Correction to Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials.

Following the work of Avenell et al. that has raised concerns about the integrity of the Yamaguchi Osteoporosis Prevention Study (YOPS) conducted by Ishida and Kawai we issue here an adjustment to all meta-analysis estimates that contained this work within our systematic review.

Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials.

Vitamin K may affect bone mineral density and fracture incidence. Since publication of a previous systematic review the integrity of some of the previous evidence has been questioned and further trials have been published. Therefore an update to the systematic review was required. INTRODUCTION: This systematic review was designed to assess the effectiveness of oral vitamin K supplementation for increasing bone mineral density and reducing fractures in adults. METHODS: MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, and WHO-ICTRP were searched for eligible trials. Randomised controlled trials assessing oral vitamin K supplementation that assessed bone mineral density or fractures in adult populations were included. A total of 36 studies were identified. Two independent reviewers extracted data using a piloted extraction form. RESULTS: For post-menopausal or osteoporotic patients, meta-analysis showed that the odds of any clinical fracture were lower for vitamin K compared to controls (OR, 0.72, 95%CI 0.55 to 0.95). Restricting the analysis to low risk of bias trials reduced the OR to 0.76 (95%CI, 0.58 to 1.01). There was no difference in vertebral fractures between the groups (OR 0.96, 95%CI 0.83 to 1.11). In the bone mineral density meta-analysis, percentage change from baseline at the lumbar spine was higher at 1 year (MD 0.93, 95%, CI - 0.02 to 1.89) and 2 years (MD 1.63%, 95%CI 0.10 to 3.16) for vitamin K compared to controls; however, removing trials at high risk of bias tended to result in smaller differences that were not statistically significant. At 6 months, it was higher in the hip (MD 0.42%, 95%CI 0.01 to 0.83) and femur (MD 0.29%, 95%CI 0.17 to 0.42). There was no significant difference at other anatomical sites. CONCLUSIONS: For post-menopausal or osteoporotic patients, there is no evidence that vitamin K affects bone mineral density or vertebral fractures; it may reduce clinical fractures; however, the evidence is insufficient to confirm this. There are too few trials to draw conclusions for other patient groups.

An approach to testing undiluted e-cigarette aerosol in vitro using 3D reconstituted human airway epithelium.

The data presented here show that to provide an estimate of the relative cytotoxicity and therefore potency of e-cigarettes, undiluted aerosol techniques can be used. With the emergence of electronic nicotine delivery systems, fit-for-purpose in vitro screening methods are required. Reconstituted 3D human airway epithelium, was exposed to undiluted aerosols at the air-liquid interface, using a Vitrocell VC 10. TEER, cilia beat frequency and cytotoxic responses were assessed. Using two smoking regimes (ISO and HCI) a 3R4F reference cigarette, produced IC50s of 5.2 and 2.1 min, 1458 ng/mL and 1640 ng/mL nicotine respectively. Using an open tank e-cigarette device, a full cytotoxicity dose-response curve was obtained giving an IC50 of 30 min with corresponding nicotine of 10,957 ng/mL, 6-14 times less cytotoxic than cigarette smoke. A commonly used e-liquid flavourant cinnamaldehyde and known skin sensitizer was added to the standard e-liquid formulation and used as an aerosolised positive control, at 0.1, 0.025, 0.01 and 0%, demonstrating a full dose response. The delivery of undiluted aerosols in vitro has resulted in increased method sensitivity, throughput and quantitative e-cigarette comparisons. A positive control aerosol generated from a 'safe' e-liquid benchmark can inform risk assessments on supportable levels of flavour ingredients.

Extreme testing of undiluted e-cigarette aerosol in vitro using an Ames air-agar-interface technique.

There is a growing consensus that e-cigarettes hold the potential for reducing the harm associated with cigarette smoking. Recently published studies have reported in vitro testing of e-cigarettes, demonstrating reduced toxicological and biological effects. Few studies however have reported the use of e-cigarettes under extreme testing conditions. To assess the full mutagenic potential of a commercially available electronic-cigarette (Vype ePen), this study investigated the delivery of aerosol under extreme conditions, using a scaled-down 35 mm plate Ames bacterial reverse mutagenicity assay. S. typhimurium strains TA98, TA100, TA97, TA104 and E. coli WP2 uvrA pKM101 with or without metabolic activation (S9), were employed. Using a modified Vitrocell VC 10 exposure system 0, 180, 360, 540, 720 or 900 puffs of undiluted e-cigarette aerosol was generated and delivered to bacterial cultures aligned to reported human consumption data. The results demonstrate that no mutagenic activity was observed in any strain under any test condition even when exposed to 900 puffs of undiluted e-cigarette aerosols +/- S9. Positive control responses were observed in all strains +/- S9. Nicotine assessments demonstrated an increased and consistent aerosol delivery, with calculated maximum doses of ∼1 mg/mL delivery of nicotine. These data demonstrate the validity of this unique testing approach and adds further information to the growing weight of evidence that e-cigarettes offer substantially reduced exposure when compared to conventional cigarette smoke. For future in vitro assessments of next generation tobacco and nicotine products, the generation, delivery and testing of undiluted aerosols can now be considered.

Higher Physiotherapy Frequency Is Associated with Shorter Length of Stay and Greater Functional Recovery in Hospitalized Frail Older Adults: A Retrospective Observational Study.

Extra physiotherapy has been associated with better outcomes in hospitalized patients, but this remains an under-researched area in geriatric medicine wards. We retrospectively studied the association between average physiotherapy frequency and outcomes in hospitalized geriatric patients. High frequency physiotherapy (HFP) was defined as ≥0.5 contacts/day. Of 358 eligible patients, 131 (36.6%) received low, and 227 (63.4%) HFP. Functional improvement (discharge versus admission) in the modified Rankin scale was greater in the HFP group (1.1 versus 0.7 points, P<0.001). The mean length of stay (LOS) of the HFP group was 6 days shorter (7 versus 13 days, P<0.001). After adjusting for age, gender, comorbidity (Charlson index), frailty (Clinical Frailty Scale), dementia and acute illness severity, HFP was an independent predictor of functional improvement, shorter LOS and likelihood of being discharged without a formal care package. Prospective research is needed to examine the effect of physiotherapy frequency and intensity in geriatric wards.

Treatment Planning and Delivery of Whole Brain Irradiation with Hippocampal Avoidance in Rats.

BACKGROUND: Despite the clinical benefit of whole brain radiotherapy (WBRT), patients and physicians are concerned by the long-term impact on cognitive functioning. Many studies investigating the molecular and cellular impact of WBRT have used rodent models. However, there has not been a rodent protocol comparable to the recently reported Radiation Therapy Oncology Group (RTOG) protocol for WBRT with hippocampal avoidance (HA) which is intended to spare cognitive function. The aim of this study was to develop a hippocampal-sparing WBRT protocol in Wistar rats. METHODS: The technical and clinical challenges encountered in hippocampal sparing during rat WBRT are substantial. Three key challenges were identified: hippocampal localization, treatment planning, and treatment localization. Hippocampal localization was achieved with sophisticated imaging techniques requiring deformable registration of a rat MRI atlas with a high resolution MRI followed by fusion via rigid registration to a CBCT. Treatment planning employed a Monte Carlo dose calculation in SmART-Plan and creation of 0.5 cm thick lead blocks custom-shaped to match DRR projections. Treatment localization necessitated the on-board image-guidance capability of the XRAD C225Cx micro-CT/micro-irradiator (Precision X-Ray). Treatment was accomplished with opposed lateral fields with 225 KVp X-rays at a current of 13 mA filtered through 0.3 mm of copper using a 40x40 mm square collimator and the lead blocks. A single fraction of 4 Gy was delivered (2 Gy per lateral field) with a 41 second beam on time per field at a dose rate of 304.5 cGy/min. Dosimetric verification of hippocampal sparing was performed using radiochromic film. In vivo verification of HA was performed after delivery of a single 4 Gy fraction either with or without HA using γ-H2Ax staining of tissue sections from the brain to quantify the amount of DNA damage in rats treated with HA, WBRT, or sham-irradiated (negative controls). RESULTS: The mean dose delivered to radiochromic film beneath the hippocampal block was 0.52 Gy compared to 3.93 Gy without the block, indicating an 87% reduction in the dose delivered to the hippocampus. This difference was consistent with doses predicted by Monte Carlo dose calculation. The Dose Volume Histogram (DVH) generated via Monte Carlo simulation showed an underdose of the target volume (brain minus hippocampus) with 50% of the target volume receiving 100% of the prescription isodose as a result of the lateral blocking techniques sparing some midline thalamic and subcortical tissue. Staining of brain sections with anti-phospho-Histone H2A.X (reflecting double-strand DNA breaks) demonstrated that this treatment protocol limited radiation dose to the hippocampus in vivo. The mean signal intensity from γ-H2Ax staining in the cortex was not significantly different from the signal intensity in the cortex of rats treated with WBRT (5.40 v. 5.75, P = 0.32). In contrast, the signal intensity in the hippocampus of rats treated with HA was significantly lower than rats treated with WBRT (4.55 v. 6.93, P = 0.012). CONCLUSION: Despite the challenges of planning conformal treatments for small volumes in rodents, our dosimetric and in vivo data show that WBRT with HA is feasible in rats. This study provides a useful platform for further application and refinement of the technique.

An inter-machine comparison of tobacco smoke particle deposition in vitro from six independent smoke exposure systems.

There are several whole smoke exposure systems used to assess the biological and toxicological impact of tobacco smoke in vitro. One such system is the Vitrocell® VC 10 Smoking Robot and exposure module. Using quartz crystal microbalances (QCMs) installed into the module, we were able to assess tobacco smoke particle deposition in real-time. We compared regional deposition across the module positions and doses delivered by six VC 10s in four independent laboratories: two in the UK, one in Germany and one in China. Gauge R&r analysis was applied to the total data package from the six VC 10s. As a percentage of the total, reproducibility (between all six VC 10s) and repeatability (error within an individual VC 10) accounted for 0.3% and 7.4% respectively. Thus Gauge R&r was 7.7%, less than 10% overall and considered statistically fit for purpose. The dose-responses obtained from the six machines across the four different locations demonstrated excellent agreement. There were little to no positional differences across the module at all airflows as determined by ANOVA (except for one machine and at three airflows only). These results support the on-going characterisation of the VC 10 exposure system and suitability for tobacco smoke exposure in vitro.

A randomized crossover study to assess the effect of an oat-rich diet on glycaemic control, plasma lipids and postprandial glycaemia, inflammation and oxidative stress in Type 2 diabetes.

AIMS: In the UK, lifestyle intervention is first-line management in Type 2 diabetes. It is unclear what type of diet is most efficacious for improving glycaemic control. This study investigated the effects of an oat-enriched diet on glycaemic control, postprandial glycaemia, inflammation and oxidative stress compared with standard dietary advice. METHODS: In a randomized crossover design, 27 volunteers with Type 2 diabetes, managed on diet and lifestyle only, were observed for two consecutive 8-week periods following either the oat-enriched diet or re-enforced standard dietary advice. Volunteers attended at baseline (habitual intake) and 8 and 16 weeks. Measurements included basic clinical measurements and fasted and postprandial (3-h) glucose and insulin in response to a healthy test meal. Markers of inflammation and oxidative stress, including high-sensitivity C-reactive protein, interleukin 6, interleukin 18, tumour necrosis factor-alpha, adiponectin, thiobarbituric acid reactive substances, oxygen radical antioxidant capacity, oxidized LDL and urinary isoprostanes, were also measured at fasting and in the postprandial period. RESULTS: There were no diet-related effects on glycaemic control or glycaemic or insulinaemic responses to the test meal. Total cholesterol (5.1 ± 1.0 vs. 4.9 ± 0.8 mmol/l, P = 0.019) concentrations declined following the oat-enriched diet compared with standard dietary advice. There was a postprandial decline in adiponectin concentration (P = 0.009), but no effect of dietary intervention. None of the measures of oxidative stress or inflammation were altered by the oat-enriched diet compared with standard dietary advice. CONCLUSION: The oat-enriched diet had a modest impact on lipid lowering, but did not impact on oxidative stress or inflammation in these volunteers with Type 2 diabetes.

Towards comprehensive characterization of Cs-137 Seeds using PRESAGE® dosimetry with optical tomography.

We describe a method to directly measure the radial dose and anisotropy functions of brachytherapy sources using polyurethane based dosimeters read out with optical CT. We measured the radial dose and anisotropy functions for a Cs-137 source using a PRESAGE® dosimeter (9.5cm diameter, 9.2cm height) with a 0.35cm channel drilled for source placement. The dosimeter was immersed in water and irradiated to 5.3Gy at 1cm. Pre- and post-irradiation optical CT scans were acquired with the Duke Large field of view Optical CT Scanner (DLOS) and dose was reconstructed with 0.5mm isotropic voxel size. The measured radial dose factor matched the published fit to within 3% for radii between 0.5-3.0cm, and the anisotropy function matched to within 4% except for θ near 0° and 180° and radii >3cm. Further improvements in measurement accuracy may be achieved by optimizing dose, using the high dynamic range scanning capability of DLOS, and irradiating multiple dosimeters. Initial simulations indicate an 8 fold increase in dose is possible while still allowing sufficient light transmission during optical CT. A more comprehensive measurement may be achieved by increasing dosimeter size and flipping the source orientation between irradiations.

Modes of inhibition of α -amylase and α -glucosidase by aqueous extract of Morinda lucida Benth leaf.

Diabetes mellitus is a metabolic disorder of glucose metabolism. The management of blood glucose level is the hallmark in the treatment of this disease. This may be achieved through the use of oral hypoglycemic drugs such as biguanides, insulin secretagogues, and α-glucosidase inhibitors. The purpose of the present study was to investigate the inhibitory effect of Morinda lucida leaf extracts on the activities of α-amylase and α-glucosidase. This was performed using α-amylase from Aspergillus oryzae and α-glucosidase from Saccharomyces cerevisiae. Aqueous extract of Morinda lucida gave the highest percentage yield (9.99%) of the plant out of the three extracts (compared to acetone and ethanolic extracts) and possesses the highest inhibitory activity against α-amylase (IC50 value of 2.30 mg/mL) and α-glucosidase (IC50 value of 2.00 mg/mL). Kinetic analysis revealed that the aqueous extract of this plant leaf inhibited the α-amylase competitively but displayed mixed noncompetitive mode of inhibition towards α-glucosidase. It can be concluded that aqueous extract of Morinda lucida exhibited the best inhibitory activity on the two enzymes studied and the presence of phytochemicals like flavonoids, saponins, and tannins may have contributed greatly to the inhibitory activity of the plant extract.

Diabetic fatty liver disease is associated with specific changes in blood-borne markers.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) can lead to cirrhosis and hepatocellular carcinoma and is strongly associated with obesity and insulin resistance. The aim of this study was to assess if plasma markers associated with NAFLD are increased in people with concomitant diabetes compared with those without. METHODS: A total of 68 participants were recruited from diabetes and liver clinics. Fatty liver disease was indicated by routine blood tests and ultrasonography. Forty-seven participants had type 2 diabetes; of them, 18 had no fatty liver disease as defined previously (DNoFLD) and 29 had fatty liver disease (DFLD); the remaining 21 had fatty liver disease but no diabetes (NonDFLD). Serum samples were analyzed for adiponectin (APN), alanine and aspartate aminotransferases and plasma for cholesterol, triglyceride, hyaluronic acid (HA), procollagen peptide III, alkaline phosphatase and fibrinogen. RESULTS: Hyaluronic acid and procollagen peptide III were significantly higher and adiponectin significantly lower in DFLD than NonDFLD and DNoFLD, the difference being particularly marked for hyaluronic acid and APN. There was no difference in these markers between NonDFLD and DNoFLD and no association between any plasma or serum marker and ultrasound grade of steatosis. CONCLUSION: We have identified markers of hepatic steatosis that appear to be specific for people with type 2 diabetes. A further longitudinal study is merited to assess the role of these markers in understanding the progression of hepatic steatosis and fibrosis in people with and without diabetes.

SU-E-T-104: Commissioning and Dosimetric Characteristics of TrueBeam System: Composite Data of Three TrueBeam Machines.

INTRODUCTION: A TrueBeam linear accelerator (TB-LINAC) is designed to deliver standard flattened and flattening-filter-free (FFF) beams. In our institute, three TB-LINAC units are installed. In this work, composite data of the three units and multi-unit comparison are presented. METHODS: Each TB-LINAC can deliver photon beams from 4MV to 15MV, electron beams from 6MeV to 22MeV, and 6MV-FFF and 10MV-FFF. Dosimetric characteristics are systematically measured for commissioning including percent depth dose (PDD), beam profile, relative scatter factor, dynamic leaf shift, output factor and MLC leakage. Critic considerations of Pion of FFF photon beams and dosimetric penumbra are investigated. RESULTS: All measured PDDs and profiles of photon and electron matched well across the three machines. Beam data were quantitatively compared and combined through average to yield composite beam data. The discrepancies among the machines were quantified using standard deviation (SD). For example, the mean SD of the PDDs among the three units is 0.12%, and the mean SD of the profiles is 0.40% for 10MV-FFF open fields. The variations of Pion of the chamber CC13 is 1.2±0.1% under 6MV-FFF and 2.0±0.5% from dmax to the 18cm-off-axis point at 35cm depth under 40×40cm2 . The measured relative output factors range from 0.866 to 1.141 with the mean discrepancy of 0.06±0.04% among the three units. The measured wedge factors range from 0.863 to 1.254 with the mean overall discrepancy of 0.04±0.04%. The mean MLC transmission and dynamic leaf shift were measured from 1.0% to 1.5% and from 0.77mm to 0.96 mm from 4MV to 15MV. The mean penumbra of various photon beams are measured from 5.88±0.09mm to 5.99±0.13mm from 4MV to 15MV at 10cm depth of 10×10 cm2 . CONCLUSIONS: Dosimetric data demonstrated that the three units could and had been matched well. The systematically measured data might be useful for future reference.

SU-D-213AB-05: Commissioning a CT Compatible LDR T&O Applicator Using Analytical Calculation with ID and 3D Dosimetry.

PURPOSE: To determine the characteristics of a new commercially available CT-compatible LDR Tandem and Ovoid (T&O) applicator using 3D dosimetry. METHODS: We characterized source attenuation through the asymmetric gold shielding in the buckets by measuring dose with diode and 3D dosimetry and compared to an analytical line integral calculation. For 3D dosimetry, a cylindrical PRESAGE dosimeter (9.5cm diameter, 9.2cm height) with a central 6mm channel bored for source placement was scanned with the Duke Large field of view Optical CT-Scanner (DLOS) before and after delivering a nominal 7.7Gy at a distance of 1 cm using a Cs-137 source loaded in the bucket. The optical CT scan time lasted approximately 15 minutes during which 720 projections were acquired at 0.5° increments, anda 3D dose distribution was reconstructed with a 0.5mm3 isotropic voxel size. The 3D dose distribution was applied to a CT-based T&O implant to determine effect of ovoid shielding on the dose delivered to ICRU 38 Point A as well as D2cc of the bladder, rectum, bowel, and sigmoid. RESULTS: Dose transmission through the gold shielding at a radial distance of 1-3cm from midplane of the source was 86.6%, 86.1, and 87.0% for analytical calculation, diode, and 3D dosimetry, respectively. For the gold shielding of the bucket, dose transmission calculated using the 3D dosimetrymeasurement was found to be lowest at oblique angles from the bucket witha minimum of ∼51%. For the patient case, attenuation from the buckets leadto a decrease in average Point A dose of ∼4% and decrease in D2cc to bladder, rectum, sigmoid, and bowel of 2%, 15%, 2%, and 7%, respectively. CONCLUSIONS: The measured 3D dose distribution provided unique insight to the dosimetry and shielding characteristics of the investigated applicator, the technique for which can be applied to commissioning of other brachytherapy applicators. John Adamovics is the owner of Heuris Pharma LLC. Partially supported by NIH Grant R01 CA100835-01.

Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure.

BACKGROUND: Apelin, the endogenous ligand for the novel G protein-coupled receptor APJ, has major cardiovascular effects in preclinical models. The study objectives were to establish the effects of acute apelin administration on peripheral, cardiac, and systemic hemodynamic variables in healthy volunteers and patients with heart failure. METHODS AND RESULTS: Eighteen patients with New York Heart Association class II to III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers participated in a series of randomized, double-blind, placebo-controlled studies. Measurements of forearm blood flow, coronary blood flow, left ventricular pressure, and cardiac output were made by venous occlusion plethysmography, Doppler flow wire and quantitative coronary angiography, pressure wire, and thoracic bioimpedance, respectively. Intrabrachial infusions of (Pyr(1))apelin-13, acetylcholine, and sodium nitroprusside caused forearm vasodilatation in patients and control subjects (all P<0.0001). Vasodilatation to acetylcholine (P=0.01) but not apelin (P=0.3) or sodium nitroprusside (P=0.9) was attenuated in patients with heart failure. Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum rate of rise in left ventricular pressure and reduced peak and end-diastolic left ventricular pressures (all P<0.05). Systemic infusions of (Pyr(1))apelin-13 (30 to 300 nmol/min) increased cardiac index and lowered mean arterial pressure and peripheral vascular resistance in patients and healthy control subjects (all P<0.01) but increased heart rate only in control subjects (P<0.01). CONCLUSIONS: Acute apelin administration in humans causes peripheral and coronary vasodilatation and increases cardiac output. APJ agonism represents a novel potential therapeutic target for patients with heart failure.

The multi-annual carbon budget of a peat-covered catchment.

This study estimates the complete carbon budget of an 11.4 km(2) peat-covered catchment in Northern England. The budget considers both fluvial and gaseous carbon fluxes and includes estimates of particulate organic carbon (POC); dissolved organic carbon (DOC); excess dissolved CO(2); release of methane (CH(4)); net ecosystem respiration of CO(2); and uptake of CO(2) by primary productivity. All components except CH(4) were measured directly in the catchment and annual carbon budgets were calculated for the catchment between 1993 and 2005 using both extrapolation and interpolation methods. The study shows that: Over the 13 year study period the total carbon balance varied between a net sink of -20 to -91 Mg C/km(2)/yr. The biggest component of this budget is the uptake of carbon by primary productivity (-178 Mg C/km(2)/yr) and in most years the second largest component is the loss of DOC from the peat profile (+39 Mg C/km(2)/yr). Direct exchanges of C with the atmosphere average -89 Mg C/km(2)/yr in the catchment. Extrapolating the general findings of the carbon budget across all UK peatlands results in an approximate carbon balance of -1.2 Tg C/yr (+/-0.4 Pg C/yr) which is larger than previously reported values. Carbon budgets should always be reported with a clear statement of the techniques used and errors involved as this is significant when comparing results across studies.

Personality traits among ADHD adults: implications of late-onset and subthreshold diagnoses.

BACKGROUND: Diagnosing attention deficit hyperactivity disorder (ADHD) in adults is difficult when diagnosticians cannot establish onset prior to the DSM-IV criterion of age 7 or if the number of symptoms does not achieve the DSM threshold for diagnosis. Previous work has assessed the validity of such diagnoses based on psychiatric co-morbidity, family history and neuropsychological functions but none of these studies have used personality as a validation criterion. METHOD: We compared four groups of adults: (1) full ADHD subjects who met all DSM-IV criteria for childhood-onset ADHD; (2) late-onset subjects who met all criteria except the age at onset criterion, (3) subthreshold subjects who did not meet full symptom criteria and (4) non-ADHD subjects who did not meet any of the above criteria. Diagnoses were made by using the Structured Clinical Interview for DSM-IV (SCID) and the Temperament and Character Inventory (TCI) was used to assess personality traits. RESULTS: We found that full ADHD and late-onset ADHD showed similar personality profiles with significant deviations on all TCI scales except reward dependence and self-transcendence. By contrast, subthreshold cases only showed deviations on novelty seeking and self-directiveness. CONCLUSIONS: These data call into question the stringent age of onset of ADHD symptom criteria for adults when making retrospective diagnoses of ADHD. Subthreshold ADHD seems to be a milder form of the disorder that is consistent with dimensional views of the disorder.

Meaningful differences in maternal smoking behaviour during pregnancy: implications for infant behavioural vulnerability.

BACKGROUND: Smoking during pregnancy has been consistently associated with risk of problem behaviour in offspring. There is debate about whether this association reflects a teratological effect or is a marker for problematic maternal characteristics. We test these "competing" hypotheses by examining whether (1) exposure is associated with an early risk pathway by testing its association with infant temperamental difficultness, and (2) whether pregnancy quitting is associated with an early protective pathway, testing its association with easy infant temperament. METHODS: We used the 9-month-old sweep of the Millennium Cohort Study, a cohort of over 18,000 infants born in 2000-2. Mothers were classified as pregnancy non-smokers, quitters and light or heavy smokers. Temperamental positive mood, receptivity to novelty and regularity were assessed with the Carey Infant Temperament Scale. RESULTS: Pregnancy quitters had infants with the highest scores of easy temperament and heavy smokers had infants with the lowest scores (F = 28.51, p<0.001). Pregnancy smoking also predicted difficult temperament: heavy smoking was associated with increased risk of low positive mood (OR = 1.17, p = 0.09). In contrast, pregnancy quitting exerted a protective effect with decreased risk of distress to novelty (OR = 0.79, p<0.01) and irregularity (OR = 0.89, p = 0.02) in these infants. CONCLUSIONS: Pathways from pregnancy smoking to offspring behaviour are complex and multi-determined. These findings suggest that both exposure and maternal characteristics associated with pregnancy smoking status contribute to offspring behavioural patterns. Research that characterises differences between quitters and persistent smokers and examines the role of these differences in prediction of early vulnerabilities and problems in adaptation over time will be important for elucidating these pathways.

Does group B streptococcal infection contribute significantly to neonatal sepsis in Antigua and Barbuda?

Group B streptococcus is the most common cause of neonatal sepsis in the United States of America (USA). This study was undertaken to determine the contribution of group B streptococcus to neonatal septicaemia in Antigua and Barbuda. From 1994 to 2002, there were about 12 000 births, with 2500Special Care Nursery admissions, 1100 (44%) with potential neonatal septicaemia. Blood cultures were done in 433/1100 (39%) and cerebrospinal fluid cultures in 52/1100 (5%). Positive cultures were seen in 41/433 (9.5%) with group B streptococcus in 1/41 (2.4%), streptococcus “species” in 3/41 (7.4%) and positive cerebrospinal fluid cultures were seen in 2/52 (one group B streptococcus) giving 5 per 12 000 or 0.4 cases per 1000 babies. Vaginal cultures from 1994 to 2002 revealed group B streptococcus in 14/163 (8.6%) of positive bacterial cultures. A sample of pregnant women from a private office had positive culture for group B streptococcus in 2/120 (1.7%). The prevalence rate of carriage (15 to 40%) and infection (1.7 to 4 per 1000 babies) was much higher in the USA in the same period. Universal screening of mothers for group B streptococcus may not be as necessary or cost-effective inAntigua and Barbuda.

Los estreptococos del grupo B son la causa más común de sepsis neonatal en los Estados Unidos (EE.UU.). Este estudio se llevó a cabo con el propósito de determinar en que medida los estreptococos del grupo B contribuyen a la septicemia neonatal en Antigua y Barbuda. Desde el año 1994 hasta el2002, hubo alrededor de 12000 nacimientos, con 2500 ingresos a la Guardería de Cuidados Especiales, 1100 (44%) con septicemia neonatal potencial. Se realizaron cultivos de sangre en 433/1100 (39%) y cultivos del líquido cefalorraquídeo cerebroespinal) en 52/1100 (5%). Seobservaron cultivos positivos en 41/433 (9.5%) con estreptococos B en 1/41 (2.4%), “especies“ de estreptococos en 3/41 (7.4%), y se observaron cultivos cefalorraquídeos positivos en 2/52 (1 de estreptococosdel grupo B), para 5 por 12 000 ó 0.4 casos por 1000 recién nacidos. Los cultivos vaginales desde el año 1994 al 2002 revelaron estreptococos del grupo B en 14/163 (8.6%) de los cultivosbacterianos positivos. Una muestra de mujeres embarazadas – provenientes de una oficina privada – tuvo un cultivo positivo para estreptococos del grupo B en 2/120 (1.7%). La tasa de prevalencia de portación (15 a 40%) e infección (1.7 a 4 por 1000 recién nacidos) fue mucho más alta en los EE.UU. en el mismo período. El pesquisaje universal de madres en relación con el estreptococo de grupo Bpuede no ser tan necesario o costo-efectivo en Antigua y Barbuda.

Clinicopathologic correlation in PGRN mutations.

BACKGROUND: Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin (PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs). METHODS: PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations. RESULTS: PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations. CONCLUSION: PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.