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1.  Parenteral opioids for maternal pain management in labour 
Background
Parenteral opioids are used for pain relief in labour in many countries throughout the world.
Objectives
To assess the acceptability, effectiveness and safety of different types, doses and modes of administration of parenteral opioids given to women in labour.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 April 2011) and reference lists of retrieved studies.
Selection criteria
We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient controlled analgesia) for women in labour. We looked at studies comparing an opioid with another opioid, placebo, other non-pharmacological interventions (TENS) or inhaled analgesia.
Data collection and analysis
At least two review authors independently assessed study eligibility, collected data and assessed risk of bias.
Main results
We included 57 studies involving more than 7000 women that compared an opioid with placebo, another opioid administered intramuscularly or intravenously or compared with TENS to the back. The 57 studies reported on 29 different comparisons, and for many outcomes only one study contributed data. Overall, the evidence was of poor quality regarding the analgesic effect of opioids, satisfaction with analgesia, adverse effects and harm to women and babies. There were few statistically significant results. Many of the studies had small sample sizes, and low statistical power. Overall findings indicated that parenteral opioids provided some pain relief and moderate satisfaction with analgesia in labour, although up to two-thirds of women who received opioids reported moderate or severe pain and/or poor or moderate pain relief one or two hours after administration. Opioid drugs were associated with maternal nausea, vomiting and drowsiness, although different opioid drugs were associated with different adverse effects. There was no clear evidence of adverse effects of opioids on the newborn. We did not have sufficient evidence to assess which opioid drug provided the best pain relief with the least adverse effects.
Authors’ conclusions
Parenteral opioids provide some relief from pain in labour but are associated with adverse effects. Maternal satisfaction with opioid analgesia was largely unreported but appeared moderate at best. This review needs to be examined alongside related Cochrane reviews examining pain management in labour. More research is needed to determine which analgesic intervention is most effective, and provides greatest satisfaction to women with acceptable adverse effects for mothers and their newborn.
doi:10.1002/14651858.CD007396.pub2
PMCID: PMC4233118  PMID: 20824859
Analgesia, Obstetrical [*methods]; Analgesics, Opioid [*administration & dosage; adverse effects]; Injections, Intramuscular; Injections, Intravenous; Labor Pain [*drug therapy]; Randomized Controlled Trials as Topic; Female; Humans; Pregnancy
2.  Pharmacokinetics of ammonium sulfate gradient loaded liposome-encapsulated oxymorphone and hydromorphone in healthy dogs 
Objective
To evaluate the pharmacokinetics, in dogs, of liposome-encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG).
Animals
Four healthy purpose-bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg.
Study Design
Randomized cross-over design.
Methods
Each dog was given either 4.0 mg kg−1 of ASG-oxymorphone or 8.0 mg kg−1 of ASG-hydromorphone SC on separate occasions with a 3-month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC-MS and pharmacokinetic parameters were calculated using commercial software and non-compartmental methods.
Results
Serum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. Cmax for ASG-oxymorphone was 7.5 ng mL−1; Cmax for ASG-hydromorphone was 5.7 ng mL−1.
Conclusions and clinical relevance
Oxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs.
doi:10.1111/vaa.12042
PMCID: PMC3740050  PMID: 23601353
3.  Labouring women who used a birthing pool in obsteric units in Italy: prospective observational study 
Background
For women at low risk of childbirth complications, water immersion during labour is a care option in many high income countries. Our aims were (a) to describe maternal characteristics, intrapartum events, interventions, maternal and neonatal outcomes for all women who used a birthing pool during labour who either had a waterbirth or left the pool and had a landbirth, and for the subgroup of women who had a waterbirth in 19 obstetric units, and (b) to compare maternal characteristics, intrapartum events, interventions, and maternal and neonatal outcomes for women who used a birthing pool with a control group of women who did not use a birthing pool for whom we prospectively collected data in a single centre.
Methods
Prospective observational study in 19 Italian obstetric units 2002-2005. Participants were: (a) 2,505 women in labour using a birthing pool in 19 obstetric units; and (b) 114 women in labour using a birthing pool and 459 women who did not use a birthing pool in one obstetric unit. Descriptive statistics were calculated for the sample as a whole and, separately, for those women who gave birth in water. Categorical data were compared using Chi square statistics and continuous data by T-tests.
Results
Overall, 95.6% of women using a birthing pool had a spontaneous vertex delivery, 63.9% of which occurred in water. Half of nulliparas and three quarters of multiparas delivered in water. Adverse maternal and neonatal outcomes were rare. There were two cases of umbilical cord snap with waterbirth. Compared with controls, significantly more women who used a birthing pool adopted an upright birth position, had hands off delivery technique, and a physiological third stage. Significantly fewer nulliparas had an episiotomy, and more had a second degree perineal tear, with no evidence of a difference for extensive perineal tears.
Conclusions
Birthing pool use was associated with spontaneous vaginal birth. The increase in second degree tears was balanced by fewer episiotomies. Undue umbilical cord traction should be avoided during waterbirth.
doi:10.1186/1471-2393-14-17
PMCID: PMC3897991  PMID: 24423216
Observational comparative study; Birthing pool; Waterbirth; Maternal and neonatal outcomes
4.  Radiofrequency ablation for early oesophageal squamous neoplasia: Outcomes form United Kingdom registry 
AIM: To report outcomes on patients undergoing radiofrequency ablation (RFA) for early oesophageal squamous neoplasia from a National Registry.
METHODS: A Prospective cohort study from 8 tertiary referral centres in the United Kingdom. Patients with squamous high grade dysplasia (HGD) and early squamous cell carcinoma (ESCC) confined to the mucosa were treated. Visible lesions were removed by endoscopic mucosal resection (EMR) before RFA. Following initial RFA treatment, patients were followed up 3 monthly. Residual flat dysplasia was treated with RFA until complete reversal dysplasia (CR-D) was achieved or progression to invasive Squamous cell cancer defined as infiltration into the submucosa layer or beyond. The main outcome measures were CR-D at 12 mo from start of treatment, long term durability, progression to cancer and adverse events.
RESULTS: Twenty patients with squamous HGD/ESCC completed treatment protocol. Five patients (25%) had EMR before starting RFA treatment. CR-D was 50% at 12 mo with a median of 1 RFA treatment, mean 1.5 (range 1-3). Two further patients achieved CR-D with repeat RFA after this time. Eighty per cent with CR-D remain dysplasia free at latest biopsy, with median follow up 24 mo (IQR 17-54). Six of 20 patients (30%) progressed to invasive cancer at 1 year. Four patients (20%) required endoscopic dilatations for symptomatic structuring after treatment. Two of these patients have required serial dilatations thereafter for symptomatic dysphagia with a median of 4 dilatations per patient. The other 2 patients required only a single dilatation to achieve an adequate symptomatic response. One patient developed cancer during follow up after end of treatment protocol.
CONCLUSION: The role of RFA in these patients remains unclear. In our series 50% patients responded at 12 mo. These figures are lower than limited published data.
doi:10.3748/wjg.v19.i36.6011
PMCID: PMC3785622  PMID: 24106401
Squamous neoplasia; Oesophageal cancer; Endoscopic mucosal resection; High-grade dysplasia; Radiofrequency ablation
5.  Pathology of Chronic Hepatitis C in Children: Liver Biopsy Findings in the Peds-C Trial 
Hepatology (Baltimore, Md.)  2008;47(3):836-843.
There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds-C Trial, designed to test the efficacy and safety of peginterferon alfa-2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment-naïve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non-overweight. In conclusion, in this cohort of HCV-infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment-naïve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.
doi:10.1002/hep.22094
PMCID: PMC3755275  PMID: 18167062
6.  Incidence of and risk factors for perineal trauma: a prospective observational study 
Background
Our aim was to describe the range of perineal trauma in women with a singleton vaginal birth and estimate the effect of maternal and obstetric characteristics on the incidence of perineal tears.
Methods
We conducted a prospective observational study on all women with a planned singleton vaginal delivery between May and September 2006 in one obstetric unit, three freestanding midwifery-led units and home settings in South East England. Data on maternal and obstetric characteristics were collected prospectively and analysed using univariable and multivariable logistic regression. The outcome measures were incidence of perineal trauma, type of perineal trauma and whether it was sutured or not.
Results
The proportion of women with an intact perineum at delivery was 9.6% (125/1,302) in nulliparae, and 31.2% (453/1,452) in multiparae, with a higher incidence in the community (freestanding midwifery-led units and home settings). Multivariable analysis showed multiparity (OR 0.52; 95% CI: 0.30–0.90) was associated with reduced odds of obstetric anal sphincter injuries (OASIS), whilst forceps (OR 4.43; 95% CI: 2.02–9.71), longer duration of second stage of labour (OR 1.49; 95% CI: 1.13–1.98), and heavier birthweight (OR 1.001; 95% CI: 1.001–1.001), were associated with increased odds. Adjusted ORs for spontaneous perineal truama were: multiparity (OR 0.42; 95% CI: 0.32–0.56); hospital delivery (OR 1.48; 95% CI: 1.01–2.17); forceps delivery (OR 2.61; 95% CI: 1.22–5.56); longer duration of second stage labour (OR 1.45; 95% CI: 1.28–1.63); and heavier birthweight (OR 1.001; 95% CI: 1.000–1.001).
Conclusions
This large prospective study found no evidence for an association between many factors related to midwifery practice such as use of a birthing pool, digital perineal stretching in the second stage, hands off delivery technique, or maternal birth position with incidence of OASIS or spontaneous perineal trauma. We also found a low overall incidence of OASIS, and fewer second degree tears were sutured in the community than in the hospital settings. This study confirms previous findings of overall high incidence of perineal trauma following vaginal delivery, and a strong association between forceps delivery and perineal trauma.
doi:10.1186/1471-2393-13-59
PMCID: PMC3599825  PMID: 23497085
Vaginal delivery; Perineal trauma; OASIS; Prospective study
7.  Dapsone-Induced Methemoglobinemia: A Dose Related Occurrence? 
Cancer  2011;117(15):3485-3492.
Objectives
Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity (CYB5RA) causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. We sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of CYB5RA.
Patients and Methods
Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, CYB5RA was assessed.
Results
Methemoglobinemia (median methemoglobin level = 9.0% [3.5–22.4]) was documented in 32 patients (19.8%). There was a 73% risk reduction in methemoglobinemia with dosing ≥20% below the target dose 2mg/kg/day (HR = 0.27; 95% confidence interval (CI) 0.09, 0.78; p=0.016), while methemoglobinemia risk was increased with dosing ≥20% above the target dose (HR = 6.25; 95% CI 2.45, 15.93; p<0.001). Sex, body mass index, and age were not associated with increased risk. CYB5RA did not differ by methemoglobinemia status (median 8.6 IU/g Hb; [5.5 – 12.1] vs. 9.1 IU/g Hb; [6.7 – 12.7]). No patient developed PCP on dapsone.
Conclusions
Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired CYB5RA level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis.
doi:10.1002/cncr.25904
PMCID: PMC3138875  PMID: 21246536
pediatric oncology; HIV; dapsone; methemoglobinemia; Drug-related complications; cytochrome b5 reductase
8.  Significant 25-Hydroxyvitamin D Deficiency in Child and Adolescent Survivors of Acute Lymphoblastic Leukemia: Treatment with Chemotherapy Compared with Allogeneic Stem Cell Transplant 
Pediatric blood & cancer  2010;56(7):1114-1119.
Background
25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL).
Procedure
In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency.
Results
There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/ dl), and 12% were deficient (<15 ng/ dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake.
Conclusions
The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.
doi:10.1002/pbc.22949
PMCID: PMC3135735  PMID: 21488156
vitamin D deficiency; acute lymphoblastic leukemia; cancer survivorship; late effects; vitamin D insufficiency
9.  Peginterferon With or Without Ribavirin Has Minimal Effect on Quality of Life, Behavioral/Emotional, and Cognitive Outcomes in Children 
Hepatology (Baltimore, Md.)  2011;53(5):1468-1475.
The aim of this study was to prospectively assess the quality of life (QOL), behavioral/emotional functioning, and cognitive status of children undergoing treatment for hepatitis C virus (HCV) infection. One hundred fourteen children (5 to 18 years old) enrolled in a multi-site randomized clinical trial (Peds-C) to evaluate peginterferon alpha 2a (PEG 2a) with ribavirin (RV) or with placebo (PL) completed several standardized measures prior to treatment and at 24 weeks, 48 weeks, 6 months following treatment, and at two annual follow-up visits. After 24 weeks of treatment, mean physical QOL scores declined significantly for both groups from baseline to 24 weeks of treatment (F = 5.8, p = 0.004), although scores remained in the average range. There were no significant time or group effects for behavioral/emotional or cognitive functioning. Three children (5%) in the PEG 2a + RV group and no children in the PEG 2a + PL group had a clinically significant increase in depression symptoms. For those children who received 48 weeks of treatment, there were no significant time or group effects on any of the outcome measures (p's > 0.05). A majority of children in both the PEG 2a + RV and PEG 2a + PL groups experienced no clinically significant change in physical QOL, behavioral adjustment, depression, or cognitive functioning during or after treatment.
Conclusion
Overall QOL and psychosocial functioning are not deleteriously impacted by PEG 2a + RV or PL treatment of children with HCV.
doi:10.1002/hep.24248
PMCID: PMC3082614  PMID: 21351116
pediatrics; HCV; parents; clinical trial; quality of life
10.  The Combination of Ribavirin and Peginterferon Is Superior to Peginterferon and Placebo for Children and Adolescents Chronic Hepatitis C 
Gastroenterology  2010;140(2):450-458.e1.
Background & Aims
Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized, controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5–17 years old with chronic hepatitis C.
Methods
HCV RNA-positive children from 11 university medical centers were randomly groups assigned to receive either the combination of peginterferon alfa-2a (PEG 2a; 180 μg/1.73 m2 body surface area, subcutaneously each week; n=59) and ribavirin (15 mg per kilogram orally in 2 doses daily) or PEG2a and placebo for 48 weeks (n=55). The primary endpoint was sustained virologic response (SVR, lack of detectable HCV RNA at least 24 weeks after stopping therapy).
Results
An SVR was achieved in 53% of children treated with PEG 2a and ribavirin, compared with 21% of children who received PEG 2a and placebo (P<0.001). Early virologic response (> 2 log10 IU reduction in HCV RNA at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year-2 follow-up visit; the durability of virologic response was 100% in both groups.
Conclusions
The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.
doi:10.1053/j.gastro.2010.10.047
PMCID: PMC3042126  PMID: 21036173
antiviral therapy; pediatric liver disease; multi-center pediatric trial
11.  Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic review and meta-analysis of randomised controlled trials 
BMC Cancer  2010;10:337.
Background
We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma.
Methods
Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate.
Results
Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above.
Conclusions
Evidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials.
doi:10.1186/1471-2407-10-337
PMCID: PMC2907344  PMID: 20587042
12.  Impact of Hepatitis C Virus Infection on Children and their Caregivers: Quality of Life, Cognitive, and Emotional Outcomes 
Objective
HCV infection is associated with decreased quality of life (QOL) and neurocognitive dysfunction in adults, but little is known about its impact on children and their caregivers.
Design and Patients
We studied the QOL, behavioral, emotional, and cognitive functioning of 114 treatment-naïve children with HCV enrolled in a placebo-controlled, randomized, multi-site clinical trial evaluating peginterferon alpa-2a alone or with ribavirin.
Outcome Measures
Baseline assessment included measures of children’s QOL, cognitive functioning, behavioral adaptation, and depression. Caregivers’ QOL was also assessed.
Results
Relative to published normative data, caregivers were more likely to believe that their children’s health was poor and would likely worsen (t = 3.93, p < 0.0001), reported higher concern about their children’s health status (t = 6.63, p < 0.0001) and that this concern limited family activities (t = 2.45, p < 0.01); they also viewed their children as having more internalizing behavioral problems (t = 1.98, p < 0.05). Only 2 (2%) children had a score in the clinically depressed range. Children with HCV had worse cognitive functioning than the normative sample, but significantly better functioning than children with attention deficit hyperactivity disorder. Caregivers’ QOL scores did not differ significantly from the normative sample, but infected mothers had lower QOL than non-infected caregivers. Caregivers were highly distressed about their children’s medical circumstances.
Conclusion
While HCV infection, in its early stages, does not lead to global impairment in QOL, cognitive, behavioral, or emotional functioning in children, it is associated with higher caregiver stress and strain on the family system, and it may be associated with some cognitive changes in children.
doi:10.1097/MPG.0b013e318185998f
PMCID: PMC2649743  PMID: 19242286
pediatrics; HCV; parents; clinical trial; quality of life
13.  Functional Adaptation to Loading of a Single Bone is Neuronally Regulated and Involves Multiple Bones 
Regulation of load-induced bone formation is considered a local phenomenon controlled by osteocytes, although it has also been hypothesized that functional adaptation may be neuronally regulated. The aim of this study was to examine bone formation in multiple bones, in response to loading of a single bone, and to determine whether adaptation may be neuronally regulated. Load-induced responses in the left and right ulnae and humeri were determined after loading of the right ulna in male Sprague-Dawley rats (69 ± 16 days). After a single period of loading at −760με, −2,000με, or −3,750με initial peak strain, rats were given calcein to label new bone formation. Bone formation and bone neuropeptide concentrations were determined at 10 days. In one group, temporary neuronal blocking was achieved by perineural anesthesia of the brachial plexus with bupivicaine during loading. We found right ulna loading induces adaptive responses in other bones in both thoracic limbs when compared to sham controls, and that neuronal blocking during loading abrogated bone formation in the loaded ulna and other thoracic limb bones. Skeletal adaptation was more evident in distal long bones, when compared with proximal long bones. We also found that the single period of loading modulated bone neuropeptide concentrations persistently for 10 days. We conclude that functional adaptation to loading of a single bone in young rapidly growing rats is neuronally regulated and involves multiple bones. Persistent changes in bone neuropeptide concentrations after a single loading period suggest that plasticity exists in the innervation of bone.
doi:10.1359/jbmr.080407
PMCID: PMC2586809  PMID: 18410233
Bone innervation; brachial plexus anesthesia; mechanical loading; bone formation; bone neuropeptides
14.  The effect of alcohol advertising, marketing and portrayal on drinking behaviour in young people: systematic review of prospective cohort studies 
BMC Public Health  2009;9:51.
Background
The effect of alcohol portrayals and advertising on the drinking behaviour of young people is a matter of much debate. We evaluated the relationship between exposure to alcohol advertising, marketing and portrayal on subsequent drinking behaviour in young people by systematic review of cohort (longitudinal) studies.
Methods
studies were identified in October 2006 by searches of electronic databases, with no date restriction, supplemented with hand searches of reference lists of retrieved articles. Cohort studies that evaluated exposure to advertising or marketing or alcohol portrayals and drinking at baseline and assessed drinking behaviour at follow-up in young people were selected and reviewed.
Results
seven cohort studies that followed up more than 13,000 young people aged 10 to 26 years old were reviewed. The studies evaluated a range of different alcohol advertisement and marketing exposures including print and broadcast media. Two studies measured the hours of TV and music video viewing. All measured drinking behaviour using a variety of outcome measures. Two studies evaluated drinkers and non-drinkers separately. Baseline non-drinkers were significantly more likely to have become a drinker at follow-up with greater exposure to alcohol advertisements. There was little difference in drinking frequency at follow-up in baseline drinkers. In studies that included drinkers and non-drinkers, increased exposure at baseline led to significant increased risk of drinking at follow-up. The strength of the relationship varied between studies but effect sizes were generally modest. All studies controlled for age and gender, however potential confounding factors adjusted for in analyses varied from study to study. Important risk factors such as peer drinking and parental attitudes and behaviour were not adequately accounted for in some studies.
Conclusion
data from prospective cohort studies suggest there is an association between exposure to alcohol advertising or promotional activity and subsequent alcohol consumption in young people. Inferences about the modest effect sizes found are limited by the potential influence of residual or unmeasured confounding.
doi:10.1186/1471-2458-9-51
PMCID: PMC2653035  PMID: 19200352
15.  Midazolam administration reverses thermal hyperalgesia and prevents GABA transporter loss in a rodent model of neuropathic pain 
Anesthesia and analgesia  2008;106(4):1296-contents.
Background
Loss of GABA inhibition in the spinal dorsal horn may contribute to neuropathic pain. Here we examined whether systemic administration of the benzodiazepine midazolam would alleviate thermal hyperalgesia due to chronic constriction injury (CCI) of the sciatic nerve.
Methods
Hyperalgesia was evaluated with the thermal paw withdrawal latency test (TWL) before, and 3 and 7 days after CCI. Animals randomly received via osmotic minipump infusion midazolam (2.0 mg/kg/h), flumazenil (0.004 mg/kg/h), midazolam plus flumazenil at the same doses, or saline (0.01 ml/kg/h). Four groups of sham-operated rats (surgery without nerve ligation) received matched treatments. Levels of the GABA transporter 1 (GAT-1) in the lumbar spinal dorsal horn were estimated using western immunoblots 7 days after surgery.
Results
Saline-treated CCI rats developed thermal hyperalgesia on day 3 with a more pronounced effect on day 7. Continuous midazolam infusion prevented thermal hyperalgesia on both days. The anti-hyperalgesic effect of midazolam was reversed by the co-administration of flumazenil. Infusion of flumazenil alone had no effect on the thermal hyperalgesia in CCI rats. Sham-operated rats treated with saline, midazolam or midazolam plus flumazenil exhibited no thermal hyperalgesia. Unexpectedly, TWL in sham animals treated with flumazenil alone were significantly decreased. Changes in GAT-1 levels paralleled the behavior. Midazolam prevented the CCI-associated decreases, and flumazenil reversed midazolam's effect. Flumazenil alone did not modify GAT-1 levels in CCI animals but in sham animals the transporter levels were significantly reduced.
Conclusions
GABA inhibition plays an important role in neuropathic pain. Continuous systemic benzodiazepine administration may prove effective in alleviating neuropathic pain.
doi:10.1213/ane.0b013e318164f1e9
PMCID: PMC2583451  PMID: 18349209
16.  An Antithrombin-Heparin Complex Increases the Anticoagulant Activity of Fibrin Clots 
Clotting blood contains fibrin-bound thrombin, which is a major source of procoagulant activity leading to clot extension and further activation of coagulation. When bound to fibrin, thrombin is protected from inhibition by antithrombin (AT) + heparin but is neutralized when AT and heparin are covalently linked (ATH). Here, we report the surprising observation that, rather than yielding an inert complex, thrombin-ATH formation converts clots into anticoagulant surfaces that effectively catalyze inhibition of thrombin in the surrounding environment.
doi:10.1155/2008/639829
PMCID: PMC3005802  PMID: 22820671
17.  Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials 
BMJ : British Medical Journal  2002;325(7365):619.
Objective
To determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.
Design
Systematic review of randomised trials that compared at least 12 weeks' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.
Participants
15 187 patients with osteoarthritis or rheumatoid arthritis.
Main outcome measures
Efficacy: Western Ontario and McMaster universities osteoarthritis index; American College of Rheumatology responder index and joint scores for rheumatoid arthritis. Tolerability: withdrawal rates for adverse effects. Gastrointestinal safety: incidence of ulcers, bleeds, perforations, and obstructions.
Results
Nine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.
Conclusion
Celecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.
What is already known on this topicLong term NSAID use is associated with the development of peptic and duodenal ulcersCOX 2 specific inhibitors are claimed to cause fewer gastrointestinal complicationsThe National Institute for Clinical Excellence has recently recommended that COX 2 specific inhibitors are used in patients with arthritis who are at risk of gastrointestinal complications but not in those taking prophylactic aspirinWhat this study addsSystematic review of randomised trials shows that celecoxib is as effective as other NSAIDs for osteoarthritis and rheumatoid arthritisCelecoxib has significantly improved gastrointestinal safety and tolerability compared with standard NSAIDsAn improvement in gastrointestinal safety was still evident in patients who were also taking aspirin
PMCID: PMC126301  PMID: 12242171
18.  Systematic review of the use of honey as a wound dressing 
Objective
To investigate topical honey in superficial burns and wounds though a systematic review of randomised controlled trials.
Data sources
Cochrane Library, MEDLINE, EMBASE, PubMed, reference lists and databases were used to seek randomised controlled trials. Seven randomised trials involved superficial burns, partial thickness burns, moderate to severe burns that included full thickness injury, and infected postoperative wounds.
Review methods
Studies were randomised trials using honey, published papers, with a comparator. Main outcomes were relative benefit and number-needed-to-treat to prevent an outcome relating to wound healing time or infection rate.
Results
One study in infected postoperative wounds compared honey with antiseptics plus systemic antibiotics. The number needed to treat with honey for good wound healing compared with antiseptic was 2.9 (95% confidence interval 1.7 to 9.7). Five studies in patients with partial thickness or superficial burns involved less than 40% of the body surface. Comparators were polyurethane film, amniotic membrane, potato peel and silver sulphadiazine. The number needed to treat for seven days with honey to produce one patient with a healed burn was 2.6 (2.1 to 3.4) compared with any other treatment and 2.7 (2.0 to 4.1) compared with potato and amniotic membrane. For some or all outcomes honey was superior to all these treatments. Time for healing was significantly shorter for honey than all these treatments. The quality of studies was low.
Conclusion
Confidence in a conclusion that honey is a useful treatment for superficial wounds or burns is low. There is biological plausibility.
doi:10.1186/1472-6882-1-2
PMCID: PMC32305  PMID: 11405898
19.  Using evidence from different sources: an example using paracetamol 1000 mg plus codeine 60 mg 
Background
Meta-analysis usually restricts the information pooled, for instance using only randomised, double-blind, placebo-controlled trials. This neglects other types of high quality information. This review explores using different information for the combination of paracetamol 1000 mg and codeine 60 mg in acute postoperative pain.
Results
Randomised, double-blind, placebo-controlled trials of paracetamol 1000 mg and codeine 60 mg had an NNT of 2.2 (95% confidence interval 1.7 to 2.9) for at least 50% pain relief over four to six hours in three trials with 197 patients. Computer simulation of randomised trials demonstrated 92% confidence that the simulated NNT was within ± 0.5 of the underlying value of 2.2 with this number of patients. The result was supported a rational dose-response relationship for different doses of paracetamol and codeine in 17 additional trials with 1,195 patients. Three controlled trials lacking a placebo and with 117 patients treated with of paracetamol 1000 mg and codeine 60 mg had 73% (95%CI 56% to 81%) of patients with at least 50% pain relief, compared with 57% (48% to 66%) in placebo controlled trials. Six trials in acute pain were omitted because of design issues, like the use of different pain measures or multiple dosing regimens. In each paracetamol 1000 mg and codeine 60 mg was shown to be better than placebo or comparators for at least one measure.
Conclusions
Different designs of high quality trials can be used to support limited information used in meta-analysis without recourse to low quality trials that might be biased.
doi:10.1186/1471-2288-1-1
PMCID: PMC32200  PMID: 11231885

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