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Background: Fibromyalgia and myofascial pain syndrome are clearly distinguishable, different clinical conditions and can interact strongly. Each condition can be managed when it is clearly identified as such and the appropriate management corrections are applied.Findings: 1. The patient learned how to manage this combination of syndromes effectively. 2. The patient learned to gain control of FMS symptoms. 3. Gaining control of symptoms from myofascial trigger points required help from a skilled physical therapist.Conclusion: The management of patients with fibromyalgia and myofascial pain syndromes is often a very complicated process. Neuromobilization techniques and treatment of trigger points were quite effective in finally achieving a good functional outcome for this patient with both conditions. [ABSTRACT FROM AUTHOR]

A single-arm pilot study explored the feasibility of adapting in Interpersonal Psychotherapy (IPT) by telephone to reduce psychological distress and to enhance coping during cancer treatment. Therapy focuses on role transitions, interpersonal conflicts, and grief precipitated by cancer. Breast cancer patients receiving high-dose chemotherapy received weekly sessions with a psychologist throughout chemotherapy and for 1 month afterwards. Patients could invite one 'partner' to receive individual telephone IPT. Psychosocial functioning was assessed using standardized measures at study entry, after chemotherapy, and following telephone IPT. Accrual and participation supplied evidence of feasibility: 14 patients and 10 partners were recruited, 82.5% of those eligible. Patients had a mean of 16 sessions; partners had a mean of 11. Participants rated their satisfaction with the program between 'good' and 'excellent'. A test of the efficacy of telephone IPT requires a larger, randomized trial. In order to standardize the intervention, a treatment manual was developed. This study indicated the importance of outreach to family members as well as to cancer patients, intensive patient education about oncology treatment and the medical care setting, and psychosocial services that continue after cancer treatment has been completed. [ABSTRACT FROM AUTHOR]

A young adult African American female presented with normocytic microangiopathic haemolytic anaemia, elevated lactate dehydrogenase and thrombocytopenia. The patient responded to therapeutic plasma exchanges (TPE) for presumed thrombotic microangiopathy caused by thrombotic thrombocytopenic purpura (TTP). After relapsing, the patient was found to have pancytopenia, megaloblastic bone marrow and low vitamin B12 consistent with pernicious anaemia, which improved with intramuscular B12 and discontinuation of TPE. B12-deficient macrocytosis was not seen at presentation due to concomitant alpha-thalassaemia. Initial clinical/laboratory improvement is attributed to B12 present in TPE plasma. B12 deficiency can mimic TTP. Vigilance is needed regarding atypical presentations of pernicious anaemia., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: The perinatal period and in utero environment are important for fetal growth, development, and fetal programming. This study aimed to determine the effect of parental anthropometry and the maternal metabolic milieu on offspring adiposity at 2 years of age., Study Design: This longitudinal birth cohort includes analysis of maternal ( n  = 337) and paternal ( n  = 219) anthropometry and maternal and fetal metabolic markers ( n  = 337), including glucose, homeostatic model of assessment (HOMA), C-peptide, and leptin from participants of the ROLO (the Randomized Control Trial of Low) pregnancy study, and their partners, to determine an association with offspring anthropometry at two years of age., Results: Linear regression, when adjusted for confounders, indicated maternal and paternal anthropometry and was associated with offspring weight and length at 2 years of age. Maternal height was negatively associated with general adiposity in the total cohort of children ( p  = 0.002) and in female children ( p  = 0.006) and central adiposity in the total child cohort ( p  < 0.001). Paternal height was also negatively associated with general adiposity in all children ( p  = 0.002) and central adiposity in total ( p  = 0.023) and female children ( p  = 0.008). Maternal glucose, insulin resistance, and fetal C-peptide positively correlated with anthropometry in total, male, and female children., Conclusion: Parental anthropometry in the perinatal period has a long-lasting effect on offspring anthropometry beyond the neonatal period. Maternal and fetal metabolic factors influence adiposity, and this extends beyond the perinatal period. Parental adiposity may play a significant role in early childhood adiposity and may be a target for interventions to decrease the risk of early childhood obesity., Key Points: · Parental height and weight were associated with offspring anthropometry and measures of offspring adiposity at 2 years of age.. · Maternal glucose, insulin resistance, and fetal C-peptide correlated with offspring anthropometry.. · Parental anthropometry has long-term effect on offspring adiposity and is seen at 2 years of age.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: The pronator quadratus (PQ) muscle is an important stabilizer of the distal radio-ulnar joint and its pain referral pattern can mimic median or ulnar neuropathy. Research on treatment safety and efficacy with dry needling is scarce., Objective: To determine if a solid filiform needle accurately and safely penetrates the PQ during simulated clinical application of dry needling., Methods: A cadaveric descriptive study was conducted. Needling insertion of PQ was performed in 10 cryopreserved forearms with a 30*0.32 mm solid filiform needle. With the forearm pronated, the needle was inserted 3 cm proximal to the ulnar styloid in an anterior direction toward the muscle. The needle was advanced into the PQ based upon clinician judgment. Safety was assessed by calculating the distance from the needle to the surrounding neurovascular bundles., Results: Accurate needle penetration of the PQ was observed in 90% of the cadavers (needle penetration: 19.8 ± 4.0 mm, 95%CI 17.0 to 22.6 mm). No neurovascular bundle was pierced during needling in any specimen forearms. The distance from the tip of the needle was 15.1 ± 4.8 mm (95%CI 11.7 to 18.5 mm) to the ulnar nerve, 15.6 ± 7.6 mm (95%CI 10.0 to 21 mm) to the ulnar artery, 11.2 ± 3.3 mm (95%CI 8.8 to 13.6 mm) to the median nerve, and 4.9 ± 1.4 mm (95%CI 3.9 to 5.9 mm) to the anterior interosseous neurovascular bundle., Conclusion: The results from this cadaveric study support the assumption that needling of the PQ by the dorsal aspect of the forearm can be accurately and safely conducted by an experienced clinician. Studies investigating the clinical safety and effectiveness of this interventions are needed.

Introduction: Childhood obesity remains a significant global health concern. Early intervention through maternal diet during pregnancy represents a possible mode of improving childhood adiposity., Aim: To examine the impact of a low glycaemic index diet during pregnancy on offspring anthropometry at 5 years of age., Methods: This is a secondary analysis of 387 children from the ROLO pregnancy study 5 years' post-intervention. At the follow-up, BMI, circumferences and skinfold thickness were obtained. A subgroup of 103 children had a DXA scan completed. Statistical analyses included Independent sample t tests, Mann Whitney-U tests and chi-square tests to compare the intervention and control groups. Adjusted analysis using linear regression controlled for significant confounders between participants who returned at follow-up and those that did not., Results: There were no significant differences in BMI (16.05 kg/m 2 vs 16.16 kg/m 2 , P = 0.403), general adiposity (36.60 mm vs 36.00 mm, P = 0.920), central adiposity (0.61 mm vs 0.60 mm, P = 0.540), total fat mass (4.91 kg vs 4.71 kg, P = 0.377) or total lean mass (14.29 kg vs 14.56 kg, P = 0.386) between the intervention and control groups, respectively. No associations were observed in 5-year outcomes in adjusted analyses when controlling for maternal age at delivery, maternal early pregnancy BMI, maternal education and gestational age., Conclusion: Our study found no evidence that a low glycaemic index diet in pregnancy impacts offspring anthropometry 5 years' post-intervention. Therefore, modulating maternal carbohydrate quality in pregnancy may not be an appropriate approach to improving weight status in childhood. Future research should investigate the impact of other dietary practices in pregnancy on child health., (© 2021 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

The supinator muscle is involved in two pain conditions of the forearm and wrist: lateral epicondylalgia and radial tunnel syndrome. Its close anatomical relationship with the radial nerve at the arcade of Frohse encourages research on dry needling approaches. Our aim was to determine if a solid filiform needle safely penetrates the supinator muscle during the clinical application of dry needling. Needle insertion of the supinator muscle was conducted in ten cryopreserved forearm specimens with a 30 × 0.32 mm filiform needle. With the forearm pronated, the needle was inserted perpendicular into the skin at the dorsal aspect of the forearm at a point located 4cm distal to the lateral epicondyle. The needle was advanced to a depth judged to be in the supinator muscle. Safety was assessed by measuring the distance from the needle to the surrounding neurovascular bundles of the radial nerve. Accurate needle penetration of the supinator muscle was observed in 100% of the forearms (needle penetration:16.4 ± 2.7 mm 95% CI 14.5 mm to 18.3 mm). No neurovascular bundle of the radial nerve was pierced in any of the specimen's forearms. The distances from the tip of the needle were 7.8 ± 2.9 mm (95% CI 5.7 mm to 9.8 mm) to the deep branch of the radial nerve and 8.6 ± 4.3 mm (95% CI 5.5 mm to 11.7 mm) to the superficial branch of the radial nerve. The results from this cadaveric study support the assumption that needling of the supinator muscle can be accurately and safely conducted by an experienced clinician.

The chemistry of copper and iron plays a critical role in normal brain function. A variety of enzymes and proteins containing positively charged Cu + , Cu 2+ , Fe 2+ , and Fe 3+ control key processes, catalyzing oxidative metabolism and neurotransmitter and neuropeptide production. Here, we report the discovery of elemental (zero-oxidation state) metallic Cu 0 accompanying ferromagnetic elemental Fe 0 in the human brain. These nanoscale biometal deposits were identified within amyloid plaque cores isolated from Alzheimer's disease subjects, using synchrotron x-ray spectromicroscopy. The surfaces of nanodeposits of metallic copper and iron are highly reactive, with distinctly different chemical and magnetic properties from their predominant oxide counterparts. The discovery of metals in their elemental form in the brain raises new questions regarding their generation and their role in neurochemistry, neurobiology, and the etiology of neurodegenerative disease., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Importance: Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist., Objective: To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections., Design, Setting, and Participants: This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers., Interventions: A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder., Main Outcomes and Measures: The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence., Results: The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, -3.4%; 95% CI, -6.9% to 0.1%; P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, -3.7%; 95% CI, -6.7% to -0.8%; P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, -1.6% to 2.1%; P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections., Conclusions and Relevance: Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin., Trial Registration: ClinicalTrials.gov Identifier: NCT02227446.

Background: Child eating behaviours can negatively contribute to the development of childhood obesity. This study investigated associations between breastfeeding habits, maternal eating behaviours and child eating behaviours, in 5-year-old children., Methods: Secundigravida women were recruited to the ROLO dietary randomised controlled trial (Dublin, Ireland) and were followed up with their children to 5 years of age. Breastfeeding exposure and duration were obtained at postnatal and infant follow-up at 2 and 6 months and 2 and 5 years. At 5 years, maternal and child eating behaviours were measured using the Three Factor Eating Questionnaire and the Child Eating Behaviour Questionnaire, respectively. Regression determined associations between breastfeeding habits and maternal eating behaviours with child eating behaviours, controlling for RCT group, maternal education level, maternal BMI at 5 years, childcare exposure and child BMI centile at 5-year follow-up., Results: There were 230 mother and child pairs analysed. One hundred and fifty-eight mothers had initiated breastfeeding. Median breastfeeding duration was 22 (IQR 33) weeks. Children who were never breastfed were more likely to express a desire to drink (B = -1.01, p = 0.022). Longer breastfeeding duration was associated with lower food responsiveness (B = -1.71, p = 0.003). Maternal uncontrolled eating was positively associated with child food responsiveness, emotional overeating and emotional undereating (B = 0.21, p < 0.001; B = 0.14, p = 0.005; B = 0.14, p = 0.005, respectively). Maternal emotional eating was associated with child emotional overeating and undereating (B = 0.27, p < 0.001, B = 0.29, p = 0.004, respectively)., Conclusion: Not breastfeeding and short breastfeeding duration may contribute to the development of obesogenic eating behaviours in children, alongside maternal eating behaviours including uncontrolled and emotional eating. These 'food approach' eating behaviours may increase risk of overweight/obesity as they are associated with increased energy intake, hence the importance of research surrounding eating behaviours.

The stable complex [bis(toluene-3,4-dithiolato)copper(iii)][NEt3H] has been synthesised and characterised as a square-planar Cu(iii) complex by X-ray photoelectron spectroscopy, cyclic voltammetry and DFT calculations. Intriguingly, when fragmented in FTICR-MS, an unusual [(toluene-3,4-dithiolate)Cu(iii)(peroxide)]- complex is formed by reaction with oxygen. Natural 1,2-dithiolenes known to bind molybdenum might stabilise Cu(iii) in vivo.

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Elevated stearoyl-CoA desaturase 1 (SCD-1) activity showed associations with obesity in cross-sectional studies. In non-pregnant populations, nutrition regulates SCD-1 transcription and activity., Objective: To investigate the longitudinal associations of maternal and fetal SCD-1 activity markers with infant anthropometry up to 2 years of age, and to explore how selected dietary intakes modulate SCD-1 activity in pregnancy., Methods: As a secondary analysis from the ROLO intervention study, which was conducted in a population at risk for macrosomia, non-esterified fatty acids (NEFA) from maternal plasma at 13 and 28 weeks' gestation and in cord blood were measured via liquid-chromatography-mass-spectrometry. Fatty acid ratios 18:1/18:0 and 16:1/16:0 were used as markers for SCD-1 activity ('desaturation indices', DIs). Relationships of DIs with infant anthropometry up to 2 years of age and maternal dietary parameters during pregnancy were investigated using adjusted linear regression models and p-values correction for multiple testing., Results: 18:1/18:0, but not 16:1/16:0, was associated with measures of infant anthropometry at birth (maternal and fetal markers) and up to 2 years of age (maternal markers only). Dietary intakes did not show strong associations with 18:1/18:0, but 16:1/16:0 was associated with absolute and relative dietary intakes., Conclusions: In a population at risk for macrosomia, maternal SCD-1 activity measured via 18:1/18:0 was involved in the fetal programming of infant obesity, but could not be substantially modulated by short-term diet in pregnancy., Clinical Trial Registration: ISRCTN Registration number: ISRCTN54392969 (http://www.isrctn.com/ISRCTN54392969)., (Copyright © 2019. Published by Elsevier Ltd.)

Background: To determine the association of maternal and fetal inflammatory factors with gender-specific infant adiposity, independent of leptin. Methods: Analysis of anthropometry from 265 mother-infant pairs at birth and 280 pairs at 6 months from the randomised control trial of low glycaemic index diet in pregnancy (ROLO) study (Randomised control trial of low glycaemic index diet) and their association with Maternal TNF-alpha, interleukin 6 and leptin as measured in early and late pregnancy and fetal levels in cord blood. Results: No associations were noted in the male cohort. On multiple regression amongst the female neonatal cohort late pregnancy IL-6 was inversely associated with sum of skinfolds ( p  ≤ .001); at 6 months infant sum of skinfolds were positively associated with early pregnancy IL-6 ( p  = .046) and central adiposity positively associated with early pregnancy TNF alpha ( p  = .018) independent of leptin. Conclusion: Although maternal inflammatory cytokines were not associated with neonatal adiposity independent of leptin (as this association is known), both IL-6 and TNF-α were associated with female infant anthropometry at 6 months of age independent of leptin. These results suggest inflammatory cytokines may exert an in-utero influence on later infant adiposity with a tendency to influence female adiposity more than male. Further research is required to ascertain whether these cytokines may be used as reliable early predictors of infant adiposity.

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor-independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1 F/F ; CDX2-cre) and crossed them with Apc Min/+ mice (Apc Min/+ ; Gfi1 F/F ; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (Apc Min/+ ; Gfi1 F/F ; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon. IMPLICATIONS: These findings reveal that GFI1 functions as a tumor suppressor gene in colorectal tumorigenesis., (©2019 American Association for Cancer Research.)

Background: Chest X-rays (CXRs) are traditionally obtained daily in all patients on invasive mechanical ventilation (IMV) in the intensive care unit (ICU). We sought to reduce overutilisation of CXRs obtained in the ICU, using a multifaceted intervention to eliminate automated daily studies., Methods: We first educated ICU staff about the low diagnostic yield of automated daily CXRs, then removed the 'daily' option from the electronic health records-based ordering system, and added a query (CXR indicated or not indicated) to the ICU daily rounding checklist to prompt a CXR order when clinically warranted. We built a report from billing codes, focusing on all CXRs obtained on IMV census days in the medical (MICU) and surgical (SICU) ICUs, excluding the day of admission and days that a procedure warranting CXR was performed. This generated the number of CXRs obtained every 1000 'included' ventilator days (IVDs), the latter defined as not having an 'absolute' clinical indication for CXR., Results: The average monthly number of CXRs on an IVD decreased from 919±90 (95% CI 877 to 963) to 330±87 (95% CI 295 to 354) per 1000 IVDs in the MICU, and from 995±69 (95% CI 947 to 1055) to 649±133 (95% CI 593 to 697) in the SICU. This yielded an estimated 1830 to 2066 CXRs avoided over 2 years and an estimated annual savings of $191 600 to $224 200. There was no increase in reported adverse events., Conclusion: ICUs can safely transition to a higher value strategy of indication-based chest imaging by educating staff, eliminating the 'daily' order option and adding a simplified prompt to avoid missing clinically indicated CXRs., Competing Interests: Competing interests: None declared.

Background: Vitamin D status in pregnancy and offspring bone health effects are well established, yet limited knowledge exists on the effect of maternal vitamin D status on offspring size/adiposity. This study examines the association of early (13 weeks), late (28 weeks) pregnancy and neonatal (umbilical) 25-hydroxyvitamin D (25OHD) on offspring size/adiposity., Methods: This analysis included mother-infant pairs from the ROLO study at birth ( n  = 292), 6-9 months ( n  = 160) and 2-2.5 years ( n  = 287) postpartum., Results: Using Institute of Medicine 2011 Report criteria, 30% of women in early pregnancy and 38% in late pregnancy were at risk of vitamin D deficiency (25OHD < 30 nmol/L). Birthweight was negatively associated with early-pregnancy 25OHD ( p  = 0.004) and neonatal 25OHD ( p  < 0.001). Birth length was not associated with 25OHD. Neonatal measures of overall adiposity were negatively associated with neonatal 25OHD ( p  = 0.001, and p  = <0.001 respectively). At 2-2.5 years there was a negative association between weight-for-age z-score and early-pregnancy 25OHD ( p  < 0.041)., Conclusions: Maternal and neonatal 25OHD were negatively associated with offspring size/adiposity at birth and offspring weight-for-age at 2-2.5 years. Results may not reflect a general population replete in vitamin D, due to high prevalence of macrosomia and high risk of deficiency in this cohort. Improvement of pregnancy vitamin D status remains a public health concern., Trial Registration: Current Controlled Trials ISRCTN54392969. 22/04/2009 retrospectively registered., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2017.)

Nitric oxide is a vital signaling molecule that controls blood flow and oxygenation and nitrite serves as an important reservoir for nitric oxide in biology. While copper containing enzymes are known to reduce nitrite to nitric oxide, herein we report a new pathway to release nitric oxide via oxygen atom transfer from nitrite at a copper(ii) site.

Childhood obesity is associated with increased risk of adult obesity and metabolic disease. Diet and lifestyle in pregnancy influence fetal programming; however the influence of specific dietary components, including low glycaemic index (GI), remains complex. We examined the effect of a maternal low GI dietary intervention on offspring adiposity at 6 months and explored the association between diet and lifestyle factors in pregnancy and infant body composition at 6 months. 280 6-month old infant and mother pairs from the control (n = 142) and intervention group (n = 138), who received low GI dietary advice in pregnancy, in the ROLO study were analysed. Questionnaires (food diaries and lifestyle) were completed during pregnancy, followed by maternal lifestyle and infant feeding questionnaires at 6 months postpartum. Maternal anthropometry was measured throughout pregnancy and at 6 months post-delivery, along with infant anthropometry. No difference was found in 6 months infant adiposity between control and intervention groups. Maternal trimester three GI, trimester two saturated fats and trimester one and three sodium intake were positively associated with offspring adiposity, while trimester two and three vitamin C intake was negatively associated. In conclusion associations were observed between maternal dietary intake and GI during pregnancy and offspring adiposity at 6 months of age.

Aim: To examine the association between maternal nutrition and lifestyle factors and offspring adiposity, using baseline and 2-year postpartum follow-up data from a randomised control trial of low glycaemic index diet., Subject and Methods: Food diaries and lifestyle questionnaires were completed during pregnancy and infant feeding and maternal lifestyle questionnaires 2 years postpartum for 281 mother and infant pairs from the ROLO study. Maternal anthropometry was measured throughout pregnancy and infant and maternal anthropometry was measured 2 years postpartum., Results: Maternal 2 year postpartum body mass index (BMI) was positively associated with offspring BMI-for-age z-score ( B  = 0.105, p  = 0.015). Trimester 2 saturated fat intake was positively associated with offspring subscapular:triceps skinfold ratio ( B  = 0.018, p  = 0.001). Trimester 1 glycaemic index was also positively associated with offspring sum of subscapular and triceps skinfolds ( B  = 0.009, p  = 0.029)., Conclusions: Maternal BMI 2 years postpartum was positively associated with offspring BMI. Pregnancy saturated fat intake was positively and polyunsaturated fat negatively associated with offspring adiposity. While further research is necessary, pregnancy and the postpartum period may be early opportunities to combat childhood obesity., Competing Interests: Compliance with ethical standards Funding This study was supported by the Health Research Board Ireland, the Health Research Centre for Health and Diet Research, The National Maternity Hospital Medical Fund and the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement No. 289346. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Background: Large for gestational age infants have an increased risk of obesity, cardiovascular and metabolic complications during life. Knowledge of the key predictive factors of neonatal adiposity is required to devise targeted antenatal interventions. Our objective was to determine the fetal metabolic factors that influence regional neonatal adiposity in a cohort of women with previous large for gestational age offspring., Methods: Data from the ROLO [Randomised COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analysed in the ROLO Kids study. Neonatal anthropometric and skinfold measurements were compared with fetal leptin and C-peptide results from cord blood in 185 cases. Analyses were performed to examine the association between these metabolic factors and birthweight, anthropometry and markers of central and generalised adiposity., Results: Fetal leptin was found to correlate with birthweight, general adiposity and multiple anthropometric measurements. On multiple regression analysis, fetal leptin remained significantly associated with adiposity, independent of gender, maternal BMI, gestational age or study group assignment, while fetal C-peptide was no longer significant., Conclusion: Fetal leptin may be an important predictor of regional neonatal adiposity. Interventional studies are required to assess the impact of neonatal adiposity on the subsequent risk of childhood obesity and to determine whether interventions which reduce circulating leptin levels have a role to play in improving neonatal adiposity measures.

Background: Micronutrients are necessary for fetal growth. However increasingly pregnant women are nutritionally replete and little is known about the effect of maternal micronutrient intakes on fetal adiposity in mothers with increased BMI. The aim of this study was to examine the association of maternal dietary micronutrient intake with neonatal size and adiposity in a cohort at risk of macrosomia., Methods: This was a cohort analysis of 554 infants from the ROLO study. Three day food diaries from each trimester were collected. Neonatal weight, length, circumferences and skinfold thicknesses were measured at birth. Multiple linear regression was used to identify associations between micronutrient intakes and neonatal anthropometry., Results: Birthweight was negatively associated with maternal trimester 3 vitamin D intake and positively associated with trimester 3 vitamin B12 intake R2adj 19.8% (F = 13.19, p <0.001). Birth length was positively associated with trimester 3 magnesium intake R2adj 12.9% (F = 8.06, p <0.001). In terms of neonatal central adiposity; abdominal circumference was positively associated with maternal trimester 3 retinol intake and negatively associated with trimester 3 vitamin E and selenium intake R2adj 11.9% (F = 2.93, p = 0.002), waist:length ratio was negatively associated with trimester 3 magnesium intake R2adj 20.1% (F = 3.92, p <0.001) and subscapular:triceps skinfold ratio was negatively associated with trimester 1 selenium intake R2adj7.2% (F = 2.00, p = 0.047)., Conclusions: Maternal micronutrient intake was associated with neonatal anthropometry even in women not at risk of malnutrition. Further research is necessary to determine optimal micronutrient intake in overweight and obese pregnant women., Trial Registration: Current Controlled Trials ISRCTN54392969.

Objective: Large for gestational age infants are at increased risk of childhood obesity and maternal nutrition impacts birthweight. The aim of this study was to assess the impact of a maternal low glycaemic index (GI) diet on neonatal anthropometry., Methods: The ROLO (Randomised Control Trial of Low Glycaemic Index Diet in Pregnancy) study was a randomized controlled trial to assess the impact of a low GI diet versus usual diet on birthweight. It took place in a tertiary maternity hospital in Ireland and women were randomized to receive either a low GI diet or no dietary intervention from early pregnancy to term. Two hundred sixty-five neonates had anthropometric measurements on day 1-2 of life, 126 in the intervention group and 139 in the control group. Measurements included birthweight, length and circumferences of the head, chest, abdominal, thigh and mid-upper arm. A subgroup of 219 (82%) neonates also had skin-fold measurements., Results: Neonates whose mothers had a low GI diet in pregnancy had lower thigh circumference (15.9 ± 1.7 cm vs. 16.6 ± 1.5 cm, P = 0.04). There was no difference between the intervention and control groups in head, chest abdominal or mid-upper arm circumferences. No difference was noted between the two groups for any skin-fold measurements (subscapular, thigh, biceps and triceps)., Conclusion: Neonatal thigh circumference was altered by maternal low GI diet in pregnancy. These findings suggest that maternal low GI diet is safe in pregnancy and may positively impact infant adiposity., (© 2014 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of International Association for the Study of Obesity.)

Antisaccade deficits reflect abnormalities in executive function linked to various disorders including schizophrenia, externalizing psychopathology, and neurological conditions. We examined the genetic bases of antisaccade error in a sample of community-based twins and parents (N = 4,469). Biometric models showed that about half of the variance in the antisaccade response was due to genetic factors and half due to nonshared environmental factors. Molecular genetic analyses supported these results, showing that the heritability accounted for by common molecular genetic variants approximated biometric estimates. Genome-wide analyses revealed several SNPs as well as two genes-B3GNT7 and NCL-on Chromosome 2 associated with antisaccade error. SNPs and genes hypothesized to be associated with antisaccade error based on prior work, although generating some suggestive findings for MIR137, GRM8, and CACNG2, could not be confirmed., (Copyright © 2014 Society for Psychophysiological Research.)

Background: The in utero environment is known to affect fetal development however many of the mechanisms by which this occurs remain unknown. The aim of this study was to examine the association between maternal dietary macronutrient intake and lifestyle throughout pregnancy and neonatal weight and adiposity., Methods: This was an analysis of 542 mother and infant pairs from the ROLO study (Randomised cOntrol trial of LOw glycaemic index diet versus no dietary intervention to prevent recurrence of fetal macrosomia). Food diaries as well as food frequency and lifestyle and physical activity questionnaires were completed during pregnancy. Maternal anthropometry was measured throughout pregnancy and neonatal anthropometry was measured at birth., Results: Multiple linear regression analysis revealed the main maternal factor associated with increased birth weight was greater gestational weight gain R2adj 23.3% (F = 11.547, p < 0.001). The main maternal factor associated with increased birth length was non-smoking status R2adj 27.8% (F = 6.193, p < 0.001). Neonatal central adiposity (determined using waist:length ratio) was negatively associated with maternal age, and positively associated with the following parameters: smoking status, maternal pre-pregnancy arm circumference, percentage energy from saturated fat in late pregnancy, postprandial glucose at 28 weeks gestation and membership of the control group with a positive trend towards association with trimester 2 glycaemic load R2adj 38.1% (F = 8.000, p < 0.001)., Conclusions: Several maternal diet and lifestyle factors were associated with neonatal anthropometry . Low glycaemic index dietary intervention in pregnancy was found to have a beneficial effect on neonatal central adiposity. Additionally, central adiposity was positively associated with maternal dietary fat intake and postprandial glucose highlighting the important role of healthy diet in pregnancy in promoting normal neonatal adiposity., Trial Registration: Current Controlled Trials ISRCTN54392969.

Unlabelled: Pregnancy increases the risk of being overweight at a later time period, particularly when there is excessive gestational weight gain. There remains a paucity of data into the effect of low glycaemic index (GI) pregnancy interventions postpartum., Aim: To examine the impact of a low glycaemic index diet during pregnancy on maternal diet 3 months postpartum., Methodology: This analysis examined the diet, weight and lifestyle of 460 participants of the ROLO study 3 months postpartum. Questionnaires on weight, physical activity, breastfeeding, supplement use, food label reading and dietary habits were completed., Results: The intervention group had significantly greater weight loss from pre-pregnancy to 3 months postpartum than the control group (1.3 vs. 0.1 kg, p = 0.022). The intervention group reported greater numbers following a low glycaemic index diet (p < 0.001) and reading food labels (p = 0.032) and had a lower glycaemic load (GL) (128 vs. 145, p = 0.014) but not GI (55 vs. 55, p = 0.809) than controls., Conclusions: Low GI dietary interventions in pregnancy result in improved health-behaviours and continued reported compliance at 3 months postpartum possibly through lower dietary GL as a result of portion control. Greater levels of weight loss from pre-pregnancy to 3 months postpartum in the intervention group may have important positive implications for overweight and obesity.

Bone marrow-derived mesenchymal stem cells (MSCs) sustain cancer cells by creating a microenvironment favorable for tumor growth. In particular, MSCs have been implicated in gastric cancer development. There is extensive evidence suggesting that Hedgehog signaling regulates tumor growth. However, very little is known regarding the precise roles of Hedgehog signaling and MSCs in tumor development within the stomach. The current study tests that hypothesis that Sonic Hedgehog (Shh), secreted from MSCs, provides a proliferative stimulus for the gastric epithelium in the presence of inflammation. Red fluorescent protein-expressing MSCs transformed in vitro (stMSCs) were transduced with lentiviral constructs containing a vector control (stMSC(vect)) or short hairpin RNA (shRNA) targeting the Shh gene (stMSC(ShhKO)). Gastric submucosal transplantation of wild-type MSCs (wtMSCs), wild-type MSCs overexpressing Shh (wtMSC(Shh)), stMSC(vect), or stMSC(ShhKO) cells in C57BL/6 control (BL/6) or gastrin-deficient (GKO) mice was performed and mice analyzed 30 and 60 days posttransplantation. Compared with BL/6 mice transplanted with wtMSC(Shh) and stMSC(vect) cells, inflamed GKO mice developed aggressive gastric tumors. Tumor development was not observed in mouse stomachs transplanted with wtMSC or stMSC(ShhKO) cells. Compared with stMSC(ShhKO)-transplanted mice, within the inflamed GKO mouse stomach, Shh-expressing stMSC(vect)- and wtMSC(Shh)-induced proliferation of CD44-positive cells. CD44-positive cells clustered in gland-like structures within the tumor stroma and were positive for Patched (Ptch) expression. We conclude that Shh, secreted from MSCs, provides a proliferative stimulus for the gastric epithelium that is associated with tumor development, a response that is sustained by chronic inflammation., (Copyright © 2014 the American Physiological Society.)

Background: Bone marrow-derived mesenchymal stem cells (BM-MSCs) promote gastric cancer in response to gastritis. In culture, BM-MSCs are prone to mutation with continued passage but it is unknown whether a similar process occurs in vivo in response to gastritis., Aim: The purpose of this study was to identify the role of chronic gastritis in the transformation of BM-MSCs leading to an activated cancer-promoting phenotype., Methods: Age matched C57BL/6 (BL/6) and gastrin deficient (GKO) mice were used for isolation of stomach, serum and mesenchymal stem cells (MSCs) at 3 and 6 months of age. MSC activation was assessed by growth curve analysis, fluorescence-activated cell sorting and xenograft assays. To allow for the isolation of bone marrow-derived stromal cells and assay in response to chronic gastritis, IRG/Vav-1(Cre) mice that expressed both enhanced green fluorescent protein-expressing hematopoietic cells and red fluorescent protein-expressing stromal cells were generated. In a parabiosis experiment, IRG/Vav-1(Cre) mice were paired to either an uninfected Vav-1(Cre) littermate or a BL/6 mouse inoculated with Helicobacter pylori., Results: GKO mice displayed severe atrophic gastritis accompanied by elevated gastric tissue and circulating transforming growth factor beta (TGFβ) by 3 months of age. Compared to BM-MSCs isolated from uninflamed BL/6 mice, BM-MSCs isolated from GKO mice displayed an increased proliferative rate and elevated phosphorylated-Smad3 suggesting active TGFβ signaling. In xenograft assays, mice injected with BM-MSCs from 6-month-old GKO animals displayed tumor growth. RFP+ stromal cells were rapidly recruited to the gastric mucosa of H. pylori parabionts and exhibited changes in gene expression., Conclusions: Gastritis promotes the in vivo activation of BM-MSCs to a phenotype reminiscent of a cancer-promoting cell.

Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Studies using Helicobacter-infected mice show that bone marrow-derived mesenchymal stem cells (MSCs) can repopulate the gastric epithelium and promote gastric cancer progression. Within the tumor microenvironment of the stomach, pro-inflammatory cytokine interferon-gamma (IFNγ) and Sonic hedgehog (Shh) are elevated. IFNγ is implicated in tumor proliferation via activation of the Shh signaling pathway in various tissues but whether a similar mechanism exists in the stomach is unknown. We tested the hypothesis that IFNγ drives MSC proliferation and recruitment, a response mediated by Shh signaling. The current study uses transplantation of an in vitro transformed mesenchymal stem cell line (stMSC(vect)), that over-expresses hedgehog signaling, in comparison to non-transformed wild-type MSCs (wtMSCs), wtMSCs transfected to over-express Shh (wtMSC(Shh)), and stMSCs transduced with lentiviral constructs containing shRNA targeting the Shh gene (stMSC(ShhKO)). The effect of IFNγ on MSC proliferation was assessed by cell cycle analysis in vitro using cells treated with recombinant IFNγ (rmIFNγ) alone, or in combination with anti-Shh 5E1 antibody, and in vivo using mice transplanted with MSCs treated with PBS or rmIFNγ. In vitro, IFNγ significantly increased MSC proliferation, a response mediated by Shh that was blocked by 5E1 antibody. The MSC population collected from bone marrow of PBS- or IFNγ-treated mice showed that IFNγ significantly increased the percentage of all MSC cell lines in S phase, with the exception of the stMSCs(ShhKO) cells. While the MSC cell lines with intact Shh expression were recruited to the gastric mucosa in response to IFNγ, stMSCs(ShhKO) were not. Hedgehog signaling is required for MSC proliferation and recruitment to the stomach in response to IFNγ.

Background & Aims: Macrophages mediate the epithelial response to Helicobacter pylori and are involved in the development of gastritis. Sonic Hedgehog (Shh) regulates gastric epithelial differentiation and function, but little is known about its immunoregulatory role in the stomach. We investigated whether gastric Shh acts as a macrophage chemoattractant during the innate immune response to H pylori infection., Methods: Mice with parietal cell-specific deletion of Shh (PC-Shh(KO)) and control mice were infected with H pylori. Levels of gastric Shh, cytokines, and chemokines were assayed by quantitative reverse-transcriptase polymerase chain reaction or by a Luminex-based multiplex assay 2, 7, or 180 days after infection. Circulating concentrations of Shh were measured by enzyme-linked immunosorbent assay. Bone marrow chimera experiments were performed with mice that have myeloid cell-specific deletion of the Hedgehog signal transduction protein Smoothened (LysMCre/Smo(KO)). Macrophage recruitment was measured in gastric tissue and peripheral blood by fluorescence-activated cell sorting analysis., Results: Control mice infected with H pylori for 6 months developed an inflammatory response characterized by infiltration of CD4(+) T cells and increased levels of interferon gamma and interleukin 1β in the stomach. PC-Shh(KO) mice did not develop gastritis, even after 6 months of infection with H pylori. Control mice had increased concentrations of Shh, accompanied by the recruitment of CD11b(+)F4/80(+)Ly6C(high) macrophages 2 days after infection. Control mice that received bone marrow transplants from control mice had an influx of macrophages to the gastric mucosa in response to H pylori infection; this was not observed in H pylori-infected control mice that received bone marrow transplants from LysMCre/Smo(KO) mice., Conclusions: H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to examine the relationship among methadone maintenance treatment, perinatal outcomes, and neonatal abstinence syndrome., Study Design: This was a retrospective cohort study of 61,030 singleton births at a large maternity hospital from 2000-2007., Results: There were 618 (1%) women on methadone at delivery. Methadone-exposed women were more likely to be younger, to book late for antenatal care, and to be smokers. Methadone exposure was associated with an increased risk of very preterm birth <32 weeks of gestation (adjusted odds ratio [aOR], 2.47; 95% confidence interval [CI], 1.40-4.34), being small for gestational age <10th percentile (aOR, 3.27; 95% CI, 2.49-4.28), admission to the neonatal unit (aOR, 9.14; 95% CI, 7.21-11.57), and diagnosis of a major congenital anomaly (aOR, 1.94; 95% CI, 1.10-3.43). There was a dose-response relationship between methadone and neonatal abstinence syndrome., Conclusion: Methadone exposure is associated with an increased risk of adverse perinatal outcomes, even when known adverse sociodemographic factors have been accounted for. Methadone dose at delivery is 1 of the determinants of neonatal abstinence syndrome., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Sonic Hedgehog (Shh) signaling has been extensively studied for its role in developmental biology and cancer biology. The association between Shh and cancer development in general is well established but the functional role of Shh in the development and progression of gastric cancer specifically is largely unknown. Bone marrow-derived stem cells, specifically mesenchymal stem cells (MSCs) infiltrate and engraft into the gastric mucosa in response to the chronic inflammatory environment of Helicobacter infection. In this review, MSC infiltration and changes in the cytokine and cellular profiles of later-stage chronic environments will be tied into their interactions with the Shh pathway. We will discuss how these changes shape tumorigenesis and tumor progression in the gastric mucosa. The current review focuses on the Shh signaling pathway and its role in the development of gastric cancer, specifically in response to Helicobacter pylori infection. We follow with an in-depth discussion of the regulation of the Hedgehog pathway during acute and chronic gastric inflammation with a focus on signaling within the MSC compartment.

The rat tail intervertebral disc has emerged as an important model to examine the mechanisms for mechanically induced degeneration and remodeling. Previous methods used to apply high precision axial compressive loading to a rat tail intervertebral disc in vivo either required anesthesia, or the permanent mounting of a loading device to the animal, and were not well described in the literature. Therefore, a new device to apply compressive loading to the rat tail intervertebral disc was developed and validated. The rat tail compressive loading system utilized a pneumatically driven device weighing 18 g, and was capable of delivering a 12.6 N sinusoidal or square waveform at frequencies up to 1.0 Hz. The system improved on previous methods in its modular construction, relative ease of fabrication, compatibility with existing tail model technology and overall cost effectiveness. The removable system eliminated the need for anesthesia and through a modular, cost effective, design allowed for the simultaneous loading of multiple animals. This system expanded the ability to accurately, ethically, and efficiently apply dynamic compressive loads to the rat tail intervertebral disc for extended periods of time in order to address questions related to disc mechanobiology.

Background: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces., Methods: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model., Results: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions., Conclusions: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.

New primers (N = 24) for the amplification and sequencing of the complete or near complete 12S ribosomal DNA, about 1000 bp of the control region, 390 bp of cytochrome oxidase I, and the near complete cytochrome b are described. The 12S ribosomal DNA primers successfully amplify DNA in tetrapods; other primers successfully amplify DNA in bufonoids and other anurans. An overview of published literature and sequence data banks identified 170 mitochondrial and 96 nuclear DNA primers that have been used or are highly likely to be useful in amphibians. Primer sequences, their locations within genes, and sequence location and identity in Xenopus and human and/or mouse are presented for each primer. The utility of each primer was estimated by identifying the smallest, yet most inclusive, taxonomic category within which each primer has been successful. Primers from all published sources are mapped together. We hope that these new primers, as well as the list of primers that have been useful in amphibians, will encourage further systematic and population genetic studies of amphibians., (Copyright 1999 Academic Press.)

Objective: This present study was designed to develop and validate rating scales for body image assessment in adolescents., Method: The figures of the Figure Rating Scale (FRS; Stunkard, Sorenson, & Schlusinger, The genetics of neurological and psychiatric disorders, 1983, pp. 115-129) used in previous research seem more appropriate for research with adults. Accordingly, we developed two forms of a body rating scale (BRS) depicting adolescent females and administered these scales and the FRS to 315 female subjects. The subjects comprise three age groups, 11-year-olds, 17-year-olds, and their mothers, all participants in the epidemiologically based Minnesota Twin Family Study. Two independent observers also rated each subject., Results: Intercorrelations among raters and scales and with body mass index were generally high and indicate comparability between the BRS measures and the FRS., Discussion: The generally excellent psychometric properties of the new scales coupled with their face validity may make them a useful tool for body image research in children and adolescents.

A number of surgical techniques are used in the treatment of herniated intervertebral discs. The purpose of this report was to introduce the technique of automated percutaneous discectomy and suggest a postoperative physical therapy program. Automated percutaneous discectomy (APD) is a new innovative surgical technique used for the treatment of herniated lumbar discs. The procedure is performed under local anaesthesia on an outpatient basis and takes approximately one hour. The success of this procedure depends upon proper patient selection based on physical examination and differential diagnosis. The role of the physical therapist in postoperative care for the APD patient is discussed. The rationale for the suggested protocol is based on the McKenzie approach to the treatment of mechanical low back pain, emphasizing patient education and prophylaxis. The concept of spinal stabilization training is also introduced to facilitate return to daily activities. J Orthop Sports Phys Ther 1992;15(1):2-9.