Choosing Wisely Canada: Canadian fertility and andrology society's list of top items physicians and patients should question in fertility medicine.

PURPOSE: To create a Choosing Wisely Canada list of the top 5 diagnostic and therapeutic interventions that should be questioned in Reproductive Endocrinology and Infertility in Canada. METHODS: The Canadian Fertility and Andrology Society (CFAS) National Working Group developed an initial list of recommendations of diagnostic and therapeutic interventions that are commonly used, but are not supported by evidence, and could expose patients to unnecessary harm. These were chosen based on their prevalence, cost, potential for harm, and quality of supporting evidence. A modified Delphi consensus was used over 5 rounds to generate ideas, review supporting evidence, assess clinical relevance, estimate recommendation impact and narrow the recommendations list to 5 items. RESULTS: Fifty unique ideas were first proposed by the working group, and after 5 rounds including a survey of Canadian Fertility and Andrology Society (CFAS) members, the final list of recommendations was created, including topics related to unnecessary investigations and interventions for patients with infertility and recurrent pregnancy loss, and those undergoing IVF. In this article, we describe not only the Delphi process used to determine the list, but also provide a summary of the evidence behind each of the final recommendations. CONCLUSIONS: The list of five recommendations highlights opportunities to initiate conversations between clinicians and patients about the risks, benefits, harms and costs of unnecessary fertility treatments and procedures in a Canadian context.

Development and Implementation of Health and Wellness CBT for Individuals with Depression and HIV.

Rates of depression are reported to be between 22-33% in adults with HIV, which is double that of the general population. Depression negatively affects treatment adherence and health outcomes of those with medical illnesses. Further, it has been shown in adults that reducing depression may improve both adherence and health outcomes. To address the issues of depression and non-adherence, Health and Wellness (H&W) Cognitive Behavioral Therapy (CBT) and medication management (MM) treatment strategies have been developed specifically for youth living with both HIV and depression. H&W CBT is based on other studies with uninfected youth and upon research on adults with HIV. H&W CBT uses problem-solving, motivational interviewing, and cognitive-behavioral strategies to decrease adherence obstacles and increase wellness. The intervention is delivered in 14 planned sessions over a 6-month period, with three different stages of CBT. This paper summarizes the feasibility and acceptability data from an open depression trial with 8 participants, 16-24 years of age, diagnosed with HIV and with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of depression, conducted at two treatment sites in the Adolescent Trials Network (ATN). Both therapists and subjects completed a Session Evaluation Form (SEF) after each session, and results were strongly favorable. Results from The Quick Inventory of Depressive Symptomatology-Clinician (QIDS-C) also showed noteworthy improvement in depression severity. A clinical case vignette illustrates treatment response. Further research will examine the use of H&W CBT in a larger trial of youth diagnosed with both HIV and depression.

Uterine length and fertility outcomes: a cohort study in the IVF population.

STUDY QUESTION: What is the relationship between pre-cycle uterine length and IVF outcome (chemical pregnancy, clinical pregnancy, spontaneous abortion and live birth)? SUMMARY ANSWER: Women at extremes of uterine length (<7.0 or >9.0 cm) were less likely to achieve live birth and women with uterine lengths <6.0 cm were also more likely to experience spontaneous abortion. WHAT IS KNOWN ALREADY: A prospective study of 807 women published in 2000 found that implantation and clinical pregnancy rates were highest in women with uterine lengths between 7.0 and 9.0 cm, though the difference was not significant. The relationship between pre-cycle uterine length and live birth has not been evaluated. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of all cycles performed after uterine length measurement at an academic hospital IVF clinic from 2001 to 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 8981 fresh cycles were performed in 5120 adult women with normal uterine anatomy. Women with uterine anomalies (unicornuate, bicornuate, septate or uterus exposed to diethylstilbestrol) were excluded and women with fibroids were identified for subanalysis. Uterine length was measured by uterine sounding. Cycles were divided by uterine length into groups: <6.0 cm (very short, n = 76), 6.0-6.9 cm (short, n = 2014), 7.0-7.9 cm (referent, n = 4984), 8.0-8.9 cm (long, n = 1664) and ≥9 cm (very long, n = 243). Multivariate logistic regression (first-cycle analyses) and generalized estimating equations (all-cycle analyses) were adjusted for age, fibroids and ART treatment (assisted hatching, intracytoplasmic sperm injection) to generate relative risk (RR) of cycle outcomes by uterine length. MAIN RESULTS AND THE ROLE OF CHANCE: Median uterine length in the IVF population was 7.0 cm (interquartile range 7.0-7.8) and was positively associated with BMI (P < 0.001) and fibroids (P = 0.02). Compared with the referent group, women with uterine lengths <6.0 cm were half as likely to achieve live birth (RR: 0.53; 95% confidence interval (CI): 0.35-0.81) and women with lengths of 6.0-6.9 cm were also less likely (RR: 0.91; CI: 0.85-0.98). Cubic regression spline identified a significant inverse U-shaped association whereby women with uterine lengths <7.0 or >9.0 cm were less likely to achieve live birth. Women with lengths <6.0 cm were also more likely to experience spontaneous abortion (RR: 2.16; CI: 1.23-3.78). Results remained consistent when excluding women with a uterine factor diagnosis (n = 8823), when limiting to the first cycle at our institution (n = 5120) and when further restricting to first-ever cycles (n = 3941). LIMITATIONS, REASONS FOR CAUTION: Optimal assessment of uterine length by ultrasound was not feasible due to time and cost limitations, though uterine sounding is a clinically relevant measurement allowing for results with practical implications. Findings from our predominantly Caucasian clinic population may not be generalizable to infertile populations with different ethnic compositions. WIDER IMPLICATIONS OF THE FINDINGS: Reproducibility of results would solidify findings and inform patient counseling in women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S): No funding was sought for this investigation. MD declares relationships with UpToDate (royalties) and WINFertlity (consultant).

Transmission dynamics and associated mortality of nosocomial COVID-19 throughout 2021: a retrospective study at a large teaching hospital in London.

BACKGROUND: The impact of nosocomial SARS-CoV-2 infections has changed significantly since 2020. However, there is a lack of up-to-date evidence of the epidemiology of these infections which is essential in order to appropriately guide infection control policy. AIMS: To identify the secondary attack rate of SARS-CoV-2 infection and associated mortality across different variants of concern. METHODS: A single-centre retrospective study of all nosocomial SARS-CoV-2 exposure events was conducted between 31st December 2020 and 31st December 2021. A secondary attack rate was calculated for nosocomial acquisition of SARS-CoV-2 infection and time to positivity. Positive contacts were assessed for all-cause 30-day mortality. RESULTS: A total of 346 sequential index exposure events were examined, and 1378 susceptible contacts identified. Two hundred susceptible contacts developed SARS-CoV-2 infection (secondary attack rate of 15.5%). The majority of index cases (59%) did not result in any secondary SARS-CoV-2 infection. Where close contacts developed SARS-CoV-2 infection, 80% were detected within the first five days since last contact with the index case. The overall associated mortality among positive contacts across 2021 was 9%, with an estimated reduction of 68% when comparing periods of high Omicron versus Alpha transmission. CONCLUSION: Our findings describe that most SARS-CoV-2 infections are detected within five days of contact with an index case; we have also demonstrated a considerably lower mortality rate with the Omicron variant in comparison to previous variants. These findings have important implications for informing and supporting infection control protocols to allow movement through the hospital, and ensure patients access care safely.

An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy.

Replication-selective oncolytic viruses constitute a rapidly evolving and new treatment platform for cancer. Gene-deleted viruses have been engineered for tumor selectivity, but these gene deletions also reduce the anti-cancer potency of the viruses. We have identified an E1A mutant adenovirus, dl922-947, that replicates in and lyses a broad range of cancer cells with abnormalities in cell-cycle checkpoints. This mutant demonstrated reduced S-phase induction and replication in non-proliferating normal cells, and superior in vivo potency relative to other gene-deleted adenoviruses. In some cancers, its potency was superior to even wild-type adenovirus. Intravenous administration reduced the incidence of metastases in a breast tumor xenograft model. dl922-947 holds promise as a potent, replication-selective virus for the local and systemic treatment of cancer.

Normal mouse peritoneum contains a large population of Ly-1+ (CD5) B cells that recognize phosphatidyl choline. Relationship to cells that secrete hemolytic antibody specific for autologous erythrocytes.

We have found that, in the peritoneums of normal adult mice, 5-15% of lymphocytes bind a fluorescent liposome probe. In ontogeny, cells with this specificity were shown to appear by 8 d after birth, and increase to the adult frequency by 2-3 wk. Some older mice contain an expanded population of these cells. We have shown that liposome binding occurs by cell surface IgM recognizing the common membrane phospholipid, phosphatidyl choline (PtC). Virtually all of these PtC-specific cells bear the cell surface marker Ly-1. Our results indicate that roughly 1 in 10 peritoneal Ly-1+ B cells has this single specificity. We have found that the precursors to all the cells that form plaques on protease-treated autologous erythrocytes (BrMRBC) are included in the PtC-specific population and can be isolated by FACS. We believe this is the first report of sorting large numbers of B cells with a single antigen specificity from normal, unimmunized animals. This method will allow for in vitro and in vivo studies of differentiative and proliferative properties of Ly-1+ B cells, which may help define their role in development and disease.

Micro-computed X-ray tomography: a new non-destructive method of assessing sectional, fly-through and 3D imaging of a soft-bodied marine worm.

The detailed examination of the internal and functional anatomy of soft-bodied marine worms has, until now, only been possible using the time consuming and destructive techniques of dissection, histology and electron microscopy. This is the first description of soft body morphology in polychaetes (Nephtys hombergii) derived by means of a bench-top X-ray micro-CT scanner. The data are augmented, for comparison, by dissections, microscopy and scanning electron microscopy of the same species to show how this non-destructive technique can rapidly and reliably produce high-quality morphological data. It can also be applied to rare or unique invertebrate soft tissue material from museum collections and also to large-scale invertebrate comparative anatomical studies possibly leading to greater evolutionary and taxonomic understanding. High-definition images were obtained without the use of special tissue enhancing stains or radio-opaque fluids and it is believed that this is the first time the technique has been successfully applied to this group of invertebrates. Extrapolation of the sectional imaging of regions of the gut and the production of three-dimensional rotating and 'fly-through' imaging can assist in assessment of aspects of functional anatomy.

Effect of the UK Psychoactive Substances Act 2016 on episodes of toxicity related to new psychoactive substances as reported to the National Poisons Information Service. A time series analysis.

BACKGROUND: There have been recent increases in use of new psychoactive substances (NPS) associated with acute health harms including hospital presentations due to toxicity and increasing numbers of deaths. In response, the UK Government enacted generic legislation on 26th May 2016 (the Psychoactive Substances Act) making it an offence to produce, possess with intent to supply, supply, import or export, or possess within a custodial setting a psychoactive substance. We studied the impact of this Act on monthly frequency of enquiries made by health professionals to the UK National Poisons Information Service (NPIS) about NPS. We also studied five commonly used 'conventional' drugs of misuse that had been controlled prior to January 2009. METHOD: Anonymised clinical enquiries to the NPIS and accesses to the poisons information database TOXBASE were reviewed retrospectively from January 2009 to December 2018 to ascertain the trends in reported toxicity for NPS, cocaine, heroin, cannabis, amphetamines and MDMA. Data were analysed using interrupted time series analysis with the date of the PSA used as an independent predictor. RESULTS: Over the period of study there were 3,866 NPIS telephone enquiries and 79,271 TOXBASE user accesses made by UK health professionals concerning NPS. There were increases in monthly TOXBASE accesses (t = 7.408, P < 0.0001) and telephone enquiries (t = 4.74, P < 0.001) over the pre-specified period January 2009 to May 2016. Comparing the period after the PSA with that before, there were significant reductions in TOXBASE accesses (t = -3.327, P < 0.001) and telephone enquiries (t = -6.97, P < 0.001), although reductions started before May 2016. There were no significant changes for the five conventional drugs. There were significant reductions in telephone enquiries (t = -3.418, P < 0.001) and non-significant reductions in TOXBASE accesses (t = -1.713, P = 0.089) for NPS between June 2016 and December 2018. Increases in telephone enquiries for cocaine and reductions TOXBASE accesses for MDMA were also observed over that period. CONCLUSIONS: There have been significant recent reductions in NPIS enquiry activity relating to NPS; although these began before enactment of the PSA in May 2016.

E5531, a pure endotoxin antagonist of high potency.

Shock due to Gram-negative bacterial sepsis is a consequence of acute inflammatory response to lipopolysaccharide (LPS) or endotoxin released from bacteria. LPS is a major constituent of the outer membrane of Gram-negative bacteria, and its terminal disaccharide phospholipid (lipid A) portion contains the key structural features responsible for toxic activity. Based on the proposed structure of nontoxic Rhodobacter capsulatus lipid A, a fully stabilized endotoxin antagonist E5531 has been synthesized. In vitro, E5531 demonstrated potent antagonism of LPS-mediated cellular activation in a variety of systems. In vivo, E5531 protected mice from LPS-induced lethality and, in cooperation with an antibiotic, protected mice from a lethal infection of viable Escherichia coli.

Field evaluations of concentrated spray applications of microencapsulated sex pheromone for codling moth (Lepidoptera: Tortricidae).

The application of a microencapsulated (MEC) sex pheromone formulation (Checkmate CM-F) for codling moth, Cydia pomonella (L.), in low volume, concentrated sprays was evaluated in a series of small plot and grower trials in apple, Malus domestica Borkhausen, and pear, Pyrus communis L. Preliminary tests found that MEC sprays applied at 172-207 kilopascals in 12-23 liters/ha deposited the highest density of microcapsules per leaf. The addition of a latex sicker did not increase the deposition of microcapsules. Small plot tests in 2004 compared the effectiveness of two low-volume sprayers against a standard high-volume spray (926 liters/ha) applied at 1,379 kilopascals. Moth catches and fruit injury were significantly lower in plots treated with the low-volume sprays compared with plots treated with the standard sprayer. These results suggest that concentrating the MEC formulation increases the deposition of microcapsules and improves its effectiveness. Larger trials were conducted with a low-volume sprayer in 4-ha plots within commercial apple (2005-2006) and pear orchards (2005) paired with similar plots treated with hand-applied pheromone dispensers. Levels of fruit injury were not significantly different between pheromone treatments in any of the three tests. Moth catches, however, were significantly higher in the MEC- versus the dispenser-treated apple plots in 2005. No difference was found in the fruit injury levels in MEC-treated apple orchards in 2005 caused by irrigation method, but moth catches were significantly higher in overhead versus undertree orchards. The advantages and current limitations of using MEC sex pheromone sprays to supplement current grower's management strategies for codling moth is discussed.

Tackling corruption in the pharmaceutical systems worldwide with courage and conviction.

Poor drug access continues to be one of the main global health problems. Global inequalities in access to pharmaceuticals are caused by a number of variables including poverty, high drug prices, poor health infrastructure, and fraud and corruption--the latter being the subject of this article. There is growing recognition among policy makers that corruption in the pharmaceutical system can waste valuable resources allocated to pharmaceutical products and services. This, in turn, denies those most in need from life-saving or life-enhancing medicines. As a result, international organizations, including the World Health Organization and the World Bank are beginning to address the issue of corruption in the health sector broadly and the pharmaceutical system specifically. This is encouraging news for improving drug access for the global poor who are most harmed by corruption as they tend to purchase less expensive drugs from unqualified or illegal drug sellers selling counterfeit or sub-standard drugs. In our paper, we illuminate what are the core issues that relate to corruption in the pharmaceutical sector. We argue that corruption in the pharmaceutical system can be detrimental to a country's ability to improve the health of its population. Moreover, unless policy makers deal with the issue of corruption, funding allocated to the pharmaceutical system to treat health conditions may simply be wasted and the inequality between rich and poor in access to health and pharmaceutical products will be aggravated.

Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration.

The localization of i.p. injected, radioiodine conjugated monoclonal antibody HMFG2 was studied in 18 patients with ovarian carcinoma. Patients were injected i.p. at time points up to 168 h before laparotomy, at which time tumor, ascites, normal tissue, and blood samples were removed and the contained radioactivity measured. In the first 10 patients, localization was compared with that of a simultaneously injected irrelevant (nonspecific) antibody (UJ13A) of the same immunoglobulin class and, in the subsequent 8 patients, with HMFG2 administered i.v. After i.p. injection, HMFG2-radioiodine was found in concentrations of 0.0001-0.0030% of the injected amount per gram in solid tumor, 0.0363-0.02560%/g in ascites, 0.0003-0.0017%/g in blood, and 0.001-0.0012%/g in normal tissue. Tumor:normal tissue ratios of 0.9-10.0 and tumor:blood ratios of 0.3-4.0 were seen up to 168 h after injection. Localization of the HMFG2 conjugate was consistently greater than that of the irrelevant antibody. For solid tumor, the i.v. route of administration resulted in consistently higher absolute levels of HMFG2 conjugate uptake but tumor:blood and tumor:normal tissue ratios were similar. On the other hand the i.p. route of administration offered consistent advantages of 4- to 71-fold over the i.v. route when HMFG2 conjugate localization on ascites cells was examined. Ascites:normal tissue and ascites:blood ratios of up to 512 and 448, respectively, were achieved. After i.p. injection, radioiodine was cleared from the body exponentially with a half-life of 50 h. Maximum circulating blood levels of 8.6 +/- 2.0% injected activity were seen at 48 h and these then decreased with a t 1/2 value of 38 h. Over 80% of injected activity was cleared in the urine as nonprotein bound iodine by 168 h.

Clinical and angiographic characteristics and outcome of patients with rest-unstable angina occurring during regular aspirin use.

Today many patients admitted with an acute coronary syndrome are already taking aspirin. Because they have symptoms despite antithrombotic therapy, these patients are presumed to be at higher risk for subsequent clinical events. In a pilot trial of antithrombotic therapy in patients with unstable angina at rest or non-Q wave infarction, 93 patients admitted within 48 h of pain were prospectively followed up for 12 weeks. On admission, 29 patients (31%) were already taking daily aspirin; 64 (68%) were receiving no antiplatelet agent. After enrollment all patients received antithrombotic therapy with either aspirin or heparin according to protocol regardless of prior aspirin use. The two groups (prior users versus nonusers of aspirin) were similar with regard to age, gender, coronary risk factors, prior antianginal medication, duration of symptomatic coronary disease, presentation with non-Q wave infarction and extent of electrocardiographic changes on admission. Quantitative analysis of coronary arteriograms (on a 0 to 10 scale) showed similar myocardium-in-jeopardy scores (JS). Follow-up events (recurrent ischemia [Isch], infarction [MI] and revascularization [Revasc]) were: (formula: see text) Aspirin users experiencing rest angina are similar to other patients with ischemic rest pain. The "resistant to aspirin" group does not constitute a subgroup that is at higher risk for cardiac events or revascularization.

The role of adrenocorticotropin testing in evaluating girls with premature adrenarche and hirsutism/oligomenorrhea.

To identify biochemical predictors for future development of hirsutism and/or oligomenorrhea (H/O) in girls with premature adrenarche (PA), we performed dexamethasone-suppressed ACTH stimulation tests in girls with PA (n = 46), young women (n = 44) with H/O, and adult women (n = 31). Cortisol, androstenedione, dehydroepiandrosterone, and 17-hydroxyprogesterone were measured. Seven girls with PA (15%) and seven with H/O (16%) had evidence of nonclassical adrenal steroid biosynthetic defects [nonclassical congenital adrenal hyperplasia (NCAH)]. Twenty-five girls with PA (54%) and 28 girls with H/O (64%) had the moderately elevated 17-hydroxyprogesterone response to ACTH that has been reported in obligate heterozygotes for 21-hydroxylase deficiency. There were no clinical features that distinguished the girls with NCAH from the others. ACTH testing is an important tool in distinguishing those girls with PA and H/O who have NCAH. Although we could find no differences in other adrenal steroid hormones that might predict which of the other girls with PA might late develop H/O, black girls comprised a substantially smaller fraction of the population with H/O than of the population with PA (2% vs. 26%; chi 2 = 8.5; P less than 0.005). This observation suggests that PA, in blacks who do not have NCAH, is more likely to be a benign condition/than in other ethnic groups.

Effect of carbon monoxide exposure on aortic and coronary intimal morphology in the rabbit. A revaluation.

Non-cholesterol-fed rabbits were exposed to carbon monoxide at concentrations in air of either 200, 2000, or 4000 parts per million (=0.02, 0.2 or 0.4%, vol/vol). Using the same criteria for intimal damage as in earlier morphological studies, no histotoxic effect on intimal/subintimal morphology of coronary arteries or the aorta could be demonstrated, when light-microscopic evaluation was performed blindly.

Inhibition of AMPA receptor-stimulated 57Co2+ influx by D- and L-2-amino-4-phosphonobutanoic acid (D- and L-AP4) and L-serine-O-phosphate (L-SOP) in cultured cerebellar granule cells.

This study describes the inhibition of 57Co2+ influx through Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, consequent to the application of L-2-amino-4-phosphonobutanoic acid (L-AP4), D-AP4 and L-serine-O-phosphate (L-SOP) in cultured cerebellar granule cells. The forskolin-stimulated accumulation of cyclic AMP was inhibited by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) with an IC50 = 491 +/- 135 nM and by L-AP4 in a biphasic manner (IC50(1) = 232 +/- 61 nM and IC50(2) = >300 microM), confirming the presence of group II and group III mGlu receptors, respectively. 57Co2+ influx was stimulated by kainate (EC50 = 42.2 +/- 11.3 microM) and, in the presence of 30 microM cyclothiazide, by (S)-5-fluorowillardiine (EC50 = 0.7 +/- 0.1 microM) and (S)-AMPA (EC50 = 2.8 +/- 0.5 microM). The effects of the latter were abolished by 10 microM 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX). L-AP4 (IC50 = >300 microM), D-AP4 (IC50 = >100 microM) and L-SOP (IC50 = 199 +/- 6 microM) inhibited 6 microM (S)-AMPA-stimulated 57Co2+ influx, whereas L-CCG-1 (up to 10 microM), 300 microM (RS)-3,5-dihydroxyphenylglycine, 300 microM (+/-)-baclofen and 1 mM carbachol were ineffective. Pre-incubation with either pertussis toxin (250 ng/ml, 48 hr), 1 mM dibutyryl cyclic AMP, or the potent group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), tested at 400 microM, failed to alter the inhibition of AMPA receptor activity by 300 microM L-SOP. Unlike 10 microM NBQX, neither L-AP4, D-AP4 or L-SOP (tested at 1 mM) inhibited the binding of 10 nM (S)-[3H]5-fluorowillardiine (a selective AMPA receptor ligand) to granule cell membranes. Therefore, in these neurones, high concentrations (>100 microM) of L-AP4, L-SOP and D-AP4 inhibit Ca2+-permeable AMPA receptors by a mechanism distinct from known mGlu receptor action and at a site independent from that for AMPA receptor agonists.

Stereoselective actions of the isomers of metitepine at 5-HT1D receptors in the guinea pig brain.

The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT receptor antagonist metitepine at the 5-HT1D binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl [125]iodotyrosinamide ([125I]GTI), and at the terminal 5-HT autoreceptor in guinea pig frontal cortex, a proposed model of 5-HT1D receptor activation. The pharmacological specificity of the [125I]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT1D recognition site labelled with [3H]5-HT. The (+) isomer of metitepine displaced [125I]GTI binding with a lower affinity (64 nM) than did the (-) isomer (18 nM), which was equiactive with the racemic mixture. The (-) isomer of metitepine was more effective than the (+) isomer at attenuating the inhibitory effects of 5-HT and sumatriptan at the guinea pig terminal 5-HT autoreceptor; the apparent pA2 of the (-) isomer was 8.0 (sumatriptan) and 7.7 (5-HT) while the apparent pA2 of the (+) isomer was 7.1 (sumatriptan) and 6.8 (5-HT). The (-) isomer was more effective than the (+) isomer at enhancing stimulated [3H]5-HT release. These findings support the identification of the guinea pig 5-HT terminal autoreceptor as a 5-HT1D receptor and reinforce the species homology between the 5-HT1B and 5-HT1D receptors.

Pharmacological differentiation of kainate receptors on neonatal rat spinal motoneurones and dorsal roots.

The objectives of this study, conducted on neonatal rat spinal cord and dorsal roots in vitro, were to characterise the actions of a range of willardiine analogues on GluR5-containing kainate receptors present in dorsal roots, to determine whether GluR5-containing receptors are also present on motoneurones, and to differentiate responses mediated by kainate receptors from those mediated by AMPA receptors on motoneurones. (S)-5-Trifluoromethyl-willardiine, (S)-5-iodowillardiine, (S)-5-iodo-6-azawillardiine and ATPA were found to be potent agonists of kainate receptors on dorsal roots (EC50 values 0.108 +/- 0.002, 0.127 +/- 0.010, 0.685 +/- 0.141 and 1.3 +/- 0.3 microM, respectively) being more potent but of lower efficacy than kainate (EC50 value 14.8 +/- 1.8 microM). (S)-5-Iodo-6-azawillardiine blocked kainate-induced depolarisations of the dorsal root, probably via its desensitising action. Kainate-induced responses of dorsal roots were weakly antagonised by (RS)-3,5-dicarboxyphenylglycine (DCPG) (apparent KD 1.5 +/- 0.4 mM). Kainate receptors containing GluR5 subunits do not appear to be present on motoneurones since (RS)-3,5-DCPG (1 mM) potentiated rather than antagonised kainate-induced depolarisations of motoneurones. Although (S)-5-iodowillardiine (a potent and selective agonist at GluR5-containing kainate receptors) depolarised motoneurones (EC50 value 5.8 +/- 0.6 microM), such depolarisations were antagonised by both (RS)-3,4- and (RS)-3,5-DCPG, which are selective AMPA receptor antagonists at motoneurones, showing a KD value of 73 microM (Schild slope, 0.96 +/- 0.09) and an apparent KD value of 123 +/- 38 microM, respectively. This accords with the previously reported activity of willardiine analogues at AMPA receptors. Since neither (RS)-3,4- nor (RS)-3,5-DCPG antagonised kainate-induced motoneuronal depolarisations but cyclothiazide enhanced and GYK153655 blocked these responses it is possible that a component of the kainate response may be mediated by a population of DCPG-insensitive AMPA receptors on motoneurones. However, it is also possible that a population of kainate receptors other than those containing GluR5 subunits, are responsible for these effects. The new compounds introduced in this study are likely to be useful tools for studying the physiological role of kainate receptors in CNS function.

Binding of the new radioligand (S)-[3H]AMPA to rat brain synaptic membranes: effects of a series of structural analogues of the non-NMDA receptor agonist willardiine.

This study examined the binding of (S)-[3H]AMPA, the radiolabelled active isomer of AMPA, to rat brain synaptic membranes. Under non-chaotropic conditions specific binding of 10 nM (S)-[3H]AMPA represented 33 +/- 2% of the total; this increased to 74 +/- 1% in the presence of 100 mM KSCN. (S)-[3H]AMPA binding was inhibited by non-NMDA receptor agonists and the antagonists NBQX and CNQX, with the following rank order of potency: NBQX > (S)-AMPA > or = quisqualate > CNQX > L-glutamate > domoate > or = kainate > (R)-AMPA. NMDA, and the metabotropic glutamate receptor agonist (1S,3R)-ACPD, up to 100 microM, did not inhibit (S)-[3H]AMPA binding. A number of willardiine analogues all effectively inhibited (S)-[3H]AMPA binding with the rank order of potency: (S)-5-fluorowillardiine > (S)-5-nitrowillardiine > (S)-5-trifluoromethylwillardiine > (S)-5-bromowillardiine approximately (S)-5-chlorowillardiine > (S)-5-cyanowillardiine > (S)-willardiine > (S)-5-iodowillardiine > (S)-6-methylwillardiine > (S)-5-methylwillardiine. This rank order closely reflects data from equilibrium measurements made, under voltage clamp, on cultured hippocampal neurons. In contrast the respective (R)-enantiomers and the racemate mixtures of (R,S)-3, 5 and 6-isowillardiine were relatively inactive. Similar IC50 values and thus rank orders of potency for the willardiines were observed in the presence of 100 mM KSCN.

Technetium-99m MAG3, a comparison with iodine-123 and iodine-131 orthoiodohippurate, in patients with renal disorders.

A Phase I study in 12 patients with renal disorders compared the simultaneous clearances of 99mTc-labeled mercaptoacetyltriglycine (MAG3) and 131I-labeled orthoiodohippurate (OIH). The ratio of MAG3 to OIH clearance was 0.61 +/- 0.08 as a result of its smaller volume of distribution, ratio 0.65 +/- 0.09, for the clearance half-lives were similar, ratio 1.09 +/- 0.12. A Phase II study performed serially in 20 patients with equal doses of [99mTc]MAG3 and [123I]OIH gave images of equal quality. The relative renal functions were highly correlated (r = 0.97, p less than 0.001) and transit time analyses gave good correlations: parenchymal transit time index r = 0.81, p less than 0.05. We conclude that [99mTc]MAG3 has some advantages over [99mTc]DTPA and is a suitable replacement for [123I]hippuran in routine renal imaging, relative function, and transit time studies, but not for the accurate estimation of the renal plasma flow.