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1.  Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDAR receptors 
Hippocampus  2012;23(1):108-115.
17β-estradiol (E2), at high circulating levels, enhances learning and memory in many women, making it a clinical treatment for hormone-related cognitive decline in aging. However, the mechanisms stimulated by E2, which are responsible for its cognitive enhancing effects, remain incompletely defined. Using an ovariectomized rat model, we previously reported that increasing plasma E2 enhances the magnitude of long-term potentiation (LTP) at hippocampal CA3-CA1 synapses, which is caused by a selective increase in current mediated by NR2B-containing NMDARs causing an increase in the NMDAR/AMPAR ratio. Whether the increase in NR2B current is causally related to the ability of E2 to enhance hippocampal dependent learning and memory has yet to be tested. Here, we find that E2 enhances performance in the novel object recognition (NOR) task with the same time course we previously showed E2 enhances the LTP magnitude, temporally linking the increase in LTP to enhanced learning and memory. Furthermore, using the selective NR2B subunit antagonist Ro25-6981, we find that the E2-enhanced NOR, like the enhanced LTP, requires hippocampal NR2B-containing NMDARs, specifically in area CA1. Finally, using whole-cell recordings and the phosphatase inhibitor orthovanadate, we investigated whether the E2-induced increase in NMDAR current is caused by an increase in the density of synaptic NMDARs and/or an increase in NMDAR subunit phosphorylation. We find that both mechanisms are responsible for the enhanced NMDAR current in E2-treated rats. Our results show that the E2-enhanced NOR requires a functional increase in NR2B-containing NMDARs, a requirement shared with the E2-enhanced LTP magnitude at CA3-CA1 synapses, supporting the hypothesis that the increase in LTP likely contributes to the enhanced learning and memory following an increase in plasma E2 levels.
doi:10.1002/hipo.22068
PMCID: PMC4038023  PMID: 22965452
Estrogen; LTP; Learning; Memory; Plasticity
2.  Acupuncture and women’s health: an overview of the role of acupuncture and its clinical management in women’s reproductive health 
Background
Acupuncture and other modalities of Chinese/East Asian medicine have been used to treat women’s health for many centuries. Gynecology specialties focus particularly on menstrual and reproductive disorders. Both the adoption of the use of acupuncture outside Asia, and the incorporation of scientific analysis in Asia have challenged biomedical conceptions of what can be achieved with this treatment method. The scale of research activity in relation to acupuncture and women’s health has increased over the last 20 years.
Objective
This review aims to explore the research evidence in relation to acupuncture use for women’s reproductive disorders, focusing on both clinical findings and experimental research on acupuncture’s mechanisms of action in relation to women’s health.
Methods
A narrative literature search was undertaken using searches of electronic databases and manual searches of journals and textbooks. The search included all literature published prior to June 2013. The literature was assessed as to the nature of the study it was reporting and findings synthesized into a commentary.
Results
For acupuncture’s mechanism of action the search resulted in 114 relevant documents; in relation to clinical reports on the use of acupuncture for women’s health 204 documents were found and assessed.
Conclusion
There is preliminary data indicating acupuncture may improve menstrual health and coping for women experiencing delays falling pregnant. There is experimental data showing that acupuncture can influence female reproductive functioning, although the actual mechanisms involved are not yet clarified. Further well-conducted clinical research would benefit our understanding of the usefulness of acupuncture to women’s health.
doi:10.2147/IJWH.S38969
PMCID: PMC3962314  PMID: 24669195
reproductive disorders; women; health; Chinese medicine; alternative medicine; acupuncture
3.  Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context 
We recently demonstrated that vasopressin (AVP) in the lateral septum modulates social play behavior differently in male and female juvenile rats. However, the extent to which different social contexts (i.e., exposure to an unfamiliar play partner in different environments) affect the regulation of social play remains largely unknown. Given that AVP and the closely related neuropeptide oxytocin (OXT) modulate social behavior as well as anxiety-like behavior, we hypothesized that these neuropeptides may regulate social play behavior differently in novel (novel cage) as opposed to familiar (home cage) social environments. Administration of the specific AVP V1a receptor (V1aR) antagonist (CH2)5Tyr(Me2)AVP into the lateral septum enhanced home cage social play behavior in males but reduced it in females, confirming our previous findings. These effects were context-specific because V1aR blockade did not alter novel cage social play behavior in either sex. Furthermore, social play in females was reduced by AVP in the novel cage and by OXT in the home cage. Additionally, females administered the specific OXT receptor antagonist desGly-NH2,d(CH2)5−[Tyr(Me)2,Thr4]OVT showed less social play in the novel as compared to the home cage. AVP enhanced anxiety-related behavior in males (tested on the elevated plus-maze), but failed to do so in females, suggesting that exogenous AVP alters social play and anxiety-related behavior via distinct and sex-specific mechanisms. Moreover, none of the other drug treatments that altered social play had an effect on anxiety, suggesting that these drug-induced behavioral alterations are relatively specific to social behavior. Overall, we showed that AVP and OXT systems in the lateral septum modulate social play in juvenile rats in neuropeptide-, sex- and social context-specific ways. These findings underscore the importance of considering not only sex, but also social context, in how AVP and OXT modulate social behavior.
doi:10.3389/fnbeh.2014.00216
PMCID: PMC4058593  PMID: 24982623
female; juvenile; lateral septum; male; oxytocin receptor; play-fighting; sex difference; V1a receptor
4.  Phenotypic characterisation of lung macrophages in asthma: over-expression of CCL17 
Background
Studies using monocyte-derived macrophages (MDM) and animal models have suggested a role for alternatively-activated (M2) macrophages in asthmatic inflammation, but in vivo evidence for this phenotype in human asthma is lacking.
Objective
Phenotypically to characterize lung macrophages from asthmatic patients in relation to disease severity and treatment.
Methods
M2 biomarkers were first identified using MDM exposed to Th2 cytokines and then used to phenotype sputum and bronchoalveolar lavage (BAL) macrophages from 12 healthy controls, 12 mild and 14 moderate asthmatics and to assess the effects of corticosteroids and phosphatidylinositol-3-kinase (PI3K) inhibitors.
Results
Sputum macrophages from asthmatics expressed significantly more CCL17 mRNA but less CD163 than macrophages from healthy individuals. However, none of the other M2 biomarkers were differentially expressed in asthma and ex vivo BAL cells spontaneously produced similar amounts of M2 cytokine/chemokines (IL-10, CCL17 and CCL22). CCL17 mRNA over-expression correlated weakly but significantly with sputum eosinophilia (p=0.0252) and was also observed in macrophages from moderate asthmatics treated with inhaled steroids, suggesting relative insensitivity to inhibition by corticosteroids. The PI3Kinase inhibitor LY294002 inhibited basal CCL17 release from BAL cells and IL-4-stimulated release from MDM.
Conclusions
This study does not support the existence in human asthma of the full M2 phenotype described to date, but points to upregulation of CCL17 in both mild and moderate asthma, providing a further source for this ligand of CCR4+ cells that contribute to airways inflammation. CCL17 expression is corticosteroid resistant but is suppressed by PI3Kinase enzyme inhibitors.
doi:10.1016/j.jaci.2012.07.023
PMCID: PMC3805016  PMID: 22981793
5.  A survey describing the use of complementary therapies and medicines by women attending a family planning clinic 
Background
Complementary medicines (CMs) are widely used by women. Although, women in Australia are frequent users of CM, few studies have examined their utilisation by women attending a family planning service. The aim of this study was to examine (i) the extent of and type of CM, (ii) women’s views about safety and efficacy, and (iii) the factors influencing women’s decision-making.
Methods
A cross-sectional survey using a convenience sample of 221women aged greater than 18 years attending a family planning (FP) service was undertaken over a two week period in Sydney, Australia. An anonymous self-administered questionnaire was designed to examine women’s current and previous use of CMs, their attitudes towards safety and effectiveness, the factors influencing their decision-making, and their disclosure of CM use to a FP health professional. Demographic questions were designed to describe the diversity of the participants. Logistic regression was used to examine the association between CM use and demographics.
Results
Sixty-seven percent of women surveyed were currently using CMs, and 83% reported use during the previous 12 months. Most respondents utilised CMs to maintain their general health or for prevention of ill health. Over 30% of women lacked information to make an informed response to questions examining their views about the safety of CMs. Forty-four percent of participants stated they discussed their use of CMs with their FP providers. The main reason why women did not mention CMs was they did not see the relevance to their consultation (43%). Lower rates of CM use were found for younger women (OR 0.24, 95% CI 0.09-0.61), and those not completing high school (OR 0.44, 95% 0.20-1.00).
Conclusion
The use of CM is very common among women attending an Australian FP clinic, however our findings may not be generalisable to all women. We identified a notable gap in women’s awareness of the potential for interactions between CM and prescribed medication. Our findings also emphasise the need for healthcare providers to initiate discussions with clients about their utilisation of CM.
doi:10.1186/1472-6882-13-224
PMCID: PMC3846927  PMID: 24025479
Complementary therapies and medicines; Women’s health; Reproductive health; Family planning; Survey
6.  A Cluster Randomized Study of The Safety of Integrated Treatment of Trachoma and Lymphatic Filariasis in Children and Adults in Sikasso, Mali 
Background
Neglected tropical diseases are co-endemic in many areas of the world, including sub Saharan Africa. Currently lymphatic filariasis (albendazole/ivermectin) and trachoma (azithromycin) are treated separately. Consequently, financial and logistical benefit can be gained from integration of preventive chemotherapy programs in such areas.
Methodology/Findings
4 villages in two co-endemic districts (Kolondièba and Bougouni) of Sikasso, Mali, were randomly assigned to coadministered treatment (ivermectin/albendazole/azithromycin) or standard therapy (ivermectin/albendazole with azithromycin 1 week later). These villages had previously undergone 4 annual MDA campaigns with ivermectin/albendazole and 2 with azithromycin. One village was randomly assigned to each treatment arm in each district. There were 7515 eligible individuals in the 4 villages, 3011(40.1%) of whom participated in the study. No serious adverse events occurred, and the majority of adverse events were mild in intensity (mainly headache, abdominal pain, diarrhoea and “other signs/symptoms”). The median time to the onset of the first event, of any type, was later (8 days) in the two standard treatment villages than in the co-administration villages. Overall the number of subjects reporting any event was similar in the co-administration group compared to the standard treatment group [18.7% (281/1501) vs. 15.8% (239/1510)]. However, the event frequency was higher in the coadministration group (30.4%) than in the standard treatment group (11.0%) in Kolondièba, while the opposite was observed in Bougouni (7.1% and 20.9% respectively). Additionally, the overall frequency of adverse events in the co-administration group (18.7%) was comparable to or lower than published frequencies for ivermectin+albendazole alone.
Conclusions
These data suggest that co-administration of ivermectin+albendazole and azithromycin is safe; however the small number of villages studied and the large differences between them resulted in an inability to calculate a meaningful overall estimate of the difference in adverse event rates between the regimens. Further work is therefore needed before co-administration can be definitively recommended.
Trial Registration
ClinicalTrials.gov; NCT01586169
Author Summary
Neglected tropical diseases are co-endemic in many areas of the world. Currently lymphatic filariasis (albendazole+ivermectin) and trachoma (azithromycin) are treated separately. Benefits can be gained from integration of preventive chemotherapy programs in such areas. To assess the safety of this approach, 4 villages in two co-endemic districts in Mali were randomly assigned to coadministered treatment (ivermectin/albendazole/azithromycin) or standard therapy (ivermectin/albendazole with azithromycin 1 week later). One village was randomly assigned to each treatment in each district. 3011(40.1%) of 7515 eligible individuals in the 4 villages participated in the study. No serious adverse events occurred, and most events were mild in intensity (mainly headache, abdominal pain, and diarrhoea). Overall the number of subjects reporting any event was similar with co-administration compared to standard treatment [18.7% (281/1501) vs. 15.8% (239/1510)]. The overall frequency of adverse events with co-administration was comparable to or lower than published frequencies for ivermectin/albendazole alone. These data suggest that co-administration is safe; however the small number of villages studied and the large differences between them meant that a meaningful estimate of the differences could not be calculated, and further work will be needed before a recommendation can be made.
doi:10.1371/journal.pntd.0002221
PMCID: PMC3649960  PMID: 23675549
7.  Coactivation of M1 muscarinic and α1 adrenergic receptors stimulates ERK and induces long-term depression at CA3-CA1 synapses in rat hippocampus 
Intact cholinergic innervation from medial septum and noradrenergic innervation from locus coeruleus are required for hippocampal dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Recently we reported that activation of either muscarinic M1 or adrenergic α1 receptors induces activity- and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common Gαq coupled signaling pathway for their induction, and investigated the net effect of coactivation of M1 and α1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires PLC activation but both plasticities are prevented by inhibiting the Src kinase family and ERK activation. Interestingly, LTD can be induced when M1 and α1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M1 and α1 receptors could function to induce long-term changes in synaptic function important for cognition.
doi:10.1523/JNEUROSCI.5058-06.2008
PMCID: PMC3625642  PMID: 18480291
synaptic plasticity; acetylcholine; norepinephrine; U0126; carbachol; methoxamine
8.  The Anti-Inflammatory Effects of Acupuncture and Their Relevance to Allergic Rhinitis: A Narrative Review and Proposed Model 
Classical literature indicates that acupuncture has been used for millennia to treat numerous inflammatory conditions, including allergic rhinitis. Recent research has examined some of the mechanisms underpinning acupuncture's anti-inflammatory effects which include mediation by sympathetic and parasympathetic pathways. The hypothalamus-pituitary-adrenal (HPA) axis has been reported to mediate the antioedema effects of acupuncture, but not antihyperalgesic actions during inflammation. Other reported anti-inflammatory effects of acupuncture include an antihistamine action and downregulation of proinflammatory cytokines (such as TNF-α, IL-1β, IL-6, and IL-10), proinflammatory neuropeptides (such as SP, CGRP, and VIP), and neurotrophins (such as NGF and BDNF) which can enhance and prolong inflammatory response. Acupuncture has been reported to suppress the expression of COX-1, COX-2, and iNOS during experimentally induced inflammation. Downregulation of the expression and sensitivity of the transient receptor potential vallinoid 1 (TRPV1) after acupuncture has been reported. In summary, acupuncture may exert anti-inflammatory effects through a complex neuro-endocrino-immunological network of actions. Many of these generic anti-inflammatory effects of acupuncture are of direct relevance to allergic rhinitis; however, more research is needed to elucidate specifically how immune mechanisms might be modulated by acupuncture in allergic rhinitis, and to this end a proposed model is offered to guide further research.
doi:10.1155/2013/591796
PMCID: PMC3586443  PMID: 23476696
9.  CNS Dopamine Transmission Mediated by Noradrenergic Innervation 
The Journal of Neuroscience  2012;32(18):6072-6080.
The pre-synaptic source of dopamine in the CA1 field of dorsal hippocampus is uncertain due to an anatomical mismatch between dopaminergic terminals and receptors. We show, in an in vitro slice preparation from C57BL6 male mice, that a dopamine (DA) D1 receptor (D1R) mediated enhancement in glutamate synaptic transmission occurs following release of endogenous DA with amphetamine exposure. It is assumed DA is released from terminals innervating from the ventral tegmental area (VTA) even though DA transporter (DAT) positive fibers are absent in hippocampus, a region with abundant D1Rs. It has been suggested this results from a lack of DAT expression on VTA terminals rather than a lack of these terminals per se. Neither a knockdown of tyrosine hydroxylase (TH) expression in the VTA by THsiRNA, delivered locally, by adeno-associated viral vector, nor localized pharmacological blockade of DAT to prevent amphetamine uptake into DA terminals, has any effect on the D1R synaptic, enhancement response to amphetamine. However, either a decrease in TH expression in the locus coeruleus (LC) or a blockade of the norepinephrine (NE) transporter prevents the DA mediated response, indicating LC terminals can release both NE and DA. These findings suggest noradrenergic fibers may be the primary source of DA release in hippocampus and corresponding DA mediated increase in synaptic transmission. Accordingly, these data imply the LC may have a role in DA transmission in the CNS in response to drugs of abuse, and potentially, under physiological conditions.
doi:10.1523/JNEUROSCI.6486-11.2012
PMCID: PMC3371362  PMID: 22553014
hippocampus; dopamine; locus coeruleus; ventral tegmental area; noradrenergic and dopaminergic
10.  Upregulation of iNOS contributes to attenuated cutaneous vasodilation in essential hypertensive humans 
Hypertension  2011;58(5):935-942.
Essential hypertension is a pro-inflammatory, pro-constrictor disease coinciding with endothelial dysfunction and inward vessel remodeling. Using the skin circulation our aim was to determine if iNOS upregulation attenuates NO-dependent cutaneous vasodilation in hypertensive humans. We hypothesized that with hypertension (1) localized iNOS inhibition would restore vasodilation in response to NO-dependent stimuli and (2) iNOS expression would be increased and phosphorylated vasodilator-stimulated phosphoprotein (pVASP) would be decreased. In vivo protocols: four intradermal microdialysis (MD) fibers were placed in 9 hypertensive and 10 normotensive (SBP: 146 ± 4 vs.113 ± 2 mmHg, p<0.001) men and women. MD fibers served as control, iNOS-inhibited (1400W), nNOS-inhibited (NPLA), and non-selective NOS-inhibited (L-NAME). Cutaneous vascular conductance was calculated (%CVCmax; sodium nitroprusside) during standardized local heating (42°C) and acetylcholine (ach) dose-response protocols (0.01, 0.1, 1, 5, 10, 50, 100 mmol/L). The NO-dependent local heating response was attenuated at control (95 ± 2 vs. 76 ± 2 %CVCmax, p<0.05) and nNOS-inhibited sites (94 ± 4 vs. 77 ± 3 %CVCmax, p<0.01) in hypertensives. iNOS inhibition augmented the NO-dependent local heating response (93 ± 2 vs. 89 ± 10 %CVCmax). Ach-induced vasodilation was attenuated in control sites at doses ≥ 0.1mM Ach in hypertensives, and was restored with iNOS inhibition (0.1 mM p<0.05; 1, 5, 10 mM p<0.001; 50, 100 mM p<0.01). In vitro iNOS expression was increased (p=0.006) and pVASP/VASP was decreased in skin from hypertensive humans (p=0.04). These data suggest that iNOS is upregulated in essential hypertensive humans and contributes to reduced NO-dependent cutaneous vasodilation.
doi:10.1161/HYPERTENSIONAHA.111.178129
PMCID: PMC3209704  PMID: 21931069
nitric oxide; inducible nitric oxide synthase; skin blood flow; hypertension; microvascular dysfunction
11.  Using a Delphi consensus process to develop an acupuncture treatment protocol by consensus for women undergoing Assisted Reproductive Technology (ART) treatment 
Background
Assisted reproductive technologies (ART) are increasingly utilised for resolving difficulties conceiving. These technologies are expensive to both the public purse and the individual consumers. Acupuncture is widely used as an adjunct to ART with indications that it may assist reducing the time to conception and increasing live birth rates. Heterogeneity is high between treatment protocols.
The aim of this study was to examine what fertility acupuncturists consider key components of best practice acupuncture during an ART cycle, and to establish an acupuncture protocol by consensus.
Methods
Fifteen international acupuncturists with extensive experience treating women during ART interventions participated in 3 rounds of Delphi questionnaires. The first round focused on identifying the parameters of acupuncture treatment as adjunct to ART, the second round evaluated statements derived from the earlier round, and the third evaluated specific parameters for a proposed trial protocol. Consensus was defined as greater than 80% agreement.
Results
Significant agreement was achieved on the parameters of best practice acupuncture, including an acupuncture protocol suitable for future research. Study participants confirmed the importance of needling aspects relating to the dose of acupuncture, the therapeutic relationship, tailoring treatment to the individual, and the role of co-interventions. From two rounds of the Delphi a consensus was achieved on seven treatment parameters for the design of the acupuncture treatment to be used in a clinical trial of acupuncture as an adjunct to ART. The treatment protocol includes the use of the traditional Chinese medicine acupuncture, use of manual acupuncture, a first treatment administered between day 6–8 of the stimulated ART cycle which is individualised to the participant, two treatments will be administered on the day of embryo transfer, and will include points SP8, SP10, LR3, ST29, CV4, and post transfer include: GV20, KD3, ST36, SP6, and PC6. Auricular points Shenmen and Zigong will be used. Practitioner intent or yi will be addressed in the treatment protocol.
Conclusions
Despite a lack of homogeneity in the research and clinical literature on ART and acupuncture, a consensus amongst experts on key components of a best practice treatment protocol was possible. Such consensus offers guidance for further research.
doi:10.1186/1472-6882-12-88
PMCID: PMC3416745  PMID: 22769059
12.  Acupuncture to improve live birth rates for women undergoing in vitro fertilization: a protocol for a randomized controlled trial 
Trials  2012;13:60.
Background
IVF is a costly treatment option for women, their partners, and the public. Therefore new therapies that improve reproductive and health outcomes are highly desirable. There is a growing body of research evaluating the effect of acupuncture administered during IVF, and specifically on the day of embryo transfer (ET). Many trials are heterogeneous and results inconsistent. There remains insufficient evidence to determine if acupuncture can enhance live birth rates when used as an adjunct to IVF treatment.
The study will determine the clinical effectiveness of acupuncture with improving the proportion of women undergoing IVF having live births. Other objectives include: determination of the cost effectiveness of IVF with acupuncture; and examination of the personal and social context of acupuncture in IVF patients, and examining the reasons why the acupuncture may or may not have worked.
Methods
We will conduct a randomized controlled trial of acupuncture compared to placebo acupuncture.
Inclusion criteria include: women aged less than 43 years; undergoing a fresh IVF or ICSI cycle; and restricted to women with the potential for a lower live birth rate defined as two or more previous unsuccessful ETs; and unsuccessful clinical pregnancies of quality embryos deemed by the embryologist to have been suitable for freezing by standard criteria. Women will be randomized to acupuncture or placebo acupuncture. Treatment is administered on days 6 to 8 of the stimulated cycle and two treatments on the day of ET. A non-randomized cohort of women not using acupuncture will be recruited to the study. The primary study outcome is the proportion of women reporting a live birth. Secondary outcomes include the proportion of women reporting a clinical pregnancy miscarriage prior to 12 weeks, quality of life, and self-efficacy. The sample size of the study is 1,168 women, with the aim of detecting a 7% difference in live births between groups (P = 0.05, 80% power).
Discussion
There remains a need for further research to add significant new knowledge to defining the exact role of certain acupuncture protocols in the management of infertility requiring IVF from a clinical and cost-effectiveness perspective.
Clinical Trial Registration
Australian and New Zealand Clinical Trial Registry ACTRN12611000226909
doi:10.1186/1745-6215-13-60
PMCID: PMC3464889  PMID: 22607192
13.  Development of an Instrument to Assess the Quality of Acupuncture: Results from a Delphi Process 
Abstract
Background
Quality acupuncture influences the outcomes of clinical research, and issues associated with effective administration of acupuncture in randomized controlled trials need to be addressed when appraising studies.
Objective
The study objective was to achieve consensus on domains and items for inclusion in a rating scale to assess quality acupuncture administered in clinical research.
Study design and subjects
An active group of Australian acupuncture researchers initially identified a pool of items assessing quality. The Delphi consensus process was then used to select and reduce the number of items, and an additional expert panel of 42 researchers were invited to participate. Participants initially ranked items along a five-point scale for the first Delphi round, and indicated an agree or disagree response during the second round. For an item to be retained into the second round, an item had to attain greater than 80% agreement that the item described a dimension of quality acupuncture and related study design.
Results
Thirty-two (32) experts agreed to participate in the study. After two rounds of the Delphi process, consensus was reached on 14 domains and 26 items relating to quality acupuncture. Domains, items, and minimum standards related to study design; rationale of the intervention; criteria relating to needling stimulation either manual or electrostimulation; duration and frequency of treatment; and practitioner training.
Conclusions
Items for inclusion in an instrument to assess quality acupuncture in clinical research were identified. Further development of the instrument including relative weighting of items and reliability testing is under way.
doi:10.1089/acm.2010.0457
PMCID: PMC3096500  PMID: 21548817
14.  Acupuncture as a therapeutic treatment option for threatened miscarriage 
Background
Threatened miscarriage involves vaginal bleeding in a pregnancy that remains viable. This is a common early pregnancy complication with increased risk factors for early pregnancy loss, preterm premature rupture of membranes (PPROM), preterm delivery, low birth weight babies and maternal antepartum haemorrhage. Currently there are no recommended medical treatment options, rather women receive advice that centres on a 'wait and see' approach. For women with a history of unexplained recurrent miscarriage providing supportive care in a subsequent pregnancy improves live birthing outcomes, but the provision of supportive care to women experiencing threatened miscarriage has to date not been examined.
Discussion
While it is known that 50-70% of miscarriages occur due to chromosomal abnormalities, the potential for therapeutic intervention amongst the remaining percentage of women remains unknown. Complementary and alternative medicine (CAM) therapies have the potential to provide supportive care for women presenting with threatened miscarriage. Within fertility research, acupuncture demonstrates beneficial hormonal responses with decreased miscarriage rates, raising the possibility acupuncture may promote specific beneficial effects in early pregnancy. With the lack of current medical options for women presenting with threatened miscarriage it is timely to examine the possible treatment benefits of providing CAM therapies such as acupuncture.
Summary
Despite vaginal bleeding being a common complication of early pregnancy there is often reluctance from practitioners to discuss with women and medical personal how and why CAM may be beneficial. In this debate article, the physiological processes of early pregnancy together with the concept of providing supportive care and acupuncture are examined. The aim is to raise awareness and promote discussion as to the beneficial role CAM may have for women presenting with threatened miscarriage.
doi:10.1186/1472-6882-12-20
PMCID: PMC3342918  PMID: 22439880
15.  A Systematic Review of the Effect of Expectancy on Treatment Responses to Acupuncture 
Randomised controlled trials (RCTs) of acupuncture often find equivalent responses to real and placebo acupuncture despite both appearing superior to no treatment. This raises questions regarding the mechanisms of acupuncture, especially the contribution of patient expectancies. We systematically reviewed previous research assessing the relationship between expectancy and treatment responses following acupuncture, whether real or placebo. To be included, studies needed to assess and/or manipulate expectancies about acupuncture and relate these to at least one health-relevant outcome. Nine such independent studies were identified through systematic searches of Medline, PsycInfo, PubMed, and Cochrane Clinical Trials Register. The methodology and reporting of these studies were quite heterogeneous, meaning that meta-analysis was not possible. A descriptive review revealed that five studies found statistically significant effects of expectancy on a least one outcome, with three also finding evidence suggestive of an interaction between expectancy and type of acupuncture (real or placebo). While there were some trends in significant effects in terms of study characteristics, their generality is limited by the heterogeneity of study designs. The differences in design across studies highlight some important methodological considerations for future research in this area, particularly regarding whether to assess or manipulate expectancies and how best to assess expectancies.
doi:10.1155/2012/857804
PMCID: PMC3235945  PMID: 22203882
16.  Moxibustion for cephalic version: a feasibility randomised controlled trial 
Background
Moxibustion (a type of Chinese medicine which involves burning a herb close to the skin) has been used to correct a breech presentation. Evidence of effectiveness and safety from systematic reviews is encouraging although significant heterogeneity has been found among trials. We assessed the feasibility of conducting a randomised controlled trial of moxibustion plus usual care compared with usual care to promote cephalic version in women with a breech presentation, and examined the views of women and health care providers towards implementing a trial within an Australian context.
Methods
The study was undertaken at a public hospital in Newcastle, New South Wales, Australia. Women at 34-36.5 weeks of gestation with a singleton breech presentation (confirmed by ultrasound), were randomised to moxibustion plus usual care or usual care alone. The intervention was administered over 10 days. Clinical outcomes included cephalic presentation at birth, the need for ECV, mode of birth; perinatal morbidity and mortality, and maternal complications. Feasibility outcomes included: recruitment rate, acceptability, compliance and a sample size for a future study. Interviews were conducted with 19 midwives and obstetricians to examine the acceptability of moxibustion, and views on the trial.
Results
Twenty women were randomised to the trial. Fifty one percent of women approached accepted randomisation to the trial. A trend towards an increase in cephalic version at delivery (RR 5.0; 95% CI 0.7-35.5) was found for women receiving moxibustion compared with usual care. There was also a trend towards greater success with version following ECV. Two babies were admitted to the neonatal unit from the moxibustion group. Compliance with the moxibustion protocol was acceptable with no reported side effects. Clinicians expressed the need for research to establish the safety and efficacy of moxibustion, and support for the intervention was given to increase women's choices, and explore opportunities to normalise birth. The sample size for a future trial is estimated to be 381 women.
Conclusion
Our findings should be interpreted with caution as the study was underpowered to detect statistical differences between groups. Acceptance by women and health professionals towards moxibustion suggest further research is warranted.
Trial Registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12609000985280
doi:10.1186/1472-6882-11-81
PMCID: PMC3192686  PMID: 21943180
breech; moxibustion; randomised controlled trial; feasibility
17.  Use of Chinese medicine by cancer patients: a review of surveys 
Chinese Medicine  2011;6:22.
Chinese medicine has been used to treat a variety of cancer-related conditions. This study aims to examine the prevalence and patterns of Chinese medicine usage by cancer patients. We reviewed articles written in English and found only the Chinese medicine usage from the studies on complementary and alternative medicine (CAM). Seventy four (74) out of 81 articles reported rates of CAM usage ranging from 2.6 to 100%. Acupuncture was reported in 71 out of 81 studies. Other less commonly reported modalities included Qigong (n = 17), Chinese herbal medicine (n = 11), Taichi (n = 10), acupressure (n = 6), moxibustion (n = 2), Chinese dietary therapy (n = 1), Chinese massage (n = 1), cupping (n = 1) and other Chinese medicine modalities (n = 19). This review also found important limitations of the English language articles on CAM usage in cancer patients. Our results show that Chinese medicine, in particular Chinese herbal medicine, is commonly used by cancer patients. Further research is warranted to include studies not written in English.
doi:10.1186/1749-8546-6-22
PMCID: PMC3148205  PMID: 21651825
18.  Acupuncture to Treat Primary Dysmenorrhea in Women: A Randomized Controlled Trial 
We examined the effectiveness of acupuncture to reduce the severity and intensity of primary dysmenorrhea. A randomized controlled trial compared acupuncture with control acupuncture using a placebo needle. Eligible women were aged 14–25 years with a diagnosis of primary dysmenorrhea. Women received nine sessions of the study treatment over 3 months. The primary outcomes were menstrual pain intensity and duration, overall improvement in dysmenorrhea symptoms and reduced need for additional analgesia, measured at 3, 6 and 12 months from trial entry. A total of 92 women were randomly assigned to the intervention (acupuncture n = 46 and control n = 46). At 3 months although pain outcomes were lower for women in the acupuncture group compared with the control group, there was no significant difference between groups. Women receiving acupuncture reported a small reduction in mood changes compared with the control group, relative risk (RR) 0.72, 95% confidence interval (CI) 0.53–1.00, P = .05. Follow-up at 6 months found a significant reduction in the duration of menstrual pain in the acupuncture group compared with the control group, mean difference –9.6, 95% CI –18.9 to –0.3, P = .04, and the need for additional analgesia was significantly lower in the acupuncture group compared with the control group, RR 0.69, 95% CI 0.49–0.96, P = .03, but the follow-up at 12 months found lack of treatment effect. To conclude, although acupuncture improved menstrual mood symptoms in women with primary dysmenorrhea during the treatment phase, the trend in the improvement of symptoms during the active phase of treatment, and at 6 and 12 months was non-significant, indicating that a small treatment effect from acupuncture on dysmenorrhea may exist. In the study, acupuncture was acceptable and safe, but further appropriately powered trials are needed before recommendations for clinical practice can be made.
doi:10.1093/ecam/nep239
PMCID: PMC3140031  PMID: 21799683
19.  Ear discharge in children presenting with acute otitis media: observational study from UK general practice 
Background
National Institute for Health and Clinical Excellence (NICE) guidance to treat otitis media in older children immediately with antibiotics only if they have ear discharge is based on limited evidence.
Aim
To determine the clinical significance and outcome of ear discharge in children with acute otitis media, in routine clinical practice.
Design of study
Observational cohort study of children with acute otitis media comparing those with and without ear discharge at presentation.
Setting
Primary care in East Somerset.
Method
Two hundred and fifty-six children aged 6 months to 10 years were recruited from primary care. Clinical features and other characteristics were recorded at presentation. Follow-up was undertaken at 2 weeks and 3 months.
Results
Children with otitis media who present with ear discharge are much more likely to be treated with antibiotics irrespective of age (adjusted odds ratio 15, 95% confidence interval [CI] = 3 to 66). Most with discharge have proven bacterial infection (58%, 95% CI = 42 to 72%). They have a more severe systemic illness, with higher axillary temperature (80% increase in odds of ear discharge for each additional degree centigrade, P = 0.02), pulse rate (9% increase in odds for each extra beat, P<0.001), and Yale score (mean 10.5 versus 9.0, P = 0.003). They may also have an increased likelihood of adverse outcome (adjusted odds ratio of pain at 1 week 2.9; further episodes of acute otitis media 3.3; hearing difficulty at 3 months 4.7; all P<0.10).
Conclusion
Ear discharge defines a group of children with otitis media who are sicker and may be at higher risk of adverse outcome. NICE guidance to treat them with antibiotics is supported.
doi:10.3399/bjgp10X483148
PMCID: PMC2814262  PMID: 20132703
acute; general practice; family practice; otorrhea; otitis media
20.  The Ethics of Traditional Chinese and Western Herbal Medicine Research: Views of Researchers and Human Ethics Committees in Australia 
Despite the growth of traditional Chinese medicine (TCM) and western herbal medicine (WHM) research in Australia, little is known about how ethics committees (HRECs) assess the ethics of TCM or WHM research. The objectives of this study were to examine the experiences of TCM and WHM researchers and HRECs with the evaluation of ethics applications. Two cross-sectional surveys were undertaken of HRECs and TCM and WHM researchers in Australia. Anonymous self-completion questionnaires were administered to 224 HRECs and 117 researchers. A response confirming involvement in TCM or WHM research applications was received from 20 HRECs and 42 researchers. The most frequent ethical issues identified by HRECs related to herbal products including information gaps relating to mode of action of herbal medicines and safety when combining herbal ingredients. Researchers concurred that they were frequently requested to provide additional information on multiple aspects including safety relating to the side effects of herbs and herb-drug interactions. Overall adherence with the principles of ethical conduct was high among TCM and WHM researchers although our study did identify the need for additional information regarding assessment of risk and risk management.
doi:10.1155/2011/256915
PMCID: PMC3004390  PMID: 21197081
21.  Estradiol and the Relationship between Dendritic Spines, NR2B Containing NMDA Receptors, and the Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses 
Psychoneuroendocrinology  2009;34S1:S130-S142.
Summary
When circulating estrogen levels decline as a natural consequence of menopause and aging in women, there is an increased incidence of deficits in working memory. In many cases, these deficits are rescued by estrogen replacement therapy. These clinical data therefore highlight the importance of defining the biological pathways linking estrogen to the cellular substrates of learning and memory. It has been known for nearly two decades that estrogen enhances dendritic spine density on apical dendrites of CA1 pyramidal cells in hippocampus, a brain region required for learning. Interestingly, at synapses between CA3-CA1 pyramidal cells, estrogen has also been shown to enhance synaptic NMDA receptor current and the magnitude of long term potentiation, a cellular correlate of learning and memory. Given that synapse density, NMDAR function, and long term potentiation at CA3-CA1 synapses in hippocampus are associated with normal learning, it is likely that modulation of these parameters by estrogen facilitates the improvement in learning observed in rats, primates and humans following estrogen replacement. To facilitate the design of clinical strategies to potentially prevent or reverse the age-related decline in learning and memory during menopause, the relationship between the estrogen-induced morphological and functional changes in hippocampus must be defined and the role these changes play in facilitating learning must be elucidated. The aim of this report is to provide a summary of the proposed mechanisms by which this hormone increases synaptic function and in doing so, it briefly addresses potential mechanisms contributing to the estrogen-induced increase in synaptic morphology and plasticity, as well as important future directions.
doi:10.1016/j.psyneuen.2009.06.003
PMCID: PMC2796081  PMID: 19596521
long term potentiation; LTP; NR2B; NMDA receptor; NMDAR; AMPA receptor; AMPAR; spine density; glutamate synapses; estradiol; estrogen; ERα; ERβ
22.  What affects anticoagulation control in patients taking warfarin? 
Background
The ageing population is taking an increasing number of both prescribed and non-prescribed medication. Little is known of the potential for adverse drug reactions between these. Warfarin is a commonly prescribed medication, well known for its potential to cause serious adverse reactions in combination with many prescription medicines. It has been suggested that herbal medicines such as garlic, either as a dietary supplement or in cooking, may also interact with warfarin, resulting in poor international normalised ratio (INR) control.
Aim
To determine whether, for patients who take garlic as well as warfarin, the proportion of the INR tests in range is lower than in comparable patients who do not take garlic.
Design of the study
Retrospective study of patients taking prescribed warfarin.
Setting
Primary care practices in Somerset and Devon.
Method
Three controls (not taking garlic) matched for age, sex, and general practice were compared with each patient self-reporting taking garlic as a supplement. INR results were assessed for the preceding 12 months. Potentially confounding factors were considered, for example diabetes mellitus; all prescribed medication; any bleeding episodes.
Results
No evidence was found to suggest that garlic consumption either as a supplement or in cooking is associated with more frequent haemorrhagic complications or less control of INR. Poor INR control may, however, be associated with taking larger numbers of prescription medicines, particularly during prescription changes.
Conclusion
Further research would be warranted into whether increased INR monitoring is needed when drug changes are made. These data render clinically significant interactions between warfarin and garlic intake unlikely.
doi:10.3399/bjgp09X453800
PMCID: PMC2714782  PMID: 22751234
anticoagulation; complementary medicine; garlic; prescriptions; warfarin
23.  Effect of negative air ions on the potential for bacterial contamination of plastic medical equipment 
Background
In recent years there has been renewed interest in the use of air ionizers to control the spread of infection in hospitals and a number of researchers have investigated the biocidal action of ions in both air and nitrogen. By comparison, the physical action of air ions on bacterial dissemination and deposition has largely been ignored. However, there is clinical evidence that air ions might play an important role in preventing the transmission of Acinetobacter infection. Although the reasons for this are unclear, it is hypothesized that a physical effect may be responsible: the production of air ions may negatively charge items of plastic medical equipment so that they repel, rather than attract, airborne bacteria. By negatively charging both particles in the air and items of plastic equipment, the ionizers minimize electrostatic deposition on these items. In so doing they may help to interrupt the transmission of Acinetobacter infection in certain healthcare settings such as intensive care units.
Methods
A study was undertaken in a mechanically ventilated room under ambient conditions to accurately measure changes in surface potential exhibited by items of plastic medical equipment in the presence of negative air ions. Plastic items were suspended on nylon threads, either in free space or in contact with a table surface, and exposed to negative ions produced by an air ionizer. The charge build-up on the specimens was measured using an electric field mill while the ion concentration in the room air was recorded using a portable ion counter.
Results
The results of the study demonstrated that common items of equipment such as ventilator tubes rapidly developed a large negative charge (i.e. generally >-100V) in the presence of a negative air ionizer. While most items of equipment tested behaved in a similar manner to this, one item, a box from a urological collection and monitoring system (the only item made from styrene acrylonitrile), did however develop a positive charge in the presence of the ionizer.
Conclusion
The findings of the study suggest that the action of negative air ionizers significantly alters the electrostatic landscape of the clinical environment, and that this has the potential to cause any Acinetobacter-bearing particles in the air to be strongly repelled from some plastic surfaces and attracted to others. In so doing, this may prevent critical items of equipment from becoming contaminated with the bacterium.
doi:10.1186/1471-2334-10-92
PMCID: PMC2873555  PMID: 20384999
24.  Building resilience: A preliminary exploration of women's perceptions of the use of acupuncture as an adjunct to In Vitro Fertilisation 
Background
In Vitro Fertilisation (IVF) is now an accepted and effective treatment for infertility, however IVF is acknowledged as contributing to, rather than lessening, the overall psychosocial effects of infertility. Psychological and counselling interventions have previously been widely recommended in parallel with infertility treatments but whilst in many jurisdictions counselling is recommended or mandatory, it may not be widely used. Acupuncture is increasingly used as an adjunct to IVF, in this preliminary study we sought to investigate the experience of infertile women who had used acupuncture to improve their fertility.
Methods
A sample of 20 women was drawn from a cohort of women who had attended for a minimum of four acupuncture sessions in the practices of two acupuncturists in South Australia. Eight women were interviewed using a semi-structured questionnaire. Six had sought acupuncture during IVF treatment and two had begun acupuncture to enhance their fertility and had later progressed to IVF. Descriptive content analysis was employed to analyse the data.
Results
Four major categories of perceptions about acupuncture in relation to reproductive health were identified: (a) Awareness of, and perceived benefits of acupuncture; (b) perceptions of the body and the impact of acupuncture upon it; (c) perceptions of stress and the impact of acupuncture on resilience; and (d) perceptions of the intersection of medical treatment and acupuncture.
Conclusion
This preliminary exploration, whilst confined to a small sample of women, confirms that acupuncture is indeed perceived by infertile women to have an impact to their health. All findings outlined here are reported cautiously because they are limited by the size of the sample. They suggest that further studies of acupuncture as an adjunct to IVF should systematically explore the issues of wellbeing, anxiety, personal and social resilience and women's identity in relation to sexuality and reproduction.
doi:10.1186/1472-6882-9-50
PMCID: PMC2799389  PMID: 20003370
25.  The Status and Future of Acupuncture Clinical Research 
Abstract
On November 8–9, 2007, the Society for Acupuncture Research (SAR) hosted an international conference to mark the tenth anniversary of the landmark National Institutes of Health Consensus Development Conference on Acupuncture. More than 300 acupuncture researchers, practitioners, students, funding agency personnel, and health policy analysts from 20 countries attended the SAR meeting held at the University of Maryland School of Medicine, Baltimore, MD. This paper summarizes important invited lectures in the area of clinical research. Specifically, included are: a review of the recently conducted German trials and observational studies on low-back pain (LBP), gonarthrosis, migraine, and tension-type headache (the Acupuncture Research Trials and the German Acupuncture Trials, plus observational studies); a systematic review of acupuncture treatment for knee osteoarthritis (OA); and an overview of acupuncture trials in neurologic conditions, LBP, women's health, psychiatric disorders, and functional bowel disorders. A summary of the use of acupuncture in cancer care is also provided. Researchers involved in the German trials concluded that acupuncture is effective for treating chronic pain, but the correct selection of acupuncture points seems to play a limited role; no conclusions could be drawn about the placebo aspect of acupuncture, due to the design of the studies. Overall, when compared to sham, acupuncture did not show a benefit in treating knee OA or LBP, but acupuncture was better than a wait-list control and standard of care, respectively. In women's health, acupuncture has been found to be beneficial for patients with premenstrual syndrome, dysmenorrhea, several pregnancy-related conditions, and nausea in females who have cancers. Evidence on moxibustion for breech presentation, induction of labor, and reduction of menopausal symptoms is still inconclusive. In mental health, evidence for acupuncture's efficacy in treating neurologic and functional bowel disorder is still inconclusive. For chronic cancer-related problems such as pain, acupuncture may work well in stand-alone clinics; however, for acute or treatment-related symptoms, integration of acupuncture care into a busy and complex clinical environment is unlikely, unless compelling evidence of a considerable patient benefit can be established.
doi:10.1089/acm.2008.SAR-4
PMCID: PMC3155101  PMID: 18803496

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