Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact it was not criminalized until April of 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self-administer 4-MMC in one hour sessions. Per infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2–3 mg/kg/hr. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were employed to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found the T1/2 of 4-MMC was about an hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4-MMC in the traditional preclinical self-administration model.
cathinone; reinforcement; stimulant; thermoregulation
The substituted cathinone compound known as mephedrone (4-methylmethcathinone; 4-MMC) has become popular with recreational users of psychomotor-stimulant compounds. Only recently have the first preclinical studies provided information about this drug in the scientific literature; nevertheless, media reports have led to drug control actions in the UK and across several US states. Rodent studies indicate that 4-MMC exhibits neuropharmacological similarity to 3,4-methylenedioxymethamphetamine (MDMA) and prompt investigation of the thermoregulatory, cardiac and locomotor effects of 4-MMC. This study focuses on the role of ambient temperature, which has been shown to shift the effects of MDMA from hyperthermic to hypothermic.
Male Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1.0–5.6 mg/kg) using an implantable radiotelemetry system under conditions of low (20°C) and high (30°C) ambient temperature. A pharmacokinetic study found a Tmax of 0.25 h and a Cmax of 1,206 ng/mL after 5.6 mg/kg 4-MMC. A dose-dependent reduction of body temperature was produced by 4-MMC at 20°C but there was no temperature change at 30°C.
Increased locomotor activity was observed after 4-MMC administration under both ambient temperatures, however, significantly more activity was observed at 30°C. Heart rate was slowed by 1.0 and 5.6 mg/kg 4-MMC at 20°C, and was slower in the 30°C vs. 20°C condition across all treatments.
These results show that the cathinone analog 4-MMC exhibits in vivo thermoregulatory properties that are distinct from those produced by MDMA.
stimulant; cathinone; thermoregulation; locomotor activity; heart rate; rat
Successful drug delivery via lipid-based systems has often been aided by the incorporation of ‘helper lipids’. While these neutral lipids enhance the effectiveness of cationic lipid-based delivery formulations, many questions remain about the nature of their beneficial effects. The structure of monolayers of the cationic lipid dimethyldioctadecylammonium bromide (DODAB) alone, and mixed with a neutral helper lipid, either diolelyphosphatidylethanolamine or cholesterol at a 1 : 1 molar ratio was investigated at the air–water interface using a combination of surface pressure–area isotherms, Brewster angle microscopy (BAM) and specular neutron reflectivity in combination with contrast variation. BAM studies showed that while pure DODAB and DODAB with cholesterol monolayers showed fairly homogeneous surfaces, except in the regions of phase transition, monolayers of DODAB with diolelyphosphatidylethanolamine were, in contrast, inhomogeneous exhibiting irregular bean-shaped domains throughout. Neutron reflectivity data showed that while the thickness of the DODAB monolayer increased from 17 to 24 Å as it was compressed from a surface pressure of 5–40 mN m−1, the thickness of the helper lipid-containing monolayers, over the same range of surface pressures, was relatively invariant at between 25 and 27 Å. In addition, the monolayers containing diolelyphosphatidylethanolamine were found to be more heavily hydrated than the monolayers of cationic lipid, alone or in combination with cholesterol, with hydration levels of 18 molecules of water per molecule of lipid being recorded for the diolelyphosphatidylethanolamine-containing monolayers at a surface pressure of 30 mN m−1 compared with only six and eight molecules of water per molecule of lipid for the pure DODAB monolayer and the cholesterol-containing DODAB monolayer, respectively.
cationic lipid; neutral helper lipid; dioleylphosphatidylcholine; cholesterol; Brewster angle microscopy; specular neutron reflectivity
Plaster of Paris (PoP) impregnated bandages have been used to maintain the position of bones and joints for over a century. Classically, wool dressing is applied to the limb before the PoP, which can then be moulded to the desired shape. A modification of this practice is to wrap the PoP bandages circumferentially in cotton before wetting and applying to the patient in an attempt to reduce inhalation of plaster dust and reduce mess. However, this may affect the water content of the cast and therefore also its setting properties and strength. This study compared the setting properties of PoP casts when used with and without cotton wrapping.
Sixty specimens, compliant with the American Society for Testing and Materials standards for three-point bending tests, were prepared, with thirty wrapped in cotton. All were weighed before and after water immersion, and wrapped around a plastic cylinder to mimic limb application. Bending stiffness and yield strength was measured on a servohydraulic materials testing machine at 2, 6, 12, 24, 48 and 72 hours.
The water content of cotton-wrapped plaster was significantly higher (50%) than that of standard plaster. It had significantly lower strength up to 24 hours and significantly lower stiffness up to 72 hours.
The initial decrease in strength and stiffness of the cast wrapped in cotton may comprise the ability of the backslab to hold the joint or bone in an optimal position. Any modification of the standard plaster slab application technique should allow for the potential adverse effects on the plaster setting properties.
Plaster of Paris; Strength; Modification of application
To determine if current validated psychometric evaluations could determine a difference in basic behavioural characteristics between surgical and medical specialties.
Two district general hospitals and one University teaching hospital in England, UK.
Internal medicine (16) and trauma and orthopaedic (20) consultants.
Main outcome measures
Aggression levels as assessed by the Buss and Warren questionnaire. The self-administered questionnaire assesses aggression in terms of physical, verbal, anger, hostility, indirect hostility and an overall assessment of aggression.
All participants had aggression scores below the population average. We found a significant difference (P < 0.01) in total level of aggression, with orthopaedic consultants scoring a mean of 61.1 (standard deviation [SD] 9.2) and physicians 51.3 (SD 9.5). When analysis of the five different subtypes of aggression was carried out, orthopaedic surgeons scored significantly higher in terms of verbal aggression (P = 0.005), hostility (P = 0.002) and indirect hostility (P = 0.03).
This study joins a growing evidence base for aspects of behaviour indicative of a given specialty. Aggression is a relatively stable behavioural characteristic from adolescence, and as such this is the first study of its type to suggest that the differences in behavioural characteristics seen between specialties are inherent, rather than learned. It is unclear if the differences observed represent an attraction of that specialty to the personality type or is required for success within the given specialty. Whether this can be used in terms of selection into higher specialty training, or influence training within specialties, requires further work.
Rapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells.
Experiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB.
Rapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment.
This report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2475-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Apoptosis; Beta cell; Diabetes mellitus; GSIS; Islet; Islet transplantation; mTOR; mTORC2; PKB; Rapamycin; RICTOR
Objectives:To examine differences in population based rates of gonorrhoea and chlamydia between black ethnic groups in Lambeth, Southwark and Lewisham Health Authority.
Methods: Episodes of gonorrhoea or chlamydia recorded among attenders at 11 genitourinary clinics in south and central London from 1 January 1994 to 31 December 1995 were retrieved. Complete data on chlamydia were only available for women. Ethnic group was assigned according to census categories—white, black Caribbean, black African, black other, Asian, or other. We calculated yearly incidence rates for episodes of gonorrhoea and chlamydia in residents of Lambeth, Southwark and Lewisham Health Authority. Random effects Poisson regression models were used to examine associations between infection rates and age, ethnic group, and material deprivation.
Results: During the study period there were 1996 episodes of gonorrhoea in men and women and 1376 episodes of chlamydia in women with complete data. For both infections rates among individuals from black Caribbean and black other ethnic groups were markedly higher than among black Africans. In men, the gonorrhoea rate among black Caribbean 20–24 year olds was 2348 (95% CI 1965 to 2831) episodes per 100 000 compared with 931 (95% CI 690 to 1288) in black African men and 111 (95% CI 100 to 124) per 100 000 in white men of the same age. Among women gonorrhoea rates were highest in black Caribbean 15–19 year olds (2612, 95% CI 2161 to 3190 per 100 000). In contrast, rates in black African women of the same age (331, 95% CI 154 to 846 per 100 000) were similar to those of white women (222, 95% CI 163 to 312). Chlamydia rates were also highest in black Caribbean 15–19 year old women (4579, 95% CI 3966 to 5314 per 100 000), compared with 1286 (95% CI 907 to 1888) in black African and 433 (95% CI 349 to 544) per 100 000 white women. Controlling for material deprivation and age only attenuated differences in rates between ethnic groups slightly.
Conclusions: There are marked differences in rates of gonorrhoea and chlamydia between different black ethnic groups, with higher rates in black Caribbeans than black Africans. This study supports the hypothesis that assortative sexual mixing patterns can restrict epidemics of sexually transmitted infections within ethnic groups. Differences in disease occurrence between black ethnic groups should be explored before combining data, even when numbers of episodes are small.
Key Words: gonorrhoea; chlamydia infections; ethnic groups
BACKGROUND: Chronic pelvic pain has often been described as a major women's health issue, but no information exists on the extent of the problem in the United Kingdom. AIM: To investigate the community prevalence of chronic pelvic pain and its effect on the lives of consulting and non-consulting women. DESIGN OF STUDY: Postal questionnaire survey. SETTING: Women aged 18 to 49 (n = 3916) randomly selected from the Oxfordshire Health Authority Register. METHOD: The questionnaire response rate (adjusted for non-deliveries) was 74% (2304/3106). Chronic pelvic pain was defined as recurrent or constant pelvic pain of at least six months' duration, unrelated to periods, intercourse, or pregnancy. Case subgroups comprised recent consulters, past consulters, and non-consulters. Women who reported dysmenorrhoea alone formed a comparison group. RESULTS: The three-month prevalence of chronic pelvic pain was 24.0% (95% CI = 22.1% to 25.8%). One-third of women reported pain that started more than five years ago. Recent consulters (32% of cases) were most affected by their symptoms in terms of pain severity, use of health care, physical and mental health scores, sleep quality, and pain-related absence from work. Non-consulters (41% of cases) did not differ from women with dysmenorrhoea in terms of symptom-related impairment. Irrespective of consulting behaviour, a high rate of symptom-related anxiety was found in women with chronic pelvic pain (31%) compared with women with dysmenorrhoea (7%). CONCLUSIONS: This study showed a high community prevalence of chronic pelvic pain in women of reproductive age. Cases varied substantially in the degree to which they were affected by their symptoms. The high symptom-related anxiety in these women emphasises the need for more information about chronic pelvic pain and its possible causes.
Purpose: The use of highly purified follicle-stimulating hormone (Metrodin-HP) was compared with that of a preparation containing follicle-stimulating hormone and luteinizing hormone (Pergonal) for production of superovulation in an IVF program.
Methods: We used the Oxford Fertility Unit database to identify patients undergoing their first cycle of IVF, using either Metrodin-HP or Pergonal. Patients were treated with a standardized drug protocol and were stratified by age and cause of infertility. Ovarian stimulation with either Metrodin-HP (Serono Laboratories) or human menopausal gonadotropin (hMG; Pergonal; Serono Laboratories) after pituitary desensitization commenced in the midluteal phase of the preceding cycle. Monitoring was performed by ultrasound and serum estradiol measurement prior to transvaginal oocyte recovery, followed by IVF and transfer of no more than three embryos.
Results: For Metrodin-HP versus Pergonal, the rates of egg retrieval (98 vs 94%), fertilization (89 vs 92%), clinical pregnancy (32.9 vs 23.4%), miscarriage (4.1 vs 4.5%), live birth (26 vs 18.5%), and ovarian hyperstimulation syndrome (5.5% vs 5.9%) were similar in both groups. The apparent increase in clinical pregnancy and live birth with Metrodin-HP did not reach statistical significance. The dosages of gonadotropins used were comparable. Estradiol levels measured on day 8 of stimulation were significantly lower in the Metrodin-HP group than in the Pergonal group, but the difference did not reach statistical significance on the day of hCG administration. Significantly more follicles (greater than 12 mm) were obtained in the Metrodin-HP group, but the numbers of eggs recovered and fertilized were similar in the two groups.
Conclusions: These findings demonstrate that highly purified FSH (Metrodin-HP) is as effective and successful as hMG (Pergonal) for ovarian stimulation in a standard IVF regimen. Exogenous luteinizing hormone (LH) is not required for satisfactory ovarian stimulation in IVF. Measurement of estradiol may be less helpful in the monitoring of Metrodin-HP cycles, but the level reached on the day of hCG administration can still be used to predict, and hence avoid, ovarian hyperstimulation syndrome.
gonadotropins; hyperstimulation; Metrodin-HP; ovarian stimulation; Pergonal
OBJECTIVES: To estimate population based incidence rates of gonorrhoea in an inner London area and examine relations with age, ethnic group, and socioeconomic deprivation. DESIGN: Cross sectional study. SETTING: 11 departments of genitourinary medicine in south and central London. SUBJECTS: 1978 first episodes of gonorrhoea diagnosed in 1994 and 1995 in residents of 73 electoral wards in the boroughs of Lambeth, Southwark, and Lewisham who attended any of the departments of genitourinary medicine. MAIN OUTCOME MEASURES: Yearly age, sex, and ethnic group specific rates of gonorrhoea per 100,000 population aged 15-59 years; rate ratios for the effects of age and ethnic group on gonorrhoea rates in women and men before and after adjustment for confounding factors. RESULTS: Overall incidence rates of gonorrhoea in residents of Lambeth, Southwark, and Lewisham were 138.3 cases yearly per 100,000 women and 291.9 cases yearly per 100,000 men aged 15-59 years. At all ages gonorrhoea rates were higher in non-white minority ethnic groups. Rate ratios for the effect of age adjusted for ethnic group and underprivilege were 15.2 (95% confidence interval 11.6 to 19.7) for women and 2.0 (1.7 to 2.5) for men aged 15-19 years compared with those over 30. After deprivation score and age were taken into account, women from black minority groups were 10.5 (8.6 to 12.8) times as likely and men 11.0 (9.7 to 12.6) times as likely as white people to experience gonorrhoea. CONCLUSIONS: Gonorrhoea rates in Lambeth, Southwark, and Lewisham in 1994-5 were six to seven times higher than for England and Wales one year earlier. The presentation of national trends thus hides the disproportionate contribution of ongoing endemic transmission in the study area. Teenage women and young adult men, particularly those from black minority ethnic groups, are the most heavily affected, even when socioeconomic underprivilege is taken into account. There is urgent need for resources for culturally appropriate research and effective intervention to prevent gonococcal infections and their long term sequelae in this population.
AIM: To review the features of gonococcal infection in men in the 1990s. METHODS: A retrospective study of all men with gonorrhoea presenting to an inner city department of genitourinary medicine in the years 1990 to 1992. RESULTS: 1749 cases of gonorrhoea were seen in 1382 men. A high incidence of gonorrhoea was found in attenders of African or Caribbean extraction. In 228 men with a known date of infection, the incubation period, a mean of 8.3 days, was longer than previously described. The mean infectious period was 12.0 days. By 14 days 86.2% of men had developed symptoms. Of 1615 men with urethral infection 81.9% complained of discharge, while dysuria occurred in 52.8%. Discharge with dysuria were present in only 48.1% of patients. In 10.2% episodes of urethral infection the patients had no symptoms referable to their gonorrhoea. Urethral gonorrhoea was diagnosed by microscopy in 94.4% of symptomatic men and in only 81.1% of asymptomatic men. Microscopy of rectal samples were positive in 46.4% of cases. In this population, a dose of 2 g of ampicillin with 1 g of probenecid gave a high cure rate of gonorrhoea as long as infection was not due to penicillinase-producing organisms. CONCLUSIONS: These data suggest that the incubation and infectious period of urethral gonorrhoea has increased compared with previous studies and that symptoms have altered. Only 48.1% of men described the classical symptoms of discharge with dysuria. Microscopy of urethral smears remains useful in symptomatic men but is less sensitive in those without symptoms.
OBJECTIVE--To examine the impact of menopausal symptoms on the overall quality of life of women. DESIGN--Data collection with a questionnaire administered by an interviewer, incorporating two different quality of life measurement techniques (time trade off and rating scale). SETTING--Specialist menopause clinic and two general practices in Oxford. SUBJECTS--63 women aged 45-60 years recruited opportunistically during a clinic or appointment with a general practitioner; no exclusion criteria. RESULTS--Subjects gave very low quality of life ratings for health states with menopausal symptoms. The time trade off method of measuring preferences for these health states (on a scale from 0 to 1, where preference for full health is given as 1) yielded utility values of 0.64 for severe menopausal symptoms and 0.85 for mild symptoms. The rating scale measurement technique yielded even lower values: utilities of 0.30 and 0.65 were obtained for severe and mild symptoms respectively. Kappa scores indicated that the two methods produced results that were poorly related but not contradictory. Comparison of quality of life ratings before and after treatment with hormone replacement therapy showed significant improvements: with the rating scale measurement technique mean increases in utility values after the relief of severe and mild menopausal symptoms were 0.56 and 0.18 respectively. CONCLUSIONS--Quality of life may be severely compromised in women with menopausal symptoms, and perceived improvements in quality of life in users of hormone replacement therapy seem to be substantial. This emphasises the need to include quality of life measurements when assessing outcomes of hormone replacement therapy. Several limitations may exist with widely applied measurement techniques, calling for the development of appropriate and well validated instruments for measuring quality of life associated with reduced health states.
OBJECTIVES--To evaluate a change in antenatal care policy to reduce antenatal clinic visits, whereby low risk multiparous women were managed by the primary care team and seen at booking and at 41 weeks' gestation at the consultant antenatal clinic. DESIGN--Comparative study of low risk multiparous women retrospectively identified through the Oxford obstetric data system and cared for by three consultants who changed their policy (group A) or three consultants who maintained their routine care (group B). SETTING--Oxfordshire Health District. SUBJECTS--2153 low risk multiparous women (1079 group A, 1074 group B) booked for consultant care at John Radcliffe Maternity Hospital between August 1985 and July 1987. MAIN MEASURES--Comparison of pregnancy outcomes, satisfaction with care, and clinic waiting times, during one year before and after the policy change (year 1, year 2). RESULTS--The proportion of women in group A with only one or two consultant clinic visits increased from 19.9% to 57.9% between years 1 and 2 (p < 0.001). Clinic waiting times did not improve. Of five perinatal deaths in group A, one (from postmaturity) could possibly be attributed to the policy change. The proportion of women reaching 42 weeks' gestation rose from 4.7% to 9.2% (p < 0.01); the proportion fully satisfied with their care rose from 68.4% to 82.1% (p < 0.025). No such changes were seen in group B. CONCLUSIONS--The change in policy was successful in reducing hospital antenatal clinic visits. The exercise identified dilemmas around evaluating changes in antenatal care settings. IMPLICATIONS--Criteria to test policy objectives should be selected carefully and rare events assessed prospectively in order to detect problems early.
Among 10 patients with endometriosis CA 125 was increased (greater than 35 U/ml) in endometriotic cyst fluid in all the patients, but only two had increased serum concentrations. Gel electrophoresis of serum, endometriotic cyst fluid, and endometriotic tissue resolved the CA 125 immunoreactive fragments from the three sources into bands of similar electrophoretic mobilities. Electrophoresis under reducing and non-reducing conditions showed immunoreactive fragments of apparent masses of 55,000 and 140,000 daltons, respectively. Analysis under reducing conditions did not result in loss of activity. CA 125 antigen is thought to be a high molecular weight glycoprotein complex. As far as is known, this is the first report describing lower molecular weight immunoreactive determinants of CA 125.
OBJECTIVE--To investigate the nature of work related to the menopause in general practice. DESIGN--Questionnaire study over six months among general practitioners after each consultation with a woman aged 40-69 at which issues related to the climacteric had been discussed. SETTING--9 General practices in the Oxford area. SUBJECTS--416 Women who had 572 consultations. MAIN OUTCOME MEASURES--Age, menopausal state, and first or subsequent consultation. Symptoms were classified together with the treatment and the outcome of the consultation. RESULTS--The consultation rate varied greatly between practices, the overall rate being 4.4%. There were many premenopausal women and women in their 60s presenting; women with hysterectomies presented more often--36% (37/103) of women with hysterectomies had more than one consultation compared with 26% (38/144) for premenopausal women and 24% (38/155) for postmenopausal women. 409 women had symptoms and 218 were prescribed oestrogen treatment. 156 of the consultations involved discussion and advice only. Only four women were referred to a local specialist clinic. CONCLUSION--There is a low overall use of hormone replacement therapy in the general postmenopausal population despite the recent media coverage of its benefits in the prevention of osteoporosis and subsequent fractures.
Reduction of HIV p24 antigenaemia by zidovudine was investigated in 34 HIV antibody-positive, asymptomatic patients in a randomised, double-blind, placebo-controlled trial. Zidovudine was shown to lower p24 antigen levels as effectively when administered twice daily as when administered four times daily. Serum levels of p24 antigen varied little over 18 weeks in patients taking placebo.