all blood glucose values was 2.93-6.38 mmol/l. Blood glucose levels were not influenced by time of day or trimester of pregnancy. A blood glucose value of 6.5 mmol/l or higher was found in 174 women, 10 of whom had an abnormal OGTT. Four of thirty women with glycosuria or signs of accelerated fetal growth and 7 of 81 women with conventional selection criteria had abnormal OGTT's. The incidence of carbohydrate intolerance during pregnancy was 1.3%. The results of this study suggest that an elevated (greater than or equal to 6.5 mmol/l) random capillary blood glucose value may be a good selection criterion for OGTT in addition to conventional selection criteria when screening for carbohydrate intolerance during pregnancy.