Women's views about physical activity as a treatment for vasomotor menopausal symptoms: a qualitative study.

BACKGROUND: Women commonly seek medical advice about menopausal symptoms. Although menopausal hormone therapy is the most effective treatment, many women prefer non-pharmacological treatments, such as physical activity. The effectiveness of physical activity has been inconclusive when assessed by randomised controlled trials, and it remains unclear how women feel about it as a possible treatment approach. The aim of the study was to explore symptomatic menopausal women's views and experiences of physical activity as a treatment for vasomotor and other menopausal symptoms. METHODS: An in-depth qualitative study was embedded within a randomised controlled trial that assessed the effectiveness of physical activity as a treatment for vasomotor menopausal symptoms in previously inactive vasomotor symptomatic women. Participants were randomised to one of two physical activity interventions or a usual care group. Both physical activity interventions involved two one-to-one consultations, plus either supporting materials or access to physical activity support groups, over 6 months. Semi-structured interviews were conducted with 17 purposively selected participants from all three trial groups after they had completed trial follow-up. Interviews were audio recorded, transcribed verbatim, and analysed by constant comparison. RESULTS: All participants talked positively about physical activity as a treatment for their menopausal symptoms, with most reporting participation had improved their hot flushes and night sweats. They reported that they had experienced improved sleep, physical health and psychological well-being. Those who received the physical activity plus social-support intervention reported their ability to cope with their menopausal symptoms had improved. Many participants commented that they would prefer doctors to discuss physical activity as a possible treatment for their hot flushes and night sweats, before offering medication. CONCLUSIONS: Based on the views and experiences of the women who participated in this study, healthcare professionals should continue discussing physical activity as a potential first treatment option with menopausal women. Furthermore, healthcare professionals should ensure they prepare, support, and encourage these women both physically and emotionally. TRIAL REGISTRATION: ISRCTN ISRCTN06495625 Registered 10/11/2010.

Exercise for vasomotor menopausal symptoms.

BACKGROUND: Evidence suggests that many perimenopausal and early postmenopausal women will experience menopausal symptoms; hot flushes are the most common. Symptoms caused by fluctuating levels of oestrogen may be alleviated by hormone therapy (HT), but a marked global decline in its use has resulted from concerns about the risks and benefits of HT. Consequently, many women are seeking alternatives. As large numbers of women are choosing not to take HT, it is increasingly important to identify evidence-based lifestyle modifications that have the potential to reduce vasomotor menopausal symptoms. OBJECTIVES: To examine the effectiveness of any type of exercise intervention in the management of vasomotor symptoms in symptomatic perimenopausal and postmenopausal women. SEARCH METHODS: Searches of the following electronic bibliographic databases were performed to identify randomised controlled trials (RCTs): Cochrane Menstrual Disorders and Subfertility Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Internet interface), MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), the Science Citation Index and the Social Science Citation Index (Web of Science), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Ovid) and SPORTDiscus. Searches include findings up to 3 March 2014. SELECTION CRITERIA: RCTs in which any type of exercise intervention was compared with no treatment/control or other treatments in the management of menopausal vasomotor symptoms in symptomatic perimenopausal/postmenopausal women. DATA COLLECTION AND ANALYSIS: Five studies were deemed eligible for inclusion. Two review authors independently selected the studies, and three review authors independently extracted the data. The primary review outcome was vasomotor symptoms, defined as hot flushes and/or night sweats. We combined data to calculate standardised mean differences (SMDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for main comparisons using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. MAIN RESULTS: We included five RCTs (733 women) comparing exercise with no active treatment, exercise with yoga and exercise with HT. The evidence was of low quality: Limitations in study design were noted, along with inconsistency and imprecision. In the comparison of exercise versus no active treatment (three studies, n = 454 women), no evidence was found of a difference between groups in frequency or intensity of vasomotor symptoms (SMD -0.10, 95% CI -0.33 to 0.13, three RCTs, 454 women, I(2) = 30%, low-quality evidence). Nor was any evidence found of a difference between groups in the frequency or intensity of vasomotor symptoms when exercise was compared with yoga (SMD -0.03, 95% CI -0.45 to 0.38, two studies, n = 279 women, I(2) = 61%, low-quality evidence). It was not possible to include one of the trials in the meta-analyses; this trial compared three groups: exercise plus soy milk, soy milk only and control; results favoured exercise relative to the comparators, but study numbers were small. One trial compared exercise with HT, and the HT group reported significantly fewer flushes in 24 hours than the exercise group (mean difference 5.8, 95% CI 3.17 to 8.43, 14 participants). None of the trials found evidence of a difference between groups with respect to adverse effects, but data were very scanty. AUTHORS' CONCLUSIONS: Evidence was insufficient to show whether exercise is an effective treatment for vasomotor menopausal symptoms. One small study suggested that HT is more effective than exercise. Evidence was insufficient to show the relative effectiveness of exercise when compared with HT or yoga.

Artificial intelligence and health inequities in primary care: a systematic scoping review and framework.

OBJECTIVE: Artificial intelligence (AI) will have a significant impact on healthcare over the coming decade. At the same time, health inequity remains one of the biggest challenges. Primary care is both a driver and a mitigator of health inequities and with AI gaining traction in primary care, there is a need for a holistic understanding of how AI affect health inequities, through the act of providing care and through potential system effects. This paper presents a systematic scoping review of the ways AI implementation in primary care may impact health inequity. DESIGN: Following a systematic scoping review approach, we searched for literature related to AI, health inequity, and implementation challenges of AI in primary care. In addition, articles from primary exploratory searches were added, and through reference screening.The results were thematically summarised and used to produce both a narrative and conceptual model for the mechanisms by which social determinants of health and AI in primary care could interact to either improve or worsen health inequities.Two public advisors were involved in the review process. ELIGIBILITY CRITERIA: Peer-reviewed publications and grey literature in English and Scandinavian languages. INFORMATION SOURCES: PubMed, SCOPUS and JSTOR. RESULTS: A total of 1529 publications were identified, of which 86 met the inclusion criteria. The findings were summarised under six different domains, covering both positive and negative effects: (1) access, (2) trust, (3) dehumanisation, (4) agency for self-care, (5) algorithmic bias and (6) external effects. The five first domains cover aspects of the interface between the patient and the primary care system, while the last domain covers care system-wide and societal effects of AI in primary care. A graphical model has been produced to illustrate this. Community involvement throughout the whole process of designing and implementing of AI in primary care was a common suggestion to mitigate the potential negative effects of AI. CONCLUSION: AI has the potential to affect health inequities through a multitude of ways, both directly in the patient consultation and through transformative system effects. This review summarises these effects from a system tive and provides a base for future research into responsible implementation.

Modulation of the proteolytic activity of the complement protease C1s by polyanions: implications for polyanion-mediated acceleration of interaction between C1s and SERPING1.

The complement system plays crucial roles in the immune system, but incorrect regulation causes inflammation and targeting of self-tissue, leading to diseases such as systemic lupus erythematosus, rheumatoid arthritis and age-related macular degeneration. In vivo, the initiating complexes of the classical complement and lectin pathways are controlled by SERPING1 [(C1 inhibitor) serpin peptidase inhibitor, clade G, member 1], which inactivates the components C1s and MASP-2 (mannan-binding lectin serine peptidase 2). GAGs (glycosaminoglycan) and DXS (dextran sulfate) are able to significantly accelerate SERPING1-mediated inactivation of C1s, the key effector enzyme of the classical C1 complex, although the mechanism is poorly understood. In the present study we have shown that C1s can bind to DXS and heparin and that these polyanions enhanced C1s proteolytic activity at low concentrations and inhibited it at higher concentrations. The recent determination of the crystal structure of SERPING1 has given rise to the hypothesis that both the serpin (serine protease inhibitor)-polyanion and protease-polyanion interactions might be required to accelerate the association rate of SERPING1 and C1s. To determine what proportion of the acceleration was due to protease-polyanion interactions, a chimaeric mutant of alpha1-antitrypsin containing the P4-P1 residues from the SERPING1 RCL (reactive-centre loop) was produced. Like SERPING1, this molecule is able to effectively inhibit C1s, but is unable to bind polyanions. DXS exerted a biphasic effect on the association rate of C1s which correlated strongly with the effect of DXS on C1s proteolytic activity. Thus, whereas polyanions are able to bind C1s and modulate its activity, polyanion interactions with SERPING1 must also play a vital role in the mechanism by which these cofactors accelerate the C1s-SERPING1 reaction.

Elucidation of the substrate specificity of the MASP-2 protease of the lectin complement pathway and identification of the enzyme as a major physiological target of the serpin, C1-inhibitor.

Complement is a central component of host defence, but unregulated activation can contribute to disease. The system can be initiated by three pathways: classical, alternative and lectin. The classical and lectin pathways are initiated by the C1 and mannose-binding lectin (MBL) or ficolin complexes, respectively, with C1s the executioner protease of the C1 complex and MASP-2 its counterpart in the lectin complexes. These proteases in turn cleave the C4 and C2 components of the system. Here we have elucidated the cleavage specificity of MASP-2 using a randomised substrate phage display library. Apart from the crucial P1 position, the MASP-2 S2 and S3 subsites (in that order) play the greatest role in determining specificity, with Gly residues preferred at P2 and Leu or hydrophobic residues at P3. Cleavage of peptide substrates representing the known physiological cleavage sequences in C2, C4 or the serpin C1-inhibitor (a likely regulator of MASP-2) revealed that MASP-2 is up to 1000 times more catalytically active than C1s. C1-inhibitor inhibited MASP-2 50-fold faster than C1s and much faster than any other protease tested to date, implying that MASP-2 is a major physiological target of C1-inhibitor.

Aerobic exercise for vasomotor menopausal symptoms: A cost-utility analysis based on the Active Women trial.

OBJECTIVE: To compare the cost-utility of two exercise interventions relative to a control group for vasomotor menopausal symptoms. DESIGN: Economic evaluation taking a UK National Health Service and Personal Social Services perspective and a societal perspective. SETTING: Primary care. POPULATION: Peri- and postmenopausal women who have not used hormone therapy in the past 3 months and experience ≥ 5 episodes of vasomotor symptoms daily. METHODS: An individual and a social support-based exercise intervention were evaluated. The former (Exercise-DVD), aimed to prompt exercise with purpose-designed DVD and written materials, whereas the latter (Exercise-Social support) with community exercise social support groups. Costs and outcomes associated with these interventions were compared to those of a control group, who could only have an exercise consultation. An incremental cost-utility analysis was undertaken using bootstrapping to account for the uncertainty around cost-effectiveness point-estimates. MAIN OUTCOME MEASURE: Cost per quality-adjusted life-year (QALY). RESULTS: Data for 261 women were available for analysis. Exercise-DVD was the most expensive and least effective intervention. Exercise-Social support was £52 (CIs: £18 to £86) and £18 (CIs: -£68 to £105) more expensive per woman than the control group at 6 and 12 months post-randomisation and led to 0.006 (CIs: -0.002 to 0.014) and 0.013 (CIs: -0.01 to 0.036) more QALYs, resulting in an incremental cost-effectiveness ratio of £8,940 and £1,413 per QALY gained respectively. Exercise-Social support had 80%-90% probability of being cost-effective in the UK context. A societal perspective of analysis and a complete-case analysis led to similar findings. CONCLUSIONS: Exercise-Social support resulted in a small gain in health-related quality of life at a marginal additional cost in a context where broader wellbeing and long-term gains associated with exercise and social participation were not captured. Community exercise social support groups are very likely to be cost-effective in the management of vasomotor menopausal symptoms.

First "hybrid" ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands.

12-Phenylacetyl-ricinoleoyl-vanillamide (phenylacetylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB(2) receptors. To improve its CB(2) affinity and temper its potency at TRPV1, the modification of the polar headgroup and the lipophilic 12-acylgroup of PhAR was pursued. Replacement of the vanillyl headgroup of PhAR with various aromatic or alkyl amino groups decreased activity at TRPV1 receptors, although the dopamine, cyclopropylamine, 1'-(R)- and 1'-(S)-methyl-ethanolamine, and ethanolamine derivatives retained significant potency (EC(50) 31-126 nM). Within these compounds, the 12-phenylacetylricinoleyl cyclopropylamide and ethanolamide were the strongest ligands at CB(2) receptors, with K(i) of 22 and 44 nM, and 14- and >20-fold selectivity over cannabinoid CB(1) receptors, respectively. The propyl- and allyl-derivatives also exhibited high affinity at CB(2) receptors (K(i)=40 and 22 nM, with 40 and >80-fold selectivity over CB(1) receptors, respectively), but no activity at TRPV1 receptors. The cyclopropyl- and allyl-derivatives behaved as CB(2) inverse agonists in the GTP-gamma-S binding assay. Addition of para-methoxy, -tert-butyl or -chlorine groups to the 12-phenylacetyl moiety of PhAR produced compounds that retained full potency at TRPV1 receptors, but with improved selectivity over CB(2) or CB(1) receptors. Thus, the manipulation of PhAR led to the development of the first CB(2)/TRPV1 dual ligands and of an entirely new class of inverse agonists at CB(2) receptors. Both types of compounds might find application in the treatment of inflammation, and represent new molecular probes to investigate the endocannabinoid-endovanilloid signalling system.

The bioassay of cannabinoids using the mouse isolated vas deferens.

The mouse isolated vas deferens is a nerve-smooth muscle preparation that serves as a highly sensitive and quantitative functional in vitro bioassay for cannabinoid CB1 receptor agonists. Additionally, it is commonly used as a bioassay for competitive surmountable CB1 receptor antagonists, and also provides a means for distinguishing neutral CB1 antagonists from CB1 inverse agonists. The bioassay of CB1 receptor agonists relies on the ability of these ligands to produce concentration-related decreases in the amplitude of electrically evoked contractions of the vas deferens. This they do by acting on naturally expressed prejunctional neuronal CB1 receptors to inhibit release of the contractile neurotransmitters, noradrenaline and ATP, that is provoked by the electrical stimulation. The bioassay of competitive surmountable CB1 receptor antagonists involves determining the ability of these compounds to produce parallel dextral shifts in CB1 receptor agonist log concentration-response curves in electrically stimulated tissues. The mouse vas deferens has also been used to measure the ability of anandamide to activate vanilloid (TRPV1) receptors, to monitor modulation by cannabinoids such as 6"-azido-2"-yne-cannabidiol and abnormal cannabidiol of contractions elicited in electrically unstimulated tissues by agonists for P2X purinoceptors or alpha1-adrenoceptors, and as a bioassay for the nonpsychoactive plant cannabinoid cannabidiol.

Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist.

Delta9-tetrahydrocannabivarin (THCV) displaced [(3)H]CP55940 from specific binding sites on mouse brain and CHO-hCB(2) cell membranes (K(i)=75.4 and 62.8 nM, respectively).THCV (1 microM) also antagonized CP55940-induced stimulation of [(35)S]GTPgammaS binding to these membranes (apparent K(B)=93.1 and 10.1 nM, respectively). In the mouse vas deferens, the ability of Delta9-tetrahydrocannabinol (THC) to inhibit electrically evoked contractions was antagonized by THCV, its apparent K(B)-value (96.7 nM) approximating the apparent K(B)-values for its antagonism of CP55940- and R-(+)-WIN55212-induced stimulation of [(35)S]GTPgammaS binding to mouse brain membranes. THCV also antagonized R-(+)-WIN55212, anandamide, methanandamide and CP55940 in the vas deferens, but with lower apparent K(B)-values (1.5, 1.2, 4.6 and 10.3 nM, respectively).THCV (100 nM) did not oppose clonidine, capsaicin or (-)-7-hydroxy-cannabidiol-dimethylheptyl-induced inhibition of electrically evoked contractions of the vas deferens. Contractile responses of the vas deferens to phenylephrine hydrochloride or beta,gamma-methylene-ATP were not reduced by 1microM THCV or R-(+)-WIN55212, suggesting that THCV interacts with R-(+)-WIN55212 at prejunctional sites. At 32 microM, THCV did reduce contractile responses to phenylephrine hydrochloride and beta,gamma-methylene-ATP, and above 3 microM it inhibited electrically evoked contractions of the vas deferens in an SR141716A-independent manner. In conclusion, THCV behaves as a competitive CB(1) and CB(2) receptor antagonist. In the vas deferens, it antagonized several cannabinoids more potently than THC and was also more potent against CP55940 and R-(+)-WIN55212 in this tissue than in brain membranes. The bases of these agonist- and tissue-dependent effects remain to be established.

Differential effects of detergents, fatty acids, cations and heating on ostrich skeletal muscle 20S proteasome.

The 20S proteasome, the catalytic core of the 26S proteasome, has previously been isolated, purified and partially characterised from ostrich skeletal muscle (Thomas, A.R., Oosthuizen, V., Naude, R.J., Muramoto, K. 2002. Biol. Chem. 383, 1267-1270). Due to the apparent latency of the 20S proteasome purified from various sources, this study focuses on further characterising the ostrich enzyme in terms of the effects of selected detergents, fatty acids and cations, as well as heating at 60 degrees C, on four of its activities. Results showed that ostrich skeletal muscle 20S proteasome was affected in a non-concentration-dependent manner by the selected detergents and fatty acids. Monounsaturated fatty acids, unlike unsaturated fatty acids, showed no major effects on the activities of the ostrich enzyme. The enzyme did not show sensitivity towards monovalent cations and the only divalent cations that showed a relevant effect were Ca2+ and Mg2+. Heating at 60 degrees C for 1-2 min had a substantial activating effect only on the peptidylglutamylpeptide-hydrolase (PGPH) and caseinolytic activities. In conclusion, many of the effects by the abovementioned reagents and conditions were noticeably different to those shown on different sources of the enzyme, further demonstrating the unique kinetic characteristics of the ostrich skeletal muscle 20S proteasome.

(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens.

The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Delta(9)-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB(1) receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB(1) receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 microM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a K(B) value (120.3 nM) well below its reported cannabinoid receptor CB(1)/CB(2) K(i) values. Cannabidiol (10 microM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; K(B)=34 nM) and [D-Ala(2), NMePhe(4), Gly-ol]enkephalin (DAMGO; K(B)=5.6 microM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to beta, gamma-methyleneadenosine 5'-triphosphate. At 3.16-10 microM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB(1) or CB(2) receptors.

6"-Azidohex-2"-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist.

Previous experiments with the mouse vas deferens have shown that cannabidiol produces surmountable antagonism of cannabinoid CB(1) receptor agonists at concentrations well below those at which it binds to cannabinoid CB(1) receptors and antagonizes alpha(1)-adrenoceptor agonists insurmountably. It also enhances electrically evoked contractions of this tissue. We have now found that subtle changes in the structure of cannabidiol markedly influence its ability to produce each of these effects, suggesting the presence of specific pharmacological targets for this non-psychoactive cannabinoid. Our experiments were performed with cannabidiol, 6"-azidohex-2"-yne-cannabidiol, abnormal-cannabidiol and 2'-monomethoxy- and 2',6'-dimethoxy-cannabidiol. Of these, 6"-azidohex-2"-yne-cannabidiol was as potent as cannabidiol in producing surmountable antagonism of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) in vasa deferentia. However, it produced this antagonism with a potency that matched its cannabinoid CB(1) receptor affinity, suggesting that, unlike cannabidiol, it is a competitive cannabinoid CB(1) receptor antagonist. Moreover, since it did not enhance the amplitude of electrically evoked contractions, it may be a neutral cannabinoid CB(1) receptor antagonist.

The roles of the proteasome, and cathepsins B, L, H and D, in ostrich meat tenderisation.

As very little research has been conducted on ostrich meat tenderisation, this study aims at investigating the roles of the proteasome and cathepsins B, L, H, and D in the tenderisation process. The enzyme activities in meat from eight ostriches during a 12-day ageing period and the corresponding physical characteristics (e.g. pH, shear force) and myofibril patterns were determined. After 12 days, substantial high remaining activities were found, especially of the proteasome, thus implicating their possible roles in the tenderisation process. The mean shear force values, however, showed no improvement in tenderness, but the myofibril patterns showed the appearance of a M(r) 32 K component. Myofibril degradation studies of the proteasome, analysed electrophoretically, also revealed a possible role of the proteasome, but under activating conditions. This study provides further insights into the tenderisation process, particularly of ostrich meat, which may ultimately be used for the advantageous manipulation of the process.

Aerobic exercise as a treatment for vasomotor menopausal symptoms: randomised controlled trial protocol.

BACKGROUND: Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience vasomotor symptoms (hot flushes/night sweats) that can be severe and disruptive and which are the principal reason for seeking medical intervention. Hormone therapy (HT) is known to be an effective treatment for troublesome hot flushes/night sweats but research has raised questions about the safety of HT and there have been negative high profile media reports about its use. Consequently many women are seeking alternatives and exercise might be one such option but there is a lack of high quality evidence on its effectiveness. AIMS: This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study in 165 women, and if found to be feasible/acceptable, continue to recruit sufficient women (n=261) to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women. METHOD: We aim to recruit inactive perimenopausal and menopausal symptomatic women not using HT and randomise them to one of two exercise interventions or usual care for six months. RESULTS: We will assess outcomes at baseline and 6 and 12 months from randomisation. CONCLUSION: We hope this RCT will contribute towards increasing the evidence regarding the question of whether exercise is an effective treatment for vasomotor symptoms in women not taking HT.

Maternal exercise and growth in breastfed infants: a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: Studies have revealed that women who breastfeed their infants may be reluctant to exercise due to concerns that to do so would adversely affect their breast milk and consequently the growth of their infants. In this review, we seek to systematically review and statistically synthesize evidence from randomized controlled trials (RCTs) that have assessed the effects of maternal exercise on breastfed infant growth (weight gain and gain in length). METHODS: Searches of the following electronic bibliographic databases were performed to identify RCTs: Cochrane Library (CENTRAL), Medline/PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and SPORT Discus. RCTs that compared any type of exercise intervention with other treatments or no treatment in women exclusively or predominately breastfeeding were eligible for inclusion, as were trials involving exercise as a cointervention. Two authors extracted data from studies independently. RESULTS: Four RCTs (5 comparisons) were included in the meta-analysis of infant weight gain that incorporated 170 participants. In breastfed infants, maternal exercise did not significantly affect infant weight gain (difference in mean weight gain = 18.6 g [95% confidence interval: -113.52 to 150.80, P = .73]). Only 1 trial assessed infant gain in length; no difference between the exercise and control groups was reported. Trials were classified as moderate or good methodological quality (moderate risk of bias). CONCLUSIONS: It appears that mothers can exercise and breastfeed without detriment to the growth of their infants, but this is based on limited evidence, and more research is required before this finding is confirmed.

Evidence that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol activates a non-CB(1), non-CB(2), non-TRPV1 target in the mouse vas deferens.

Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC(50)=13.3 nM). This it appeared to do by acting on prejunctional neurones as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB(1) receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 microM; apparent K(B)=222.2 nM) but not by the CB(2) receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (1 microM) or capsazepine (10 microM). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G(i/o) proteins from CB(1) receptors by alpha(2)-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB(1), CB(2), TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB(1) receptors.

Allosteric modulation of the cannabinoid CB1 receptor.

We investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)-ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB1 receptor. In equilibrium binding assays, the Org compounds significantly increased the binding of the CB1 receptor agonist [3H]CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol], indicative of a positively cooperative allosteric effect. The same compounds caused a significant, but incomplete, decrease in the specific binding of the CB1 receptor inverse agonist [3H]SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], indicative of a limited negative binding cooperativity. Analysis of the data according to an allosteric ternary complex model revealed that the estimated affinity of each Org compound was not significantly different when the radioligand was [3H]CP 55,940 or [3H]SR 141716A. However, the estimated cooperatively factor for the interaction between modulator and radioligand was greater than 1 when determined against [3H]CP 55,940 and less than 1 when determined against [3H]SR 141716A. [3H]CP 55,940 dissociation kinetic studies also validated the allosteric nature of the Org compounds, because they all significantly decreased radioligand dissociation. These data suggest that the Org compounds bind allosterically to the CB1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site. In contrast to the binding assays, however, the Org compounds behaved as insurmountable antagonists of receptor function; in the reporter gene assay, the guanosine 5'-O-(3-[35S]thio)triphosphate binding assay and the mouse vas deferens assay they elicited a significant reduction in the Emax value for CB1 receptor agonists. The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.

Purification and characterization of the 20S proteasome from ostrich skeletal muscle.

The proteasome is a high molecular weight, multisubunit and multicatalytic enzyme. Here we report the purification and characterization of ostrich skeletal muscle 20S proteasome. It was purified to homogeneity with Mr 700,000, pI 6.67 and a 'ladder' of 22.2-33.5 kDa bands on SDS-PAGE. The amino acid composition and amino-terminal sequences showed large identities to those of other species. For the three major activities, pH and temperature optima ranged between 8.0-11.0 and 40-70 degrees C, and stabilities between 5-12 and up to 40-60 degrees C. Substrate specificity and inhibitory effects were also studied. Many similarities to other sources were shown, with a few significant differences.