Five year trends in maternal smoking behaviour reported at the first prenatal appointment.

BACKGROUND: Maternal smoking is a key modifiable risk factor in preventing adverse pregnancy outcomes such as intrauterine growth restriction, preterm birth and stillbirth. AIM: This observational study examined annual trends of maternal smoking reported at the first prenatal visit in women who delivered in a large university maternity hospital for the 5 years 2011-2015. METHODS: We examined clinical and sociodemographic data computerised routinely for women who presented for prenatal care at the hospital between 2011 and 2015. Multinomial logistic regression was used to determine the maternal characteristics, health behaviours and psychiatric history associated with smoking behaviours. RESULTS: Of the 42,509 women the mean age was 31.4 ± 5.5 years, mean Body Mass Index (BMI) was 25.6 ± 5.1 kg/m2, and 39.5% were nulliparas. Overall, 52.6% reported they had never smoked, 34.9% were ex-smokers, 10.5% smoked ≤10 cigarettes per day, 1.9% smoked ≥11 cigarettes per day and 0.1% smoked e-cigarettes. Between 2011 and 2015 the prevalence of maternal cigarette smoking decreased from 14.3 to 10.9% (P < 0.001). Smoking during pregnancy was most strongly associated with younger age, multiparity, unemployment, unplanned pregnancy, a history of psychiatric problems, alcohol intake and illicit drug usage. CONCLUSIONS: The number of women who reported smoking at the first prenatal visit decreased annually. Amongst women who continue to smoke during pregnancy, there is a clustering of adverse lifestyle behaviour and psychological problems that may need to be addressed if smoking cessation interventions are going to succeed in improving fetal programming.

Evaluation of point-of-care maternal glucose measurements for the diagnosis of gestational diabetes mellitus.

OBJECTIVE: Using updated laboratory standards as the reference, we aimed to compare point-of-care (POC) maternal capillary glucose testing with the diagnostic accuracy of reference and customary venous samples. DESIGN, SETTING, POPULATION: Women screened selectively with a one-step 75-g oral glucose tolerance test (OGTT) at 24-28 weeks' gestation were conveniently recruited to this prospective observational study. METHODS: Two venous samples and one capillary sample were taken at each OGTT time point. Venous sample one was a fluoride-EDTA (FE) tube placed on an ice-slurry until cell separation and analysis within 30 minutes (reference standard). Venous sample two was transported in a tube containing FE (without ice) (customary practice). A capillary sample was used for POC testing. Various cut-off points for the POC sample were examined to evaluate diagnostic accuracy. MAIN OUTCOME MEASURES: The sensitivity, specificity, positive and negative predictive values and accuracy of POC capillary glucose for the diagnosis of GDM. RESULTS: Of 108 women, GDM was detected in 47.2% (n = 51), 17.6% (n = 19) and 24.1% (n = 26) using the reference standard, customary practices and POC, respectively (P < 0.001). However, based on adjustment of the POC fasting diagnostic threshold from ≥5.1 to ≥4.8 mol/l (aPOC), sensitivity, specificity, PPV, NPV and accuracy improved to 92.5, 76.5, 69.8, 94.5 and 94.5%, respectively. CONCLUSIONS: POC capillary maternal glucose tests were superior to customary laboratory practices for diagnosing GDM. This has considerable potential, particularly in healthcare settings where facilities for phlebotomy are distant from the laboratory or pre-analytical sample handling is substandard. TWEETABLE ABSTRACT: Adjusted point-of-care glucose measurements have potential in the diagnosis of gestational diabetes mellitus.

Maternal obesity and physical activity and exercise levels as pregnancy advances: an observational study.

BACKGROUND: Increases in clinical complications associated with maternal obesity have generated interest in increasing physical activity (PA) and exercise levels as an intervention to improve pregnancy outcomes. AIMS: The objective of this study was to examine the relationship between BMI categorisation and PA and exercise levels as pregnancy advances. METHODS: This was an observational study in a large university maternity hospital. Women were recruited at their convenience before they left hospital after delivering a baby weighing 500 g or more. They completed a detailed customised physical activity and exercise questionnaire. BMI categorisation was based on the measurement of weight and height in early pregnancy. RESULTS: Of the 155 women recruited, 42.5 % (n = 66) were primigravidas and 10.3 % (n = 16) were smokers. Mean Body Mass Index (BMI) was 24.6 kg/m(2) and 14.2 % (n = 22) were obese, based on a BMI >29.9 kg/m(2). Overall, women decreased their exercise from an average 194 min (range 0-650 min) per week pre-pregnancy to 98 min antenatally (range 0-420 min) (p < 0.0001). Obese women exercised least pre-pregnancy and antenatally at 187.5 and 75 min per week, respectively, compared with 193.2 and 95.5 min per week in the normal BMI group and 239.3 and 106.7 min per week in the overweight group. The mean gestation at which all women reduced their activity levels was 29 weeks. CONCLUSIONS: We found that women decreased their PA  and exercise levels significantly in the third trimester and, thus, in the absence of a medical contra-indication there is considerable scope for an exercise intervention to improve activity  and exercise levels as pregnancy advances. However, an increase in PA levels in obese women needs further studies to determine whether it will improve the clinical outcomes for the woman and her offspring.

Maternal Obesity and Neck Circumference.

Obese women are more likely to require general anaesthesia for an obstetric intervention than non-obese. Difficult tracheal intubation and oxygen desaturation is more common in pregnancy. Failed tracheal intubation has been associated with an increase in neck circumference (NC). We studied the relationship between maternal obesity and NC as pregnancy advanced in women attending a standard antenatal clinic. Of the 96 women recruited, 13.5% were obese. The mean NC was 36.8cm (SD 1.9) in the obese women compared with 31.5cm (SD 1.6) in women with a normal BMI (p < 0.001) at 18-22 weeks gestation. In the obese women it increased on average by 1.5cm by 36-40 weeks compared with an increase of 1.6 cm in women with a normal BMI. The antenatal measurement of NC is a simple, inexpensive tool that is potentially useful for screening obese women who may benefit from an antenatal anaesthetic assessment.

Identifying the immunomodulatory components of helminths.

Immunomodulatory components of helminths offer great promise as an entirely new class of biologics for the treatment of inflammatory diseases. Here, we discuss the emerging themes in helminth-driven immunomodulation in the context of therapeutic drug discovery. We broadly define the approaches that are currently applied by researchers to identify these helminth molecules, highlighting key areas of potential exploitation that have been mostly neglected thus far, notably small molecules. Finally, we propose that the investigation of immunomodulatory compounds will enable the translation of current and future research efforts into potential treatments for autoimmune and allergic diseases, while at the same time yielding new insights into the molecular interface of host-parasite biology.

In vivo efficacy of anuran trypsin inhibitory peptides against staphylococcal skin infection and the impact of peptide cyclization.

Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

Effects of arginine 10 to lysine substitution on ω-conotoxin CVIE and CVIF block of Cav2.2 channels.

BACKGROUND AND PURPOSE: ω-Conotoxins CVIE and CVIF (CVIE&F) selectively inhibit Cav2.2 channels and are lead molecules in the development of novel analgesics. At physiological membrane potentials, CVIE&F block of Cav2.2 channels is weakly reversible. To improve reversibility, we designed and synthesized arginine CVIE&F analogues in which arginine was substituted for lysine at position 10 ([R10K]CVIE&F), and investigated their serum stability and pharmacological actions on voltage-gated calcium channels (VGCCs). EXPERIMENTAL APPROACH: Changes in peptide structure due to R10K substitution were assessed by NMR. Peptide stability in human serum was analysed by reversed-phase HPLC and MS over a 24 h period. Two-electrode voltage-clamp and whole-cell patch clamp techniques were used to study [R10K]CVIE&F effects on VGCC currents in Xenopus oocytes and rat dorsal root ganglion neurons respectively. KEY RESULTS: R10K substitution did not change the conserved ω-conotoxin backbone conformations of CVIE&F nor the ω-conotoxin selectivity for recombinant or native Cav2.2 channels, although the inhibitory potency of [R10K]CVIF was better than that of CVIF. At -80 mV, the R10K chemical modification significantly affected ω-conotoxin-channel interaction, resulting in faster onset kinetics than those of CVIE&F. Heterologous and native Cav2.2 channels recovered better from [R10K]CVIE&F block than CVIE&F. In human serum, the ω-conotoxin half-lives were 6-10 h. CVIE&F and [R10K]CVIE&F were more stable than CVID. CONCLUSIONS AND IMPLICATIONS: R10K substitution in CVIE&F significantly alters the kinetics of ω-conotoxin action and improves reversibility without diminishing conotoxin potency and specificity for the Cav2.2 channel and without diminishing the serum stability. These results may help generate ω-conotoxins with optimized kinetic profiles for target binding.

Improved quality of life in adults undergoing tonsillectomy for recurrent tonsillitis. Is adult tonsillectomy really a low priority treatment?

There is a paucity of studies on patient-reported outcome measures in adult tonsillectomy. Our aim was to add to the body of health-related quality of life (HRQOL) evidence on adult tonsillectomy at a time when this intervention is being branded a low priority treatment in the United Kingdom (UK). We designed a prospective questionnaire study that was carried out in two UK district general hospitals. 41 patients were recruited into the study and completed a pre-operative short form 36 questionnaire. All 41 were contacted at least 1 year after tonsillectomy and were asked to complete the same SF-36 questionnaire and three additional HRQOL questions. There was a significant improvement in quality of life shown by both the mean SF-36 scores and the HRQOL questions. The SF-36 summary measures and the total SF-36 scores improved significantly (p < 0.01). The study emphasises the importance of tonsillectomy being available on the National Health Service to adults with recurrent tonsillitis. This proven quality of life improvement is also highly likely to confer a secondary health economic benefit from less GP attendances and fewer missed work days.

[CT evaluation of locoregional spread of carcinoma of the gallbladder]. / Evaluation de l'extension locorégionale des tumeurs de la vésicule biliaire par la tomodensitométrie.

OBJECTIVE: This study aims to assess the diagnostic capability of CT to preoperatively detect evidence of locoregional spread of gallbladder cancer. PATIENTS AND METHODS: Two radiologists independently performed retrospective review of CT scans on 20 patients who had undergone surgical resection for carcinoma of the gallbladder. Local spread was categorized by the TNM system and the results were correlated with surgical and pathologic findings. RESULTS: All cases of hepatic spread (14 cases), common bile duct extension (four cases), pancreatic spread (three cases) and duodenal spread (three cases) were correctly diagnosed by helical CT. One of three cases of peritoneal spread and two of three cases of gastric spread were misdiagnosed. CT evaluation of T stage (T1: one case [5%]; T2: four cases [20%]; T3: four cases [20%], and T4: 11 cases [55%]) was accurate in 85%. The sensitivity and positive predictive value (PPV) of T1-T2 lesions were 80%. The specificity and negative predictive value (NPV) were 93%. For T4 lesions sensitivity, specificity, PPV and NPV were 100%. CONCLUSION: Helical CT provided 85% accuracy in the diagnosis of the locoregional extent of gallbladder cancer. It allows an acceptable classification according to the TNM staging system and predicts prognosis.

Lichen sclerosis et atrophicus masquerading as tonsillar squamous cell carcinoma.

OBJECTIVE: We report a case of a 70-year-old man of Asian origin with lichen sclerosus et atrophicus affecting the tonsil, which presented as a painful, enlarging, exophytic lesion mimicking squamous cell carcinoma. METHOD: We present a case report and a review of the world literature regarding lichen sclerosus et atrophicus. RESULTS: Lichen sclerosus is a chronic, benign, inflammatory dermatosis of the skin and mucous membranes which mostly affects the female genitalia, presenting as white plaques with epidermal atrophy. The cause is unknown, although a number of aetiologies have been proposed. The prevalence is unknown. Women have been reported to be affected six to 10 times more than men, and the condition has no known racial preference. CONCLUSION: Our patient illustrates a rare case of the condition lichen sclerosus et atrophicus; to our knowledge, this case represents the first report of tonsillar involvement of the condition. The case presented a diagnostic challenge.

Circular proteins in plants: solution structure of a novel macrocyclic trypsin inhibitor from Momordica cochinchinensis.

Much interest has been generated by recent reports on the discovery of circular (i.e. head-to-tail cyclized) proteins in plants. Here we report the three-dimensional structure of one of the newest such circular proteins, MCoTI-II, a novel trypsin inhibitor from Momordica cochinchinensis, a member of the Cucurbitaceae plant family. The structure consists of a small beta-sheet, several turns, and a cystine knot arrangement of the three disulfide bonds. Interestingly, the molecular topology is similar to that of the plant cyclotides (Craik, D. J., Daly, N. L., Bond, T., and Waine, C. (1999) J. Mol. Biol. 294, 1327-1336), which derive from the Rubiaceae and Violaceae plant families, have antimicrobial activities, and exemplify the cyclic cystine knot structural motif as part of their circular backbone. The sequence, biological activity, and plant family of MCoTI-II are all different from known cyclotides. However, given the structural similarity, cyclic backbone, and plant origin of MCoTI-II, we propose that MCoTI-II can be classified as a new member of the cyclotide class of proteins. The expansion of the cyclotides to include trypsin inhibitory activity and a new plant family highlights the importance and functional variability of circular proteins and the fact that they are more common than has previously been believed. Insights into the possible roles of backbone cyclization have been gained by a comparison of the structure of MCoTI-II with the homologous acyclic trypsin inhibitors CMTI-I and EETI-II from the Cucurbitaceae plant family.

Solution structure of BSTI: a new trypsin inhibitor from skin secretions of Bombina bombina.

The three-dimensional solution structure of BSTI, a trypsin inhibitor from the European frog Bombina bombina, has been solved using (1)H NMR spectroscopy. The 60 amino acid protein contains five disulfide bonds, which were unambiguously determined to be Cys (4--38), Cys (13--34), Cys (17--30), Cys (21--60), and Cys (40--54) by experimental restraints and subsequent structure calculations. The main elements of secondary structure are four beta-strands, arranged as two small antiparallel beta-sheets. The overall fold of BSTI is disk shaped and is characterized by the lack of a hydrophobic core. The presumed active site is located on a loop comprising residues 21--34, which is a relatively disordered region similar to that seen in many other protease inhibitors. However, the overall fold is different to other known protease inhibitors with the exception of a small family of inhibitors isolated from nematodes of the family Ascaris and recently also from the haemolymph of Apis mellifera. BSTI may thus be classified as a new member of this recently discovered family of protease inhibitors.

The cystine knot motif in toxins and implications for drug design.

The cystine knot structural motif is present in peptides and proteins from a variety of species, including fungi, plants, marine molluscs, insects and spiders. It comprises an embedded ring formed by two disulfide bonds and their connecting backbone segments which is threaded by a third disulfide bond. It is invariably associated with nearby beta-sheet structure and appears to be a highly efficient motif for structure stabilization. Because of this stability it makes an ideal framework for molecular engineering applications. In this review we summarize the main structural features of the cystine knot motif, focussing on toxin molecules containing either the inhibitor cystine knot or the cyclic cystine knot. Peptides containing these motifs are 26-48 residues long and include ion channel blockers, haemolytic agents, as well as molecules having antiviral and antibacterial activities. The stability of peptide toxins containing the cystine knot motif, their range of bioactivities and their unique structural scaffold can be harnessed for molecular engineering applications and in drug design. Applications of cystine knot molecules for the treatment of pain, and their potential use in antiviral and antibacterial applications are described.

Role of phosphorylation in the conformation of tau peptides implicated in Alzheimer's disease.

A series of peptides corresponding to isolated regions of Tau (tau) protein have been synthesized and their conformations determined by (1)H NMR spectroscopy. Immunodominant peptides corresponding to tau(224-240) and a bisphosphorylated derivative in which a single Thr and a single Ser are phosphorylated at positions 231 and 235 respectively, and which are recognized by an Alzheimer's disease-specific monoclonal antibody, were the main focus of the study. The nonphosphorylated peptide adopts essentially a random coil conformation in aqueous solution, but becomes slightly more ordered into beta-type structure as the hydrophobicity of the solvent is increased by adding up to 50% trifluoroethanol (TFE). Similar trends are observed for the bisphosphorylated peptide, with a somewhat stronger tendency to form an extended structure. There is tentative NMR evidence for a small population of species containing a turn at residues 229-231 in the phosphorylated peptide, and this is strongly supported by CD spectroscopy. A proposal that the selection of a bioactive conformation from a disordered solution ensemble may be an important step (in either tubulin binding or in the formation of PHF) is supported by kinetic data on Pro isomerization. A recent study showed that Thr231 phosphorylation affected the rate of prolyl isomerization and abolished tubulin binding. This binding was restored by the action of the prolyl isomerase Pin1. In the current study, we find evidence for the existence of both trans and cis forms of tau peptides in solution but no difference in the equilibrium distribution of cis-trans isomers upon phosphorylation. Increasing hydrophobicity decreases the prevalence of cis forms and increases the major trans conformation of each of the prolines present in these molecules. We also synthesized mutant peptides containing Tyr substitutions preceding the Pro residues and found that phosphorylation of Tyr appears to have an effect on the equilibrium ratio of cis-trans isomerization and decreases the cis content.

Acyclic permutants of naturally occurring cyclic proteins. Characterization of cystine knot and beta-sheet formation in the macrocyclic polypeptide kalata B1.

Kalata B1 is a prototypic member of the unique cyclotide family of macrocyclic polypeptides in which the major structural features are a circular peptide backbone, a triple-stranded beta-sheet, and a cystine knot arrangement of three disulfide bonds. The cyclotides are the only naturally occurring family of circular proteins and have prompted us to explore the concept of acyclic permutation, i.e. opening the backbone of a cross-linked circular protein in topologically permuted ways. We have synthesized the complete suite of acyclic permutants of kalata B1 and examined the effect of acyclic permutation on structure and activity. Only two of six topologically distinct backbone loops are critical for folding into the native conformation, and these involve disruption of the embedded ring in the cystine knot. Surprisingly, it is possible to disrupt regions of the beta-sheet and still allow folding into native-like structure, provided the cystine knot is intact. Kalata B1 has mild hemolytic activity, but despite the overall structure of the native peptide being retained in all but two cases, none of the acyclic permutants displayed hemolytic activity. This loss of activity is not localized to one particular region and suggests that cyclization is critical for hemolytic activity.

Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif.

Several macrocyclic peptides ( approximately 30 amino acids), with diverse biological activities, have been isolated from the Rubiaceae and Violaceae plant families over recent years. We have significantly expanded the range of known macrocyclic peptides with the discovery of 16 novel peptides from extracts of Viola hederaceae, Viola odorata and Oldenlandia affinis. The Viola plants had not previously been examined for these peptides and thus represent novel species in which these unusual macrocyclic peptides are produced. Further, we have determined the three-dimensional structure of one of these novel peptides, cycloviolacin O1, using (1)H NMR spectroscopy. The structure consists of a distorted triple-stranded beta-sheet and a cystine-knot arrangement of the disulfide bonds. This structure is similar to kalata B1 and circulin A, the only two macrocyclic peptides for which a structure was available, suggesting that despite the sequence variation throughout the peptides they form a family in which the overall fold is conserved. We refer to these peptides as the cyclotide family and their embedded topology as the cyclic cystine knot (CCK) motif. The unique cyclic and knotted nature of these molecules makes them a fascinating example of topologically complex proteins. Examination of the sequences reveals they can be separated into two subfamilies, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularization of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip. Here we define the structural features of the two apparent subfamilies of the CCK peptides which may be significant for the likely defense related role of these peptides within plants.

Non-physician practitioners in radiation oncology: advanced practice nurses and physician assistants.

PURPOSE: With changes in reimbursement and a decrease in the number of residents, there is a need to explore new ways of achieving high quality patient care in radiation oncology. One mechanism is the implementation of non-physician practitioner roles, such as the advanced practice nurse (APN) and physician assistant (PA). This paper provides information for radiation oncologists and nurses making decisions about: (1) whether or not APNs or PAs are appropriate for their practice, (2) which type of provider would be most effective, and (3) how best to implement this role. METHODS: Review of the literature and personal perspective. CONCLUSIONS: Specific issues addressed regarding APN and PA roles in radiation oncology include: definition of roles, regulation, prescriptive authority, reimbursement, considerations in implementation of the role, educational needs, and impact on resident training. A point of emphasis is that the non-physician practitioner is not a replacement or substitute for either a resident or a radiation oncologist. Instead, this role is a complementary one. The non-physician practitioner can assist in the diagnostic work-up of patients, manage symptoms, provide education to patients and families, and assist them in coping. This support facilitates the physician's ability to focus on the technical aspects of prescribing radiotherapy.