Background 17alpha-hydroxyprogesterone caproate (17P) administration reportedly improves outcome for women with a previous spontaneous preterm delivery. This study, using in vitro strips of human uterine smooth muscle, aimed to investigate the direct non-genomic effects of 17P on spontaneous and induced contractions in tissues obtained during pregnancy, and in the non-pregnant state.
Background
17alpha-hydroxyprogesterone caproate (17P) administration reportedly improves outcome for women with a previous spontaneous preterm delivery. This study, using in vitro strips of human uterine smooth muscle, aimed to investigate the direct non-genomic effects of 17P on spontaneous and induced contractions in tissues obtained during pregnancy, and in the non-pregnant state.Methods Biopsies of human myometrium were obtained at elective cesarean section, and from hysterectomy specimens, and dissected strips suspended for isometric recordings. The effects of 17P (1 nmol/L -10 micro mol/L) on spontaneous and agonist-induced (oxytocin 0.5 nmol/L for pregnant, phenylephrine 10 μmol/L for non-pregnant) contractions were measured. Integrals of contractile activity, including the mean maximal inhibition values (MMI) observed at the maximal concentration, were compared with those from simultaneously run control strips.
Methods
Biopsies of human myometrium were obtained at elective cesarean section, and from hysterectomy specimens, and dissected strips suspended for isometric recordings. The effects of 17P (1 nmol/L -10 micro mol/L) on spontaneous and agonist-induced (oxytocin 0.5 nmol/L for pregnant, phenylephrine 10 μmol/L for non-pregnant) contractions were measured. Integrals of contractile activity, including the mean maximal inhibition values (MMI) observed at the maximal concentration, were compared with those from simultaneously run control strips.Results There was no significant direct effect exerted by 17P on pregnant or non-pregnant human myometrial contractility. The MMI ± SEM for spontaneous contractions in pregnant myometrium was 4.9% ± 7.2 (n = 6; P = 0.309) and for oxytocin-induced contractions was 2.2% ± 1.3 (n = 6; P = 0.128). For non-pregnant myometrium, the MMI ± SEM for spontaneous contractions was 8.8% ± 11.0 (n = 6; P = 0.121) and for phenylephrine induced contractions was -7.9% ± 6.5 (n = 6; P = 0.966).
Results
There was no significant direct effect exerted by 17P on pregnant or non-pregnant human myometrial contractility. The MMI ± SEM for spontaneous contractions in pregnant myometrium was 4.9% ± 7.2 (n = 6; P = 0.309) and for oxytocin-induced contractions was 2.2% ± 1.3 (n = 6; P = 0.128). For non-pregnant myometrium, the MMI ± SEM for spontaneous contractions was 8.8% ± 11.0 (n = 6; P = 0.121) and for phenylephrine induced contractions was -7.9% ± 6.5 (n = 6; P = 0.966).Conclusions The putative benefits of 17P for preterm labor prevention are not achieved, even partially, by a direct utero-relaxant effect. These findings outline the possibility that genomic effects of 17P, achieved over long periods of administration, are required for its reported therapeutic benefits.
Conclusions
The putative benefits of 17P for preterm labor prevention are not achieved, even partially, by a direct utero-relaxant effect. These findings outline the possibility that genomic effects of 17P, achieved over long periods of administration, are required for its reported therapeutic benefits.

Background Preterm delivery constitutes a major problem in obstetric practice because of the large associated contribution to perinatal mortality and morbidity [ 1 , 2 ]. A significant proportion of all preterm deliveries are due to spontaneous preterm labor [ 2 ]. Despite much research effort, until recently, no effective method of preventing or treating preterm labor, and improving neonatal outcome, has been available. Meta-analysis of various tocolytic compounds in clinical practice has revealed that while they resulted in a delay in the interval to delivery, of time periods up to a week, they did not reduce the incidence of preterm delivery at different gestational ages [ 3 ]. More importantly, their use, in comparison to placebo, was not associated with any benefit in terms of objective measures of neonatal wellbeing or morbidity. It has however been recently reported that weekly injections of 17-alpha-hydroxyprogesterone caproate (17P), in women who have had a previous spontaneous preterm delivery, significantly reduces the risk of preterm delivery before 37, 35 and 32 week's gestation [ 4 ]. In addition, infants of women treated with 17P had significantly lower rates of necrotising enterocolitis, intraventricular haemorrhage and the need for supplemental oxygen. While evidence for the use of progestational compounds for prevention of preterm delivery, and recurrent miscarriage, has been conflicting [ 5 - 7 ], meta-analysis restricted to trials of 17P has suggested a significant reduction in the preterm delivery rate. This reported benefit of 17P, while being a welcome development in therapeutic strategies for preterm labor, has raised many questions in relation to whether the same benefit would apply to low risk groups, and the potential effects, if any, from the castor-oil injection of placebo used [ 8 , 9 ]. One of the most important questions relates to the mechanism by which the drug works and there are currently no data to answer this. Progestins have the potential to exert both genomic and non-genomic effects. The aims of this study were focused specifically on the latter mechanism i.e. to investigate the direct effects of 17P on contractions of isolated human myometrium, both spontaneous and agonist-induced, in tissue obtained during pregnancy and in the non-pregnant state.
Background
Preterm delivery constitutes a major problem in obstetric practice because of the large associated contribution to perinatal mortality and morbidity [ 1 , 2 ]. A significant proportion of all preterm deliveries are due to spontaneous preterm labor [ 2 ]. Despite much research effort, until recently, no effective method of preventing or treating preterm labor, and improving neonatal outcome, has been available. Meta-analysis of various tocolytic compounds in clinical practice has revealed that while they resulted in a delay in the interval to delivery, of time periods up to a week, they did not reduce the incidence of preterm delivery at different gestational ages [ 3 ]. More importantly, their use, in comparison to placebo, was not associated with any benefit in terms of objective measures of neonatal wellbeing or morbidity.It has however been recently reported that weekly injections of 17-alpha-hydroxyprogesterone caproate (17P), in women who have had a previous spontaneous preterm delivery, significantly reduces the risk of preterm delivery before 37, 35 and 32 week's gestation [ 4 ]. In addition, infants of women treated with 17P had significantly lower rates of necrotising enterocolitis, intraventricular haemorrhage and the need for supplemental oxygen. While evidence for the use of progestational compounds for prevention of preterm delivery, and recurrent miscarriage, has been conflicting [ 5 - 7 ], meta-analysis restricted to trials of 17P has suggested a significant reduction in the preterm delivery rate. This reported benefit of 17P, while being a welcome development in therapeutic strategies for preterm labor, has raised many questions in relation to whether the same benefit would apply to low risk groups, and the potential effects, if any, from the castor-oil injection of placebo used [ 8 , 9 ]. One of the most important questions relates to the mechanism by which the drug works and there are currently no data to answer this. Progestins have the potential to exert both genomic and non-genomic effects. The aims of this study were focused specifically on the latter mechanism i.e. to investigate the direct effects of 17P on contractions of isolated human myometrium, both spontaneous and agonist-induced, in tissue obtained during pregnancy and in the non-pregnant state.Methods Patient Recruitment and Tissue collection Patient recruitment took place in the Department of Obstetrics and Gynaecology, University College Hospital Galway. Ethical committee approval for tissue collection was obtained from the Research Ethics Committee at University College Hospital Galway and recruitment was by written informed consent. The biopsies were excised from the upper lip of the lower uterine segment incision in the midline i.e. upper portion of lower uterine segment. Women undergoing induction of labor were excluded from the study. For hysterectomy specimens, all women were pre-menopausal and undergoing abdominal hysterectomy without evidence of malignant uterine disease. Biopsies of myometrial tissue from hysterectomy specimens were obtained from the fundus. The biopsies were immediately placed in Krebs-Henseleit physiological salt solution (PSS), pH 7.4, containing: 4.7 mmol/L KCl, 118 mmol/L NaCl, 1.2 mmol/L Mg 2 SO 4 , 1.2 mmol/L CaCl 2 , 1.2 mmol/L KPO 4 , 25 mmol/L NaHCO 3 , and 11 mmol/L glucose. Tissues were stored at 4° C and used within 12 hours of collection. Tissue Bath Experiments Longitudinal myometrial strips were dissected measuring approximately 2 × 2 × 10 mm. The strips were mounted for isometric recording under 2 grams of tension in organ tissue baths, as previously described [ 10 - 12 ]. The tissue baths contained 10 ml of Krebs-Henseleit physiologic salt solution maintained at 37°C, pH 7.4 and gassed continuously with 95%O 2 /5%CO 2 . Myometrial strips were allowed to equilibrate for at least 60 minutes, during which time the Krebs-Henseleit physiologic salt solution was changed every 15 minutes. After the equilibration period, regular spontaneous myometrial contractions were allowed to develop. In separate experiments contractions were induced by the addition of oxytocin (0.5 nmol/L) to pregnant myometrial strips, and phenylephrine (10 μmol/L) to strips obtained from non-pregnant myometrium. Once regular phasic contractions had developed, the integrated tension for the first 20 minutes was calculated, and this value served as a control since no significant spontaneous reduction in myometrial contractility was observed over the duration of experiments in control strips (without addition of vehicle or 17P). The mechanical response of tissues was then measured by calculation of the integral of selected areas for 20 minute periods, corresponding to the cumulative exposure to 17P or vehicle, using the PowerLab hardware data acquisition system and Chart v3.6 software (AD Instruments, Hastings, UK). At 20 minute intervals 17P was added in a cumulative manner at concentrations of 1 nmol/L, 10 nmol/L, 100 nmol/L, 1 μmol/L, and 10 μmol/L (i.e., 1 × 10 -9  - 1 × 10 -5 M). Control strips (i.e. without exposure to 17P) were run simultaneously and for a similar duration, consisting of two separate groups of experiments as follows: 1. exposure of strips to PSS only; 2. exposure of strips to PSS and the vehicle for 17P. The overall duration of experiments was therefore 3 hours which is in accordance with standard in vitro myometrial experiments, allowing for an accurate drug exposure period of 20 minutes. The effects of 17P were assessed by subtracting the integrals of contractility measured after each bath exposure of 17P, from those obtained in control experiments (vehicle only). This allowed for calculation of the net effect of 17P on myometrial contractility. Potential effects of the vehicle were obtained by subtraction of the mean integrals measured after vehicle exposure, from those obtained without addition of vehicle i.e. spontaneous or agonist-induced contractions in PSS only. Percentage contractility was calculated by expressing the net integral measured after each 17P concentration addition, as a percentage of the integral calculated in the 20 minute period prior to any 17P addition. The mean maximal inhibition (MMI) refers to the mean percentage relaxation [i.e. 100% - mean contractility measured for each separate n sample of non-pregnant and pregnant myometrium] observed at the maximal bath concentration of 17P (i.e. 10 μmol/L), or corresponding concentration of vehicle for control strips. Drugs and Solutions Oxytocin, phenylephrine and 17P were purchased from Sigma-Aldrich, Dublin, Ireland. Because 17P is a lipid soluble compound it was necessary to dissolve it in a lipophilic vehicle. The vehicle used consisted of 75% Dimethyl sulfoxide (DMSO): 25% ethanol, to make a 1 mmol/L (10 -3 M) stock solution of 17P. The resultant final tissue bath concentrations of DMSO and ethanol, at the maximum concentration of 17P investigated (i.e. 10 μmol/L or 10 -5 M), were 0.83% and 0.28% respectively, allowing for the cumulative effect at each bath addition. DMSO and ethanol were purchased from Sigma-Aldrich, Dublin, Ireland. Fresh Krebs-Henseleit physiological salt solution was made daily. Fresh 17P solutions were prepared on the day of experimentation and were maintained at room temperature for the duration of the experiment. Statistical Analysis The integrals of contractile activity measured were compared to control values, and expressed as a percentage of that measured before drug addition. The effects of 17P on myometrial contractility were calculated for each 20-minute period of exposure from 1 nmol/L-10 μmol/L, and compared with the measurements obtained from control strips (ie. spontaneous, oxytocin-induced or phenylephrine-induced contractility, in the presence and absence of vehicle). The integrals of contractile activity were compared using a one-way ANOVA, which was followed by a Tukey HSD post-hoc. A value of P < 0.05 was accepted as statistical significance.
Methods
Patient Recruitment and Tissue collection Patient recruitment took place in the Department of Obstetrics and Gynaecology, University College Hospital Galway. Ethical committee approval for tissue collection was obtained from the Research Ethics Committee at University College Hospital Galway and recruitment was by written informed consent. The biopsies were excised from the upper lip of the lower uterine segment incision in the midline i.e. upper portion of lower uterine segment. Women undergoing induction of labor were excluded from the study. For hysterectomy specimens, all women were pre-menopausal and undergoing abdominal hysterectomy without evidence of malignant uterine disease. Biopsies of myometrial tissue from hysterectomy specimens were obtained from the fundus. The biopsies were immediately placed in Krebs-Henseleit physiological salt solution (PSS), pH 7.4, containing: 4.7 mmol/L KCl, 118 mmol/L NaCl, 1.2 mmol/L Mg 2 SO 4 , 1.2 mmol/L CaCl 2 , 1.2 mmol/L KPO 4 , 25 mmol/L NaHCO 3 , and 11 mmol/L glucose. Tissues were stored at 4° C and used within 12 hours of collection.
Patient Recruitment and Tissue collection
Patient recruitment took place in the Department of Obstetrics and Gynaecology, University College Hospital Galway. Ethical committee approval for tissue collection was obtained from the Research Ethics Committee at University College Hospital Galway and recruitment was by written informed consent. The biopsies were excised from the upper lip of the lower uterine segment incision in the midline i.e. upper portion of lower uterine segment. Women undergoing induction of labor were excluded from the study. For hysterectomy specimens, all women were pre-menopausal and undergoing abdominal hysterectomy without evidence of malignant uterine disease. Biopsies of myometrial tissue from hysterectomy specimens were obtained from the fundus. The biopsies were immediately placed in Krebs-Henseleit physiological salt solution (PSS), pH 7.4, containing: 4.7 mmol/L KCl, 118 mmol/L NaCl, 1.2 mmol/L Mg 2 SO 4 , 1.2 mmol/L CaCl 2 , 1.2 mmol/L KPO 4 , 25 mmol/L NaHCO 3 , and 11 mmol/L glucose. Tissues were stored at 4° C and used within 12 hours of collection.Tissue Bath Experiments Longitudinal myometrial strips were dissected measuring approximately 2 × 2 × 10 mm. The strips were mounted for isometric recording under 2 grams of tension in organ tissue baths, as previously described [ 10 - 12 ]. The tissue baths contained 10 ml of Krebs-Henseleit physiologic salt solution maintained at 37°C, pH 7.4 and gassed continuously with 95%O 2 /5%CO 2 . Myometrial strips were allowed to equilibrate for at least 60 minutes, during which time the Krebs-Henseleit physiologic salt solution was changed every 15 minutes. After the equilibration period, regular spontaneous myometrial contractions were allowed to develop. In separate experiments contractions were induced by the addition of oxytocin (0.5 nmol/L) to pregnant myometrial strips, and phenylephrine (10 μmol/L) to strips obtained from non-pregnant myometrium. Once regular phasic contractions had developed, the integrated tension for the first 20 minutes was calculated, and this value served as a control since no significant spontaneous reduction in myometrial contractility was observed over the duration of experiments in control strips (without addition of vehicle or 17P). The mechanical response of tissues was then measured by calculation of the integral of selected areas for 20 minute periods, corresponding to the cumulative exposure to 17P or vehicle, using the PowerLab hardware data acquisition system and Chart v3.6 software (AD Instruments, Hastings, UK). At 20 minute intervals 17P was added in a cumulative manner at concentrations of 1 nmol/L, 10 nmol/L, 100 nmol/L, 1 μmol/L, and 10 μmol/L (i.e., 1 × 10 -9  - 1 × 10 -5 M). Control strips (i.e. without exposure to 17P) were run simultaneously and for a similar duration, consisting of two separate groups of experiments as follows: 1. exposure of strips to PSS only; 2. exposure of strips to PSS and the vehicle for 17P. The overall duration of experiments was therefore 3 hours which is in accordance with standard in vitro myometrial experiments, allowing for an accurate drug exposure period of 20 minutes. The effects of 17P were assessed by subtracting the integrals of contractility measured after each bath exposure of 17P, from those obtained in control experiments (vehicle only). This allowed for calculation of the net effect of 17P on myometrial contractility. Potential effects of the vehicle were obtained by subtraction of the mean integrals measured after vehicle exposure, from those obtained without addition of vehicle i.e. spontaneous or agonist-induced contractions in PSS only. Percentage contractility was calculated by expressing the net integral measured after each 17P concentration addition, as a percentage of the integral calculated in the 20 minute period prior to any 17P addition. The mean maximal inhibition (MMI) refers to the mean percentage relaxation [i.e. 100% - mean contractility measured for each separate n sample of non-pregnant and pregnant myometrium] observed at the maximal bath concentration of 17P (i.e. 10 μmol/L), or corresponding concentration of vehicle for control strips.
Tissue Bath Experiments
Longitudinal myometrial strips were dissected measuring approximately 2 × 2 × 10 mm. The strips were mounted for isometric recording under 2 grams of tension in organ tissue baths, as previously described [ 10 - 12 ]. The tissue baths contained 10 ml of Krebs-Henseleit physiologic salt solution maintained at 37°C, pH 7.4 and gassed continuously with 95%O 2 /5%CO 2 . Myometrial strips were allowed to equilibrate for at least 60 minutes, during which time the Krebs-Henseleit physiologic salt solution was changed every 15 minutes. After the equilibration period, regular spontaneous myometrial contractions were allowed to develop. In separate experiments contractions were induced by the addition of oxytocin (0.5 nmol/L) to pregnant myometrial strips, and phenylephrine (10 μmol/L) to strips obtained from non-pregnant myometrium.Once regular phasic contractions had developed, the integrated tension for the first 20 minutes was calculated, and this value served as a control since no significant spontaneous reduction in myometrial contractility was observed over the duration of experiments in control strips (without addition of vehicle or 17P). The mechanical response of tissues was then measured by calculation of the integral of selected areas for 20 minute periods, corresponding to the cumulative exposure to 17P or vehicle, using the PowerLab hardware data acquisition system and Chart v3.6 software (AD Instruments, Hastings, UK). At 20 minute intervals 17P was added in a cumulative manner at concentrations of 1 nmol/L, 10 nmol/L, 100 nmol/L, 1 μmol/L, and 10 μmol/L (i.e., 1 × 10 -9  - 1 × 10 -5 M). Control strips (i.e. without exposure to 17P) were run simultaneously and for a similar duration, consisting of two separate groups of experiments as follows: 1. exposure of strips to PSS only; 2. exposure of strips to PSS and the vehicle for 17P. The overall duration of experiments was therefore 3 hours which is in accordance with standard in vitro myometrial experiments, allowing for an accurate drug exposure period of 20 minutes. The effects of 17P were assessed by subtracting the integrals of contractility measured after each bath exposure of 17P, from those obtained in control experiments (vehicle only). This allowed for calculation of the net effect of 17P on myometrial contractility. Potential effects of the vehicle were obtained by subtraction of the mean integrals measured after vehicle exposure, from those obtained without addition of vehicle i.e. spontaneous or agonist-induced contractions in PSS only. Percentage contractility was calculated by expressing the net integral measured after each 17P concentration addition, as a percentage of the integral calculated in the 20 minute period prior to any 17P addition. The mean maximal inhibition (MMI) refers to the mean percentage relaxation [i.e. 100% - mean contractility measured for each separate n sample of non-pregnant and pregnant myometrium] observed at the maximal bath concentration of 17P (i.e. 10 μmol/L), or corresponding concentration of vehicle for control strips.Drugs and Solutions Oxytocin, phenylephrine and 17P were purchased from Sigma-Aldrich, Dublin, Ireland. Because 17P is a lipid soluble compound it was necessary to dissolve it in a lipophilic vehicle. The vehicle used consisted of 75% Dimethyl sulfoxide (DMSO): 25% ethanol, to make a 1 mmol/L (10 -3 M) stock solution of 17P. The resultant final tissue bath concentrations of DMSO and ethanol, at the maximum concentration of 17P investigated (i.e. 10 μmol/L or 10 -5 M), were 0.83% and 0.28% respectively, allowing for the cumulative effect at each bath addition. DMSO and ethanol were purchased from Sigma-Aldrich, Dublin, Ireland. Fresh Krebs-Henseleit physiological salt solution was made daily. Fresh 17P solutions were prepared on the day of experimentation and were maintained at room temperature for the duration of the experiment.
Drugs and Solutions
Oxytocin, phenylephrine and 17P were purchased from Sigma-Aldrich, Dublin, Ireland. Because 17P is a lipid soluble compound it was necessary to dissolve it in a lipophilic vehicle. The vehicle used consisted of 75% Dimethyl sulfoxide (DMSO): 25% ethanol, to make a 1 mmol/L (10 -3 M) stock solution of 17P. The resultant final tissue bath concentrations of DMSO and ethanol, at the maximum concentration of 17P investigated (i.e. 10 μmol/L or 10 -5 M), were 0.83% and 0.28% respectively, allowing for the cumulative effect at each bath addition. DMSO and ethanol were purchased from Sigma-Aldrich, Dublin, Ireland. Fresh Krebs-Henseleit physiological salt solution was made daily. Fresh 17P solutions were prepared on the day of experimentation and were maintained at room temperature for the duration of the experiment.Statistical Analysis The integrals of contractile activity measured were compared to control values, and expressed as a percentage of that measured before drug addition. The effects of 17P on myometrial contractility were calculated for each 20-minute period of exposure from 1 nmol/L-10 μmol/L, and compared with the measurements obtained from control strips (ie. spontaneous, oxytocin-induced or phenylephrine-induced contractility, in the presence and absence of vehicle). The integrals of contractile activity were compared using a one-way ANOVA, which was followed by a Tukey HSD post-hoc. A value of P < 0.05 was accepted as statistical significance.
Statistical Analysis
The integrals of contractile activity measured were compared to control values, and expressed as a percentage of that measured before drug addition. The effects of 17P on myometrial contractility were calculated for each 20-minute period of exposure from 1 nmol/L-10 μmol/L, and compared with the measurements obtained from control strips (ie. spontaneous, oxytocin-induced or phenylephrine-induced contractility, in the presence and absence of vehicle). The integrals of contractile activity were compared using a one-way ANOVA, which was followed by a Tukey HSD post-hoc. A value of P < 0.05 was accepted as statistical significance.Results There were 6 women recruited for the study at the time of elective cesarean section. The reasons for cesarean section included previous cesarean section (n = 2), breech presentation (n = 2), unstable lie (n = 1) and postmaturity with poor cervical Bishop score (n = 1). The mean age, ± standard error of the mean (SEM), was 36.3 ± 2.8 years (range 26–46). The median gestation at the time of cesarean section was 39 weeks (range 38–41). In relation to parity, 2 of the women were para 0, 1 was para 1, and 3 were of parity greater than 1, at the time of recruitment. There were 6 women recruited at the time of abdominal hysterectomy. The reasons for hysterectomy included menorrhagia (n = 4), irregular vaginal bleeding (n = 1), and fibroids with an ovarian cyst (n = 1). The mean age ± SEM was 42.2 ± 2.4 years (range 36–50). For non-pregnant myometrial tissue representative recordings are shown in Figure  1 . In Figure  1A  a recording of spontaneous myometrial contractions is shown. In Figure  1B , the effects of vehicle for 17P on spontaneous contractions is demonstrated, and in Figure  1C  the effects of addition of 17P are shown. The results of the calculated integrals are provided in Table  1 . Bath exposure of the strips from hysterectomy specimens to 17P did not result in any alteration in contractile activity, at any of the bath concentrations studied, in comparison to vehicle only experiments (spontaneous contractions: P = 0.121; phenylephrine-induced contractions: P = 0.966). Figure 1 Effects of 17P on myometrial contractility in non-pregnant tissue. Representative recordings of spontaneous contractions in PSS only (A), the effects of cumulative additions of 17P vehicle (B), and the effects of cumulative additions of 17P (C) are shown. Table 1 Mean Maximal Inhibition Values for Vehicle and 17P. Myometrial Contractility Non-Pregnant Pregnant Net Vehicle Relaxation ± SEM Net 17P Relaxation ± SEM Net Vehicle Relaxation ± SEM Net 17P Relaxation ± SEM Spontaneous -0.6% ± 12.1 (n = 6) 8.8% ± 11.0 (n = 6) 49.7% ± 11.9 (n = 6) ♦ 4.9% ± 7.2 (n = 6) *Agonist-Induced 31.8% ± 5.0 (n = 6) -7.9% ± 6.5 (n = 6) 56.2% ± 2.3 (n = 6) ¶ 2.2% ± 1.3 (n = 6) *Phenylephrine-induced in non-pregnant myometrium and oxytocin-induced in pregnant myometrium. ♦  P = 0.022 in comparison to controls with PSS only ¶  P < 0.001 in comparison to controls with PSS only The results obtained from myometrium during pregnancy are similarly shown in Figure  2 , and in Table  1 . Figures  2A ,  2B  and  2C  demonstrate recordings of oxytocin-induced contractions, the effects of vehicle, and the effects of 17P respectively. There was no significant net relaxant or uterotonic effect exerted by 17P on pregnant myometrial contractility, at any of the bath concentrations studied experiments (spontaneous contractions P = 0.309; oxytocin-induced contractions: P = 0.128). No significant difference was observed between the effects of 17P on contractility in either pregnant or non-pregnant myometrium. Figure 2 Effects of 17P on myometrial contractility in pregnant tissue. Representative recordings of oxytocin-induced contractions in PSS only (A), the effects of cumulative additions of 17P vehicle (B), and the effects of cumulative additions of 17P (C) are shown. The vehicle for 17P independently exerted a uterorelaxant effect on spontaneous and agonist-induced contractions in pregnant myometrial tissue only (spontaneous contractions P = 0.022; oxytocin-induced contractions: P = 0.000), and this was not observed in non-pregnant myometrial tissue (spontaneous contractions P = 0.241; phenylephrine-induced contractions: P = 0.068) (Table  1 ).
Results
There were 6 women recruited for the study at the time of elective cesarean section. The reasons for cesarean section included previous cesarean section (n = 2), breech presentation (n = 2), unstable lie (n = 1) and postmaturity with poor cervical Bishop score (n = 1). The mean age, ± standard error of the mean (SEM), was 36.3 ± 2.8 years (range 26–46). The median gestation at the time of cesarean section was 39 weeks (range 38–41). In relation to parity, 2 of the women were para 0, 1 was para 1, and 3 were of parity greater than 1, at the time of recruitment. There were 6 women recruited at the time of abdominal hysterectomy. The reasons for hysterectomy included menorrhagia (n = 4), irregular vaginal bleeding (n = 1), and fibroids with an ovarian cyst (n = 1). The mean age ± SEM was 42.2 ± 2.4 years (range 36–50).For non-pregnant myometrial tissue representative recordings are shown in Figure  1 . In Figure  1A  a recording of spontaneous myometrial contractions is shown. In Figure  1B , the effects of vehicle for 17P on spontaneous contractions is demonstrated, and in Figure  1C  the effects of addition of 17P are shown. The results of the calculated integrals are provided in Table  1 . Bath exposure of the strips from hysterectomy specimens to 17P did not result in any alteration in contractile activity, at any of the bath concentrations studied, in comparison to vehicle only experiments (spontaneous contractions: P = 0.121; phenylephrine-induced contractions: P = 0.966).Mean Maximal Inhibition Values for Vehicle and 17P.*Phenylephrine-induced in non-pregnant myometrium and oxytocin-induced in pregnant myometrium.♦  P = 0.022 in comparison to controls with PSS only¶  P < 0.001 in comparison to controls with PSS onlyThe results obtained from myometrium during pregnancy are similarly shown in Figure  2 , and in Table  1 . Figures  2A ,  2B  and  2C  demonstrate recordings of oxytocin-induced contractions, the effects of vehicle, and the effects of 17P respectively. There was no significant net relaxant or uterotonic effect exerted by 17P on pregnant myometrial contractility, at any of the bath concentrations studied experiments (spontaneous contractions P = 0.309; oxytocin-induced contractions: P = 0.128). No significant difference was observed between the effects of 17P on contractility in either pregnant or non-pregnant myometrium.The vehicle for 17P independently exerted a uterorelaxant effect on spontaneous and agonist-induced contractions in pregnant myometrial tissue only (spontaneous contractions P = 0.022; oxytocin-induced contractions: P = 0.000), and this was not observed in non-pregnant myometrial tissue (spontaneous contractions P = 0.241; phenylephrine-induced contractions: P = 0.068) (Table  1 ).Discussion These results demonstrate that 17P does not appear to exert a direct relaxant effect on human myometrial contractions in vitro, in tissue obtained during the third trimester of pregnancy, or in the non-pregnant state. These findings are in contrast to the inhibitory effect of progesterone derivatives on spontaneous contractions in animal uterine tissues [ 13 , 14 ], and therefore suggest that the reported benefit of 17P in preventing preterm delivery in women who have had a previous preterm delivery, involves other mechanisms of action, presumably via its genomic effects. It seems likely that prolonged exposure of uterine smooth muscle to 17P, with resultant activation of the progesterone receptor isoforms, has the potential to modify gene transcription in order to maintain physiological uterine quiescence. However no direct effect on contractile activity was observed in our study over a period of hours of exposure. Previous studies, using various progestins, have yielded conflicting results in terms of the direct effects of these metabolites on human myometrial contractility in vitro. Progesterone metabolites, in some studies, have been reported to decrease both the frequency and amplitude of contractions [ 15 - 17 ], while other reports have outlined that progesterone stimulates the frequency and tonus of contractions in term human myometrium [ 18 , 19 ]. It has been hypothesized that progesterone addition to myometrial strips only enhances contractility if the tissue specimen was never deprived of progesterone i.e. placed immediately in a medium containing progesterone [ 19 ]. The studies to date have included various progesterone metabolites but we are unaware of any previous studies evaluating the effects of 17P on human myometrial contractions in vitro. The focus on 17P in this study has arisen from the recently reported randomized clinical trial outlining its benefits clinically for recurrent preterm labor. 17P is a naturally occurring progesterone which has been isolated from corpus luteum and adrenal gland. The synthetic caproate ester, like the naturally occurring compound, is a steroid, is highly lipophilic and is inactive when administered orally. To achieve solubility for clinical studies, the vehicle used for injection was castor-oil [ 4 ]. This led to significant controversy in relation to the potential effect of castor-oil on myometrial contractions in the placebo arm of the recently reported study [ 8 ]. For laboratory, or in vitro studies, achieving the required solubility of progestins can also be a difficult process. Efforts to achieve solubility in previous reports have included the use of Hepes buffer and ultrasound baths [ 19 , 20 ] with a resultant maximum 50% solubility. After numerous attempts at solubility for 17P in our studies, the most appropriate vehicle was a combination of DMSO and ethanol. While both of these compounds may exert an effect on uterine contractility, the maximal bath concentrations of both solvents was 0.83% and 0.28% respectively, which is acceptable for in vitro studies of this nature. In addition, control experiments, with PSS only, and PSS plus vehicle, were simultaneously run, to clearly evaluate any potential effect of vehicle. It is however apparent from our results, that addition of vehicle only did exert a significant relaxant effect on myometrium obtained during pregnancy, but no effect of vehicle was observed in myometrium obtained in the non-pregnant state. For both tissues, addition of 17P did not alter contractile activity. While the vehicle effects observed were sizeable, the experiment design, the numbers of patients recruited, and the reproducibility of the results, clearly indicate that 17P does not exert a direct effect on human myometrial contractility. In addition, while the experiments described here investigated the effects of 17P added cumulatively, separate experiments (data not shown) using a single dose (the highest dose) revealed similar results i.e. there was no evidence of tachyphylaxis over the duration of the experiments. There are some limitations to the methodology used in our study. The tissue biopsies from the non-pregnant uterus were obtained from the body of the uterus, while those obtained at the time of caesarean section were excised from the lower uterine segment. The results were similar for both tissue types, and there is reasonable evidence to suggest that the functional characteristics of lower and upper uterine segment myometrium are similar [ 21 ]. At present there are no data pertaining to differential progesterone receptor expression levels between upper and lower uterine segments. There are also obvious ethical constraints in obtaining biopsies from the upper segment of the uterus at cesarean section, and it is not feasible to dissect strips with certainty from the lower segment of the non-pregnant uterus. Secondly, the tissue samples obtained during pregnancy were all recruited from women at term. It could be that preterm myometrium displays a different responsiveness. Finally, in vivo administration of 17P could potentially result in the formation of a metabolite with a more efficient uterorelaxant effect.
Discussion
These results demonstrate that 17P does not appear to exert a direct relaxant effect on human myometrial contractions in vitro, in tissue obtained during the third trimester of pregnancy, or in the non-pregnant state. These findings are in contrast to the inhibitory effect of progesterone derivatives on spontaneous contractions in animal uterine tissues [ 13 , 14 ], and therefore suggest that the reported benefit of 17P in preventing preterm delivery in women who have had a previous preterm delivery, involves other mechanisms of action, presumably via its genomic effects. It seems likely that prolonged exposure of uterine smooth muscle to 17P, with resultant activation of the progesterone receptor isoforms, has the potential to modify gene transcription in order to maintain physiological uterine quiescence. However no direct effect on contractile activity was observed in our study over a period of hours of exposure.Previous studies, using various progestins, have yielded conflicting results in terms of the direct effects of these metabolites on human myometrial contractility in vitro. Progesterone metabolites, in some studies, have been reported to decrease both the frequency and amplitude of contractions [ 15 - 17 ], while other reports have outlined that progesterone stimulates the frequency and tonus of contractions in term human myometrium [ 18 , 19 ]. It has been hypothesized that progesterone addition to myometrial strips only enhances contractility if the tissue specimen was never deprived of progesterone i.e. placed immediately in a medium containing progesterone [ 19 ]. The studies to date have included various progesterone metabolites but we are unaware of any previous studies evaluating the effects of 17P on human myometrial contractions in vitro. The focus on 17P in this study has arisen from the recently reported randomized clinical trial outlining its benefits clinically for recurrent preterm labor.17P is a naturally occurring progesterone which has been isolated from corpus luteum and adrenal gland. The synthetic caproate ester, like the naturally occurring compound, is a steroid, is highly lipophilic and is inactive when administered orally. To achieve solubility for clinical studies, the vehicle used for injection was castor-oil [ 4 ]. This led to significant controversy in relation to the potential effect of castor-oil on myometrial contractions in the placebo arm of the recently reported study [ 8 ]. For laboratory, or in vitro studies, achieving the required solubility of progestins can also be a difficult process. Efforts to achieve solubility in previous reports have included the use of Hepes buffer and ultrasound baths [ 19 , 20 ] with a resultant maximum 50% solubility. After numerous attempts at solubility for 17P in our studies, the most appropriate vehicle was a combination of DMSO and ethanol. While both of these compounds may exert an effect on uterine contractility, the maximal bath concentrations of both solvents was 0.83% and 0.28% respectively, which is acceptable for in vitro studies of this nature. In addition, control experiments, with PSS only, and PSS plus vehicle, were simultaneously run, to clearly evaluate any potential effect of vehicle. It is however apparent from our results, that addition of vehicle only did exert a significant relaxant effect on myometrium obtained during pregnancy, but no effect of vehicle was observed in myometrium obtained in the non-pregnant state. For both tissues, addition of 17P did not alter contractile activity. While the vehicle effects observed were sizeable, the experiment design, the numbers of patients recruited, and the reproducibility of the results, clearly indicate that 17P does not exert a direct effect on human myometrial contractility. In addition, while the experiments described here investigated the effects of 17P added cumulatively, separate experiments (data not shown) using a single dose (the highest dose) revealed similar results i.e. there was no evidence of tachyphylaxis over the duration of the experiments.There are some limitations to the methodology used in our study. The tissue biopsies from the non-pregnant uterus were obtained from the body of the uterus, while those obtained at the time of caesarean section were excised from the lower uterine segment. The results were similar for both tissue types, and there is reasonable evidence to suggest that the functional characteristics of lower and upper uterine segment myometrium are similar [ 21 ]. At present there are no data pertaining to differential progesterone receptor expression levels between upper and lower uterine segments. There are also obvious ethical constraints in obtaining biopsies from the upper segment of the uterus at cesarean section, and it is not feasible to dissect strips with certainty from the lower segment of the non-pregnant uterus. Secondly, the tissue samples obtained during pregnancy were all recruited from women at term. It could be that preterm myometrium displays a different responsiveness. Finally, in vivo administration of 17P could potentially result in the formation of a metabolite with a more efficient uterorelaxant effect.Conclusions Whether 17P injections become incorporated for routine use in the management of preterm labor remains to be seen. Questions surrounding its true benefits, the associated difficulties in terms of vehicle solubility and placebo, and the mechanism of action, remain. Our findings highlight the solubility problems for scientific evaluation as occurred in clinical studies. Whatever the possible mechanism of action of 17P in reducing the incidence and adverse sequelae of preterm labor, this study demonstrates that it does not exert a direct relaxant effect, unlike other conventional methods of tocolysis investigated, and raised the likeliehood of a genomic effect secondary to long term administration during pregnancy.
Conclusions
Whether 17P injections become incorporated for routine use in the management of preterm labor remains to be seen. Questions surrounding its true benefits, the associated difficulties in terms of vehicle solubility and placebo, and the mechanism of action, remain. Our findings highlight the solubility problems for scientific evaluation as occurred in clinical studies. Whatever the possible mechanism of action of 17P in reducing the incidence and adverse sequelae of preterm labor, this study demonstrates that it does not exert a direct relaxant effect, unlike other conventional methods of tocolysis investigated, and raised the likeliehood of a genomic effect secondary to long term administration during pregnancy.Authors' contributions DJS performed the experiments and wrote the manuscript. MWO'R performed the experiments. AMF analysed the data and wrote the manuscript. JJM designed, supervised the study and wrote the manuscript. All authors read and approved the final manuscript.
Authors' contributions
DJS performed the experiments and wrote the manuscript. MWO'R performed the experiments. AMF analysed the data and wrote the manuscript. JJM designed, supervised the study and wrote the manuscript. All authors read and approved the final manuscript.


Background In 2002 the Australian National Competitive Grants System was opened to the Institute of Advanced Studies at the Australian National University as part of a commitment to transparency, competitiveness, and collaboration in national research funding.
Background
In 2002 the Australian National Competitive Grants System was opened to the Institute of Advanced Studies at the Australian National University as part of a commitment to transparency, competitiveness, and collaboration in national research funding.Results The block grant to the John Curtin School of Medical Research had progressively eroded over many years. Access to the National Competitive Grants Schemes and associated infrastructure (through an agreed 'buy-in' price of 20% of block funding) has succeeded in its aims and in reversing this progressive effective decrease in funding.
Results
The block grant to the John Curtin School of Medical Research had progressively eroded over many years. Access to the National Competitive Grants Schemes and associated infrastructure (through an agreed 'buy-in' price of 20% of block funding) has succeeded in its aims and in reversing this progressive effective decrease in funding.Conclusion Access to the National Competitive Grant Scheme has allowed the John Curtin School of Medical Research to contribute more broadly to Australia's health and medical research effort through increased collaboration, in a transparent and competitive funding environment.
Conclusion
Access to the National Competitive Grant Scheme has allowed the John Curtin School of Medical Research to contribute more broadly to Australia's health and medical research effort through increased collaboration, in a transparent and competitive funding environment.

Discussion Australia has developed a unique blend of medical research institutions, from universities, teaching hospitals, independent medical research institutes to a range of smaller centres. Universities with medical schools have been the primary forces in medical research and many of the university teaching hospitals fostered the development of research institutes within their grounds [ 1 ]. The spectacular development of medical research in Australia over the last 50 years was reviewed recently in recognition of Australia's Centenary of Federation celebrations [ 2 ]. The Australian National University (ANU) was established as a research university [ 1 ] with four founding schools. The John Curtin School of Medical Research (JCSMR) was funded for its first 50 years through a one-line Commonwealth Grant to the ANU. Although the School had always sought external funds (its first grant was £1500 to Frank Fenner from the Rural Credits Development Fund in 1952), it was ineligible for National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) and other national competitive grants. The School unquestionably benefited from generous (by local standards) funding in its early years and its science profited accordingly. Fundamental discoveries have included Nobel Prize winning work on the elucidation of mechanisms of transmission of signals in the nervous system (Eccles) and the discovery of the role of the major histocompatibility complex (Doherty and Zinkernagel). Today, the School has a wide range of research in such areas as infection, neurosciences, genomics and molecular bioscience, and has spawned a major national research facility, the Australian Phenomics Facility. Some key discoveries in recent years are summarised in Table  1 . Table 1 Recent Research Achievements, John Curtin School of Medical Research Year Achievement Researchers(s) Comment Reference 1999 Heparanase cloned Hulett, Freeman and colleagues Inhibiting the enzyme is the basis of cancer treatments based on sulfated polysaccharides Nature Medicine 5:803-809, 1999 2001 First diabetes susceptibility gene identified Slattery and colleagues Serendipitous discovery providing a potential therapeutic target in type 1 diabetes Proc Nat Acad Sci, USA 98:11533-11538, 2001 2002 Amiloride derivatives block ion channel activity and enhancement of virus-like particle budding caused by an HIV-1 protein Gage and colleagues Research on compounds that block viral ion channels raises the possibility of inhibiting viruses that utilize ion channels Eur. Biophys. J. 31:26-35, 2002 2002 Antibody 'tail sequence' identified that has significant implications for immunological memory Martin and Goodnow Finding has wide implications for vaccination, allergy and autoimmunity Nature Immunology 3:182-188, 2002 2002 Phase II clinical trials of PI 88 anti-cancer drug Parish and colleagues Promising results in treating advanced melanoma Eur. J Cancer 38(S7):74, 2002 2003 New approach to vaccination against cancer Parish Approach is potentially less susceptible to immune evasion Immunology and Cell Biology 81, 106-113, 2003. It can be argued that JCSMR's position as one of the original block-funded research schools of the Institute of Advances Studies (IAS) has given it the opportunity to pursue long-term, independent medical research. Many staff and alumni of JCSMR, including its present Director, argue that the Nobel Prizes, the Albert Einstein World Award, the Japan Prize, the Copley Medal, and a host of other international awards attest to the success of this funding strategy over the past 50 years, and that the scientific achievements that those prizes signify could only have been made by research that could be conducted over long (10 to 20 year) time frames. But the funding climate has changed dramatically over the last few decades. Twenty five years ago many tenured Australian university or teaching hospital staff were able to undertake research even without external funding. Infrastructure was relatively generous, there was still funding for university technical research staff, hospitals provided drugs and consumables and even beds at no cost to the researcher, and research activities merged relatively seamlessly into those of teaching and patient care. Today research is increasingly separated from teaching and care, and the days of in-kind support are long gone. Research is an investment for the nation and the future, but in contemporary funding climates within universities and hospitals it is increasingly becoming an optional extra, undertaken only when researchers are able to attract sufficient external resources. The change in environment and the disappearance of cross subsidisation from patient care and/or teaching has both advantages and disadvantages. Today's research (and research funding) is more transparent: what is spent on research as opposed to care and teaching, at least at the micro level, is much better defined. And, in parallel, the loss of capacity to undertake research that is not peer reviewed has almost certainly raised research standards. The negatives are equally obvious. The University of Melbourne submission to the Wills review stated 'The danger is that if the importance of the nexus between research and learning is not visible to tertiary students because University research is allowed to run down through poor infrastructure, equipment or lack of opportunity of research scientists then research institutes and teaching hospitals will inevitably suffer from a lack of quality of graduates available to them'[ 3 ]. The JCSMR has not been exempted from these pressures, and over the last 20 years the value of the block grant has been progressively eroded. The JCSMR grant was a one-line grant to the Director, which provided flexibility, but inhibited collaboration because of restrictive rules around the National Competitive Grants Scheme. Accordingly, a desire for transparency, competitiveness and collaboration led to a decision in 2000 by the Commonwealth Government that the IAS of the ANU could enter the National Competitive Grants Scheme. The negotiations that led to partial entry of JCSMR into the NHMRC schemes in 2001 (for 2002) were long and complex. However the negotiations between JCSMR and NHMRC were paralleled by those between the ARC and ANU and led to a jointly agreed 'buy in' price of 20% of 2000 funding for the IAS to gain access to the various national funding, research training and related schemes. This was $1.7 million per annum for JCSMR access to the National Competitive Grant Schemes and a similar amount for access to the training and infrastructure schemes. It was determined initially that entry would be phased, but after one year the ARC determined that the phase-in was unnecessary and gave the IAS full entry from 2002 (for 2003), and the NHMRC followed suit. The JCSMR felt that, at last, it was able to redress the competitive disadvantage the School faced because of its essentially fixed funding over the last 10 to 15 years, at a time when government funding for the NHMRC system had doubled and then redoubled, from around $65 million in the late eighties to $176 million in 1999 to $381 million in 2004. The rest of the system waited, not without apprehension, for the outcome, but there had long been a wish within the research community that JCSMR be subject to the same forms of peer review as the broader medical research community. Removing barriers to collaboration, the outcome of these changes, is important for 21 st  century approaches to improving health. The World Health Organisation has stated that the likely trends in global health in the 21 st  century include widespread absolute and relative poverty, demographic changes, ageing, growth of cities, epidemiological changes, continuing high influence of infectious diseases, increasing incidence of non-communicable diseases, injuries and violence, global environmental threats to human survival, new technologies, information and telemedicine services, advances in biotechnology, evolving partnerships for health that include private and public sectors and civil society, and globalisation of trade, travel and the spread of values and ideas. Research to deal with global health problems will therefore necessarily be multidisciplinary, involving biomedical, clinical, public health and health services research, and include the social sciences, information sciences and engineering, physics, chemistry, ecology and environmental sciences and economics. As part of the IAS, the JCSMR is accordingly strongly positioned. Not that this need for a multidisciplinary approach is really a new concept – in 1902 Osler stated that the remit of medical research was 'to wrest from nature the secrets which have perplexed philosophers in all ages, to trace to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and the cure of disease – these are our ambitions' [ 4 ]. In the first three years that JCSMR has been eligible to apply for research funding, their researchers have been awarded a total of $18 million (88% NHMRC, 12% ARC) in competitive funding for periods of up to five years. All three NHMRC program grants held by researchers at the JCSMR are collaborative with other Australian institutions and School researchers hold four ARC linkage grants. This collaboration bodes well for Australian health and for biotechnology growth. In a highly competitive world, Australian researchers need every opportunity to succeed.
Discussion
Australia has developed a unique blend of medical research institutions, from universities, teaching hospitals, independent medical research institutes to a range of smaller centres. Universities with medical schools have been the primary forces in medical research and many of the university teaching hospitals fostered the development of research institutes within their grounds [ 1 ]. The spectacular development of medical research in Australia over the last 50 years was reviewed recently in recognition of Australia's Centenary of Federation celebrations [ 2 ].The Australian National University (ANU) was established as a research university [ 1 ] with four founding schools. The John Curtin School of Medical Research (JCSMR) was funded for its first 50 years through a one-line Commonwealth Grant to the ANU. Although the School had always sought external funds (its first grant was £1500 to Frank Fenner from the Rural Credits Development Fund in 1952), it was ineligible for National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) and other national competitive grants. The School unquestionably benefited from generous (by local standards) funding in its early years and its science profited accordingly. Fundamental discoveries have included Nobel Prize winning work on the elucidation of mechanisms of transmission of signals in the nervous system (Eccles) and the discovery of the role of the major histocompatibility complex (Doherty and Zinkernagel). Today, the School has a wide range of research in such areas as infection, neurosciences, genomics and molecular bioscience, and has spawned a major national research facility, the Australian Phenomics Facility. Some key discoveries in recent years are summarised in Table  1 .Recent Research Achievements, John Curtin School of Medical ResearchYearAchievementResearchers(s)CommentReferenceIt can be argued that JCSMR's position as one of the original block-funded research schools of the Institute of Advances Studies (IAS) has given it the opportunity to pursue long-term, independent medical research. Many staff and alumni of JCSMR, including its present Director, argue that the Nobel Prizes, the Albert Einstein World Award, the Japan Prize, the Copley Medal, and a host of other international awards attest to the success of this funding strategy over the past 50 years, and that the scientific achievements that those prizes signify could only have been made by research that could be conducted over long (10 to 20 year) time frames.But the funding climate has changed dramatically over the last few decades. Twenty five years ago many tenured Australian university or teaching hospital staff were able to undertake research even without external funding. Infrastructure was relatively generous, there was still funding for university technical research staff, hospitals provided drugs and consumables and even beds at no cost to the researcher, and research activities merged relatively seamlessly into those of teaching and patient care. Today research is increasingly separated from teaching and care, and the days of in-kind support are long gone. Research is an investment for the nation and the future, but in contemporary funding climates within universities and hospitals it is increasingly becoming an optional extra, undertaken only when researchers are able to attract sufficient external resources.The change in environment and the disappearance of cross subsidisation from patient care and/or teaching has both advantages and disadvantages. Today's research (and research funding) is more transparent: what is spent on research as opposed to care and teaching, at least at the micro level, is much better defined. And, in parallel, the loss of capacity to undertake research that is not peer reviewed has almost certainly raised research standards. The negatives are equally obvious. The University of Melbourne submission to the Wills review stated 'The danger is that if the importance of the nexus between research and learning is not visible to tertiary students because University research is allowed to run down through poor infrastructure, equipment or lack of opportunity of research scientists then research institutes and teaching hospitals will inevitably suffer from a lack of quality of graduates available to them'[ 3 ].The JCSMR has not been exempted from these pressures, and over the last 20 years the value of the block grant has been progressively eroded. The JCSMR grant was a one-line grant to the Director, which provided flexibility, but inhibited collaboration because of restrictive rules around the National Competitive Grants Scheme. Accordingly, a desire for transparency, competitiveness and collaboration led to a decision in 2000 by the Commonwealth Government that the IAS of the ANU could enter the National Competitive Grants Scheme. The negotiations that led to partial entry of JCSMR into the NHMRC schemes in 2001 (for 2002) were long and complex. However the negotiations between JCSMR and NHMRC were paralleled by those between the ARC and ANU and led to a jointly agreed 'buy in' price of 20% of 2000 funding for the IAS to gain access to the various national funding, research training and related schemes. This was $1.7 million per annum for JCSMR access to the National Competitive Grant Schemes and a similar amount for access to the training and infrastructure schemes. It was determined initially that entry would be phased, but after one year the ARC determined that the phase-in was unnecessary and gave the IAS full entry from 2002 (for 2003), and the NHMRC followed suit.The JCSMR felt that, at last, it was able to redress the competitive disadvantage the School faced because of its essentially fixed funding over the last 10 to 15 years, at a time when government funding for the NHMRC system had doubled and then redoubled, from around $65 million in the late eighties to $176 million in 1999 to $381 million in 2004. The rest of the system waited, not without apprehension, for the outcome, but there had long been a wish within the research community that JCSMR be subject to the same forms of peer review as the broader medical research community.Removing barriers to collaboration, the outcome of these changes, is important for 21 st  century approaches to improving health. The World Health Organisation has stated that the likely trends in global health in the 21 st  century include widespread absolute and relative poverty, demographic changes, ageing, growth of cities, epidemiological changes, continuing high influence of infectious diseases, increasing incidence of non-communicable diseases, injuries and violence, global environmental threats to human survival, new technologies, information and telemedicine services, advances in biotechnology, evolving partnerships for health that include private and public sectors and civil society, and globalisation of trade, travel and the spread of values and ideas. Research to deal with global health problems will therefore necessarily be multidisciplinary, involving biomedical, clinical, public health and health services research, and include the social sciences, information sciences and engineering, physics, chemistry, ecology and environmental sciences and economics. As part of the IAS, the JCSMR is accordingly strongly positioned. Not that this need for a multidisciplinary approach is really a new concept – in 1902 Osler stated that the remit of medical research was 'to wrest from nature the secrets which have perplexed philosophers in all ages, to trace to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and the cure of disease – these are our ambitions' [ 4 ].In the first three years that JCSMR has been eligible to apply for research funding, their researchers have been awarded a total of $18 million (88% NHMRC, 12% ARC) in competitive funding for periods of up to five years. All three NHMRC program grants held by researchers at the JCSMR are collaborative with other Australian institutions and School researchers hold four ARC linkage grants. This collaboration bodes well for Australian health and for biotechnology growth. In a highly competitive world, Australian researchers need every opportunity to succeed.


Obesity, in particular visceral adiposity, is positively correlated with insulin resistance and type 2 diabetes. Although the link is well established in humans and in rodent models, the mechanisms involved in obesity-related insulin resistance are not clear. One possibility is that hormones secreted by adipocytes compromise peripheral insulin sensitivity, and a number of candidates for such adipocyte signals have been identified. One of them, resistin, was discovered a few years ago by Mitchell Lazar and colleagues, who showed that the protein is expressed by mouse adipocytes and regulated by a group of anti-diabetic drugs called thiazolidinediones. Several lines of evidence from functional studies in rodents suggested that resistin could be the missing mechanistic link between obesity and diabetes.The human homolog of resistin has subsequently been under intense investigation, but initial studies revealed more differences than similarities between the human and rodent proteins: human resistin is mostly expressed in macrophages, not in adipocytes, and its serum levels do not correlate as clearly with obesity, insulin resistance, or diabetes. Similarly, genetic association studies between allelic variants of the resistin gene and metabolic abnormalities have so far been inconclusive. These results prompted some of the scientists in the field who had jumped on the resistin bandwagon after the initial results in rodents to jump off again. Others, including the resistin discoverers, continue their quest to uncover resistin's role in humans, and have started to think outside the framework defined by the mouse data.Starting with the role of macrophages in inflammation and encouraged by the fact that obesity and insulin resistance are associated with markers of systemic inflammation, Lazar and colleagues examined the resistin response to inflammatory stimulators. As they report in this issue, resistin production in macrophages and serum levels in patients are significantly increased by these stimulators. This response can be blocked by the thiazolidinedione rosiglitazone and by aspirin, two drugs that have dual anti-inflammatory and insulin-sensitizing actions and antagonize the immune regulator NF-kappaB. The researchers go on to show that activation of NF-kappaB is sufficient to induce resistin expression. And NF-kappaB is necessary for the resistin response to inflammatory stimuli.Lazar and colleagues now view obesity as a state of chronic inflammation and speculate that in obese individuals inflammatory cytokines lead to elevated production of resistin by macrophages and elevated serum resistin levels, which in turn contribute to insulin resistance and diabetes. This is consistent with some studies that have found higher resistin levels in obese individuals and patients with insulin resistance and/or diabetes, but not all studies have found such differences.Jeffrey Flier, an obesity researcher who was not involved in the study, calls the article “an excellent and timely paper that demonstrates the fact that inflammatory pathways induce resistin expression and levels in human monocytes ex vivo, and in intact humans. The work appears to provide a novel link between inflammation and insulin resistance, through monocyte derived resistin.” He points out, however, that “several other factors also appear to contribute directly to insulin resistance in inflammation (e.g., cytokines themselves, without invoking resistin) so the full biologic implications of the high resistin levels for insulin resistance in humans cannot be determined from this study.” Resistin, it seems, continues to resist easy interpretations.