Effect of exercise intensity and duration on capillary glucose responses in pregnant women at low and high risk for gestational diabetes.

BACKGROUND: Exercise may influence glucose metabolism during pregnancy. We examined the effect of exercise intensity and duration on capillary glucose responses in pregnant women at low and high risk for gestational diabetes mellitus (GDM) who followed a modified GDM meal plan. METHODS: Randomization occurred at study entry (16-20 weeks' gestation) into a low-intensity [30% heart rate reserve, low risk-30%I, n = 12; high risk-30%I, n = 11] or vigorous-intensity (70% heart rate reserve, low risk-70%I, n = 12; R-70%I, n = 11) exercise program with similar nutritional control. Exercise consisted of walking three to four times a week, gradually increasing time from 25 to 40 min/session. Free-living capillary glucose concentrations were measured once a week pre-exercise and post-exercise. RESULTS: Capillary glucose responses to exercise were strongly influenced by an interaction between GDM risk, exercise duration and exercise intensity (p = 0.006). Decreases in glucose concentrations were observed after 25 (4 ± 13%), 35 (21 ± 12%) and 40 min (15 ± 18%) of walking in high risk-30%I women, with the most noticeable decline after 35 and 40 min. In the high risk-70%I, glucose concentrations decreased significantly only after 25 (22 ± 14%) and 35 min (7 ± 23%) and increasing the exercise time attenuated glucose concentrations decline. In low risk women, regardless of exercise intensity and duration, decreases in glucose concentrations were significant and similar. CONCLUSION: To achieve the best decline in glucose concentrations, pregnant women who follow a modified GDM meal plan should walk for 25 min/session at vigorous intensity or for 35-40 min/session at low intensity if they are at risk for GDM and for at least 25 min at either low or vigorous intensity if they are at low risk for GDM.

Walking program of low or vigorous intensity during pregnancy confers an aerobic benefit.

Walking is the most popular activity during pregnancy and may confer an aerobic benefit. However, the minimum intensity threshold of a maternal walking program for an aerobic conditioning response is unknown. The purpose was to examine the effect of a walking program of a low-intensity (LI, 30% heart rate reserve, HRR) or vigorous-intensity (VI, 70%HRR) on maternal cardiorespiratory responses to a standard submaximal treadmill test. Normal weight pregnant women were randomized at study entry (16-20 weeks of gestation) to the LI (n=23) or VI (n=21) walking program, with nutritional control. Participants performed a steady-state treadmill exercise test at their prescribed intensity pre- and post-intervention (34-36 weeks) to evaluate changes in cardiorespiratory responses. Increasing body mass due to pregnancy was similar between the groups throughout the study. From pre- to post-intervention, relative (mL kg - 1 min - 1) VO2 and VCO2 during steady-state submaximal treadmill exercise did not change in the LI group but decreased in the VI group (- 1.25±2.71, p=0.02 and - 1.50±2.64, p=0.005, respectively). Both groups presented increases in oxygen pulse (p≤0.002). Our results showed that the energy cost of walking was not affected by the increase in maternal body weight in the LI group and was decreased in the VI group, suggesting an aerobic conditioning response in both groups, although the VI group presented a greater response. All women presented similar body mass throughout the intervention and delivered healthy babies, indicating that a prenatal walking program of low or vigorous intensity, combined with healthy eating habits, is safe and beneficial to the mother and fetus.

Comparative Efficacy of Intramuscular and Scarification Routes of Administration of Live Smallpox Vaccine in a Murine Challenge Model.

In recent years concern has mounted regarding the possibility of a re-emergence of smallpox through biowarfare or bioterrorism. There is also concern over the incidence of human monkeypox in endemic areas and the potential for monkeypox to be accidentally transported to non-endemic areas. In the event of re-emergence of smallpox or emergence of monkeypox, the accepted route of administration for live replicating smallpox vaccine is dermal scarification, which generates a virus-shedding lesion that persists for several days at the vaccination site. The lesion is a potential source of contact transmission of vaccine to individuals who may be contra-indicated for receipt of the live vaccine. In this study, we compare dermal scarification with intramuscular vaccination for replicating smallpox vaccine in a mouse lethal challenge model. Comparisons are made over multiple vaccine and challenge doses and data recorded for lethality, disease severity, and antibody responses. Qualitative and quantitative differences between the two routes are observed, and for the intramuscular route the febrile response is not suppressed after subsequent virulent vaccinia virus challenge. However both routes generate an immune response and protect from severe disease and death. Although dermal scarification is the preferred route of vaccination for the general population, intramuscular vaccination may be an option for people who are not contraindicated for the live vaccine, but who are close contacts of people who are contraindicated for the live vaccine, in an emergency situation.

Cyclopropane-derived peptidomimetics. Design, synthesis, evaluation, and structure of novel HIV-1 protease inhibitors.

Toward establishing the general efficacy of using trisubstituted cyclopropanes as peptide mimics to stabilize extended peptide structures, the cyclopropanes 20a-d were incorporated as replacements into 9-13, which are analogues of the known HIV-1 protease inhibitors 14 and 15. The syntheses of 20a-d commenced with the Rh2[5(S)-MEPY]4-catalyzed cyclization of the allylic diazoesters 16a-d to give the cyclopropyl lactones 17a-d in high enantiomeric excess. Opening of the lactone moiety using the Weinreb protocol and straightforward refunctionalization of the intermediate amides 18a-d gave 20a-d. A similar sequence of reactions was used to prepare the N-methyl-2-pyridyl analogue 28. Coupling of 20a-d and 28 with the known diamino diol 22 delivered 9-13. Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having Kis of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14(IC50 = 0.22 nM) from which they were derived. On the other hand 13 (Ki = 80 nM) was a weaker inhibitor than its analogue 15 (Ki = 0.11 nM). The solution structures of 9 and 10 were analyzed by NMR spectroscopy and simulated annealing procedures that included restraints derived from homo- and heteronuclear coupling constants and NOEs; because of the molecular symmetry of9 and 10, a special protocol to treat the NOE data was used. The final structure was checked by restrained and free molecular dynamic calculations using an explicit DMSO solvent box. The preferred solution conformations of 9 and 10 are extended structures that closely resemble the three-dimensional structure of 10 bound to HIV-1 protease as determined by X-ray crystallographic analysis of the complex. This work convincingly demonstrates that extended structures of peptides may be stabilized by the presence of substituted cyclopropanes that serve as peptide replacements. Moreover, the linear structure enforced in solution by the two cyclopropane rings in the pseudopeptides 9-12 appears to correspond closely to the biologically active conformation of the more flexible inhibitors 14 and 15. The present work, which is a combination of medicinal, structural, and quantum chemistry, thus clearly establishes that cyclopropanes may be used as structural constraints to reduce the flexibility of linear pseudopeptides and to help enforce the biologically active conformation of such ligands in solution.

A Conformationally Restricted ß-Strand HIV Protease Inhibitor.

The use of cyclopropanes as a conformationally restricted subunits in biological systems has been the subject of intense study by our group and others (1-10). Our recent efforts have focused on the use of 1, 2, 3-trisubstituted cyclopropanes as novel [-NH-Cα-] or [-CO-Cα-] bond replacements in pseudopeptides to restrict both side-chain orientation and enforce backbone secondary structures. To test these assumptions, the cyclopropane containing analog 1 (Fig. 1) was modeled after the potent HIV protease inhibitor 2, which together with a series of related derivatives was developed at Abbott Laboratories (11). This pseudopeptide contains a symmetrical diamino diol motif 8 (Fig. 2) flanked by Cbz-protected valine residues and is known to bind in a ß-strand fashion at the enzyme-active site (12). Our analog 1 was designed to restrict the orientation of the valine residues and to mimic this "extended" backbone conformation. Comparison of enzyme inhibition constants for both compound 1 and the parent inhibitor 2 will then elucidate the efficacy of the cyclopropane as a conformationally restrictive subunit. Fig. 1. HIV protease inhibitors. Fig. 2. Synthesis of the cyclopropane containing inhibitor 1.

Influence of patient age on normalized effective doses calculated for CT examinations.

Monte Carlo simulations of CT examinations have been performed to estimate effective doses, normalized to axial air kerma, for six mathematical phantoms representing ages from newborn to adult, and for three CT scanner models covering a range of designs. Organ doses were calculated for CT exposures of contiguous, 1 cm wide, transverse slices in each phantom and summed to give normalized effective doses for scans of four regions of the trunk and head. In all cases an inverse trend is observed between normalized effective dose and phantom age, with the dose to the newborn from head and neck scans being 2.2-2.5 times higher than that to the adult, depending on scanner model. Corresponding increases for scans of the trunk region are more variable between scanners and range from a factor of 1.3 to 2.4. If typical clinical exposure conditions for adults are also utilized for children, then, for example, the effective dose to the newborn from a chest scan could be above 15 mSv. It is concluded that CT has the potential to deliver significantly greater radiation doses to children than to adults and in view of their greater susceptibility to radiation effects, special efforts should be made in clinical practice to reduce doses to children by the use of size-specific scan protocols.

Nuclear medicine activity in the United Kingdom.

A survey of the extent of diagnostic and therapeutic nuclear medicine procedures in the UK has been conducted, and information collected on the types of imaging equipment employed and the typical activities of radiopharmaceuticals administered to patients. A total of 380,000 administrations took place in 1982, corresponding to approximately 6.8 per thousand head of population. 84% were imaging investigations, 13% were non-imaging diagnostic procedures and about 3% were for therapy. Bone scans accounted for 25% of all procedures and 99Tcm was the radionuclide of choice for 75% of investigations. Gamma cameras are superseding rectilinear scanners and most are being purchased together with dedicated image processing computers. Their average annual workload is 922 patients per year. There was considerable variation between the typical administered activities reported by different hospitals for the same procedure, and in some cases the figures reported exceeded the maximum usual activities recommended by the Administration of Radioactive Substances Advisory Committee.

Doses to patients from routine diagnostic X-ray examinations in England.

A collaborative survey between the National Radiological Protection Board and the Hospital Physicists' Association has been conducted to ascertain current levels of exposure for patients undergoing 10 routine types of X-ray examination in England. The main part of this study consisted of measurements on nearly 3200 patients attending 20 randomly selected English hospitals. The energy imparted to each patient was determined from a measurement of the total exposure-area product for the examination. In addition, thermoluminescent dosemeters were attached to the patient's skin to enable the derivation of doses to the major radiosensitive organs, either directly or using appropriate conversion factors calculated for a mathematical phantom by a Monte Carlo technique. Histograms are presented showing the wide distributions often observed in the doses for each type of examination. Mean values of exposure-area product, energy imparted to the patient, entrance skin dose per film and organ dose are reported, together with coefficients of variation. Comparison of the results with those from similar surveys in the UK and abroad is complicated by inconsistencies in the reporting of such data, but substantial differences are sometimes apparent, particularly for the estimates of organ doses. The present measurements will provide a useful baseline for future measurements and will be used to evaluate the collective dose to the population from medical exposures and the radiation risks from the various radiological procedures.

Opening farm gates: community as educator.

This paper presents the experience of five undergraduate Bachelor of Nursing students who undertook a clinical practice placement in a rural community. This, our first engagement with nursing, was a profound learning experience. We did not expect the intense contributions the rural community as a whole would make to our understandings of rural health care in general, and rural nursing in particular. Initially, we felt like outsiders to the rural community as well as the profession of nursing. The interwoven nature of community relationships combined with our acute sense of being highly visible in the township led to us developing a sense of vulnerability. We believed we needed to portray a professional image during all social interactions with the community and this compounded our insecurities during the clinical placement. Before long, we found the rural population embracing and very supportive of our placement. However, we found ourselves questioning whether we would return to a rural community to work as nurses on the basis of our lack of privacy during this time.

National reference doses for common radiographic, fluoroscopic and dental X-ray examinations in the UK.

The National Patient Dose Database (NPDD) is maintained by the Radiation Protection Division of the Health Protection Agency. The latest review of the database analysed the data collected from 316 hospitals over a 5-year period to the end of 2005. The information supplied amounted to a total of 23 000 entrance surface dose measurements and 57 000 dose-area product measurements for single radiographs, and 208 000 dose-area product measurements along with 187 000 fluoroscopy times for diagnostic examinations or interventional procedures. In addition, patient dose data for dental X-ray examinations were included for the first time in the series of 5-yearly reviews. This article presents a summary of a key output from the NPDD - national reference doses. These are based on the third quartile values of the dose distributions for 30 types of diagnostic X-ray examination and 8 types of interventional procedure on adults, and for 4 types of X-ray examination on children. The reference doses are approximately 16% lower than the corresponding values in the previous (2000) review, and are typically less than half the values of the original UK national reference doses that were derived from a survey in the mid-1980s. This commentary suggests that two of the national reference doses from the 2000 review be retained as diagnostic reference levels because the older sample size was larger than for the 2005 review. No clear evidence could be found for the use of digital imaging equipment having a significant effect on dose.

Comparative efficacy of modified vaccinia Ankara (MVA) as a potential replacement smallpox vaccine.

International concern over the potential consequences of a Bioterrorist or Biowarfare associated release of variola virus have prompted renewed interest in the vaccines for smallpox. The traditional live, replicating vaccine strains are subject to novel safety concerns associated with historical production methods in domesticated ruminants and the additional hazards that vaccinia virus poses for people with immune system abnormalities or a history of eczematous skin conditions. In this study we have examined the longevity and efficacy of immunity induced by a non-replicating smallpox vaccine candidate, modified vaccinia Ankara (MVA) in a murine model using intranasal and aerosol routes of infection. Two-step vaccinations of MVA followed by traditional Lister vaccine are compared with either Lister alone or MVA alone, and the longevity of the protection induced by MVA is assessed. MVA is found to be broadly similar to Lister. Although protection is shown to decay with time, when administered at a standard human dose the longevity of protection induced by MVA is comparable to that induced by Lister.

National survey of doses from CT in the UK: 2003.

A review of patient doses from CT examinations in the UK for 2003 has been conducted on the basis of data received from over a quarter of all UK scanners, of which 37% had multislice capability. Questionnaires were employed to collect scan details both for the standard protocols established at each scanner for 12 common types of CT examination on adults and children, and for samples of individual patients. This information was combined with published scanner-specific CT dose index (CTDI) coefficients to estimate values of the standard dose indices CTDI(w) and CTDI(vol) for each scan sequence. Knowledge of each scan length allowed assessment of the dose-length product (DLP) for each examination, from which effective doses were then estimated. When compared with a previous UK survey for 1991, wide variations were still apparent between CT centres in the doses for standard protocols. The mean UK doses for adult patients were in general lower by up to 50% than those for 1991, although doses were slightly higher for multislice (4+) (MSCT) relative to single slice (SSCT) scanners. Values of CTDI(vol) for MSCT were broadly similar to European survey data for 2001. The third quartile values of these dose distributions have been used to derive UK national reference doses for examinations on adults (separately for SSCT and MSCT) and children as initial tools for promoting patient protection. The survey has established the PREDICT (Patient Radiation Exposure and Dose in CT) database as a sustainable national resource for monitoring dose trends in CT through the ongoing collation of further survey data.

Comparative efficacy of replicating smallpox vaccine strains in a murine challenge model.

There is currently considerable concern about the vulnerability of human populations to biowarfare or bioterrorist attacks with variola virus (VARV). Traditional smallpox vaccines were manufactured using the lymph of ruminants infected with the vaccinia virus (VACV). However, these production methods do not meet current standards for vaccines, especially since the emergence of transmissable spongiform encephalopathies in domesticated ruminants. This study has examined the protective efficacy of the Lister (Elstree) vaccine strain from various sources in a murine lethal challenge model. Considerable variation in efficacy is observed between the Lister material obtained from the American Type Culture Collection (ATCC) and the same strain obtained from vaccine stockpiles. A new, tissue-culture derived Lister vaccine is assessed against a bench-mark of multiple lots from a historical stockpile of the traditional vaccine. Apparent qualitative differences are observed between historical and new vaccines. Statistically significant differences are observed between different batches of the traditional vaccine, and the efficacy of the tissue-culture produced vaccine falls within this range.

Early and late reactions in contact sensitivity in the mouse.

Several phases of plasma extravasation have been identified during the course of a contact sensitivity challenge reaction in mice. An early reaction at 1 h is seen which may be mast cell mediated. This is followed by the main phase of extravasation at 3-4 h. This phase is not seen in mice sensitized for less than 5 days and is transferable passively by serum. Between 8 and 15 h there is a prolonged period of moderately intense extravasation which represents the delayed hypersensitivity component of the reaction. Beyond 15 h there is virtually no further extravasation.

Cyclopropane-derived peptidomimetics. design, synthesis, and evaluation of novel Ras farnesyltransferase inhibitors.

Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.

Studies on the total synthesis of disorazole C1. An advanced macrocycle intermediate.

Synthesis of protected tetradehydro-(6,6'-S)-(14,14'-S)-(16,16'-R)-disorazole (3), a potential precursor to the natural product disorazole C1 (1), is described. Key features of this work include (a) an unprecedented sequential 1,5 O --> O silyl rearrangement/Horner-Wadsworth-Emmons reaction used to construct 18, (b) a highly convergent Sonogashira reaction between the dienyl iodide 7 and the alkyne 8 to assemble the dienyne monomeric fragment 5, and (c) the selective cyclization of 5 to give either the cyclic monomer 23 or the dimer 3.

Genital mycoplasmosis in rats: a model for intrauterine infection.

PROBLEM: Microbial infections of the chorioamnion and amniotic fluid have devastating effects on pregnancy outcome and neonatal morbidity and mortality. The mechanisms by which bacterial pathogens cause adverse effects are best addressed by an animal model of the disease with a naturally-occurring pathogen. METHOD OF STUDY: Intrauterine infection in humans as well as genital mycoplasmosis in humans and rodents is reviewed. We describe a genital infection in rats, which provides a model for the role of infection in pregnancy, pregnancy wastage, low birth weight, and fetal infection. RESULTS: Infection of Sprague-Dawley rats with Mycoplasma pulmonis either vaginally or intravenously resulted in decreased litter size, increased adverse pregnancy outcome, and in utero transmission of the microorganism to the fetus. CONCLUSION: Mycoplasma pulmonis is an ideal model to study maternal genital infection during pregnancy, the impact of infections on pregnancy outcome, fetal infection, and maternal-fetal immune interactions.