Early Release Science of the exoplanet WASP-39b with JWST NIRSpec PRISM.

Transmission spectroscopy1-3 of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres4,5. However, these previous inferences with the Hubble and Spitzer Space Telescopes were hindered by the observations' relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species-in particular the primary carbon-bearing molecules6,7. Here we report a broad-wavelength 0.5-5.5 µm atmospheric transmission spectrum of WASP-39b8, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec's PRISM mode9 as part of the JWST Transiting Exoplanet Community Early Release Science Team Program10-12. We robustly detect several chemical species at high significance, including Na (19σ), H2O (33σ), CO2 (28σ) and CO (7σ). The non-detection of CH4, combined with a strong CO2 feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO2 (2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST's sensitivity to a rich diversity of exoplanet compositions and chemical processes.

Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists.

The pharmacology of several commonly described 5-hydroxytryptamine (5-HT)(2C) receptor agonists was investigated in vivo and in vitro at rat 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. The 5-HT(2C) receptor agonist, (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine fumarate (Ro 60-0175), did not induce a significant head-twitch response when given alone, yet when administered to rats subsequent to an acute challenge with the selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbomyl] indoline (SB-242084), a robust head-twitch response was observed which was blocked by the selective 5-HT(2A) receptor antagonists R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4-piperidine-methanol (MDL 100907) or ketanserin. The preferential 5-HT(2C) receptor agonists Ro 60-0175, 6-chloro-2-[1-piperazinyl]-pyrazine HCl (MK-212), 1-(3-chlorophenyl)piperazine hydrochloride (mCPP), 1-(3-trifluoromethylphenyl)piperazine hydrochloride (TFMPP), and (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrollidine HCl (ORG-37684), the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), the 5-HT(2B) receptor agonist 1-[5-thienylmethoxy-1-1H-3-indoyl] propan-2-amine hydrochloride (BW-723C86), and nor-D-fenfluramine were administered to rats subsequent to an acute challenge of SB-242084. Under such conditions, each agonist, with the exception of BW-723C86, induced a dose-dependent increase in the incidence of head twitches. The pharmacology of the same agonists was determined at cloned rat 5-HT(2) receptors using a fluorometric imaging plate reader (FLIPR). Both the in vivo and in vitro data suggest that for some ligands, previous reports have overestimated their in vivo selectivity for the 5-HT(2C) receptor.

Agonist-induced functional desensitization of recombinant human 5-HT2 receptors expressed in CHO-K1 cells.

The desensitization characteristics of recombinant human 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors (VSV and INI isoforms) stably expressed in CHO-K1 (Chinese hamster ovary) cells was investigated by calcium fluorimetry. Comparative desensitization characteristics of the agonists 5-HT, m-chlorophenylpiperazine (mCPP), and 2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI) were performed. Human 5-HT(2C (INI)) receptors exhibited a greater degree of desensitization to all agonists tested than edited 5-HT(2C (VSV)) receptors. A 2-hr exposure to 5-HT resulted in a significantly larger reduction in response upon re-exposure to 5-HT at 5-HT(2C (INI)) receptors, as compared to 5-HT(2C (VSV)) receptors (72% and 47% respectively, P < 0.01). Both receptor isoforms were expressed at similar densities. Human 5-HT(2B) receptors exhibited the most dramatic degree of desensitization, with prior exposure to 5-HT reducing subsequent response to 5-HT by 80%, with an extremely rapid time-course (t(1/2) < 5 min). The response at 5-HT(2A) receptors was reduced by 54%. The partial agonists mCPP and DOI also elicited desensitization, generally in line with their relative efficacies at each receptor, but exhibited more rapid kinetic profiles than 5-HT. Heterologous desensitization of an endogenously expressed G(q/11)-coupled purinergic receptor was also examined following preincubation of the cell lines with 10 microM 5-HT. Only stimulation of 5-HT(2C (VSV)) receptors resulted in a profound attenuation of subsequent ATP mediated responses. These results demonstrate differing degrees of both homologous and heterologous desensitization of 5-HT(2) receptors. Additionally, the different desensitization profiles of 5-HT(2C (INI)) and 5-HT(2C (VSV)) receptor may be due to signal transduction differences caused by RNA editing.

Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells.

1. The goal of this study was to characterize the agonist pharmacology of human 5-HT2A, 5-HT2B and 5-HT2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2. We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 3. Stimulation of all three receptors by 5-HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non-transfected control CHO-K1 cells. 4. The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW-723C86, d-norfenfluramine, Ro 60-0175 and LSD exhibited the following rank order of potency; 5-HT2B>5-HT2C>5-HT2A. Piperazines such as m-Chlorophenylpiperazine (mCPP), ORG-12962, MK-212 and also ORG-37684 exhibited a rank order of potency of 5-HT2C>5-HT2B>5-HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5-HT2A>5-HT2B>5-HT2C. 5. Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5-HT2C receptors but <25% at either 5-HT2A or 5-HT2B receptors. 6. Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.

Manchester and Oxford University Scale for the psychopathological assessment of dementia.

There is increasing awareness of the importance of psychopathological and behavioral changes in dementia and a need for a technique to measure these noncognitive features. Such a schedule should keep screening questions to a minimum, include a severity measure, exclude symptoms resulting from physical illness, be as brief as possible, and not mix domains of psychopathology. To test the reliability, sensitivity, and validity of a newly developed test, 30 carers were interviewed four times during 6 weeks. An obligatory stem question in each category was followed by supplementary questions. The interviewer recorded the presence of each symptom, its severity, when each symptom started, its duration, and whether it was still present. To detect the presence of delusions, the informant was asked about the patient's insight. Satisfactory differences in mean kappa values were demonstrated in test-retest and interrater reliability and validity compared with other techniques. This test may be useful to measure the outcome of drug trials, for correlating psychopathological and behavioral changes with autopsy findings and in epidemiological surveys.

Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD).

BACKGROUND: There is increasing awareness of the importance of psychopathological and behavioural changes in dementia and a need for an instrument to measure these features which achieves an appropriate compromise between brevity and breadth. We describe a newly developed 59-item instrument: the MOUSEPAD. METHOD: Reliability, sensitivity and validity were examined with 30 carers, each of whom was interviewed four times over six weeks. RESULTS: For different symptom groups, kappa ranged from 0.43 to 0.93 for test-retest reliability, from 0.56 to 1.0 for inter-rater reliability, and from 0.43 to 0.67 for the validation study. CONCLUSIONS: The scale may be useful as an outcome measure in drug trials, for correlating psychopathological and behavioural changes with post-mortem findings, and in epidemiological surveys.

Effect of fluoxetine on melatonin in patients with seasonal affective disorder and matched controls.

BACKGROUND: The aim was to investigate the secretion profile of melatonin and seasonal affective disorder before and after treatment with fluoxetine. METHOD: A six-week case-controlled study with repeated overnight blood sampling was conducted. Ten patients fulfilling the criteria for major depressive disorder, seasonal type, with a 29-item Hamilton Depression Rating Scale (HDRS) score of at least 20 were compared with ten age- and sex-matched healthy controls in a clinical laboratory. The effects of fluoxetine (20 mg/day) on the HDRS and melatonin concentration were measured. RESULTS: Fluoxetine significantly reduced melatonin levels in both groups. There was no significant difference in melatonin secretion between the groups. CONCLUSIONS: The effect of fluoxetine differs from tricyclics and fluvoxamine, both of which increase melatonin.

The effect of temazepam on melatonin secretion and light sensitivity.

Seven healthy male volunteers had their light sensitivity (melatonin suppression) and melatonin phase measured before and after treatment with temazepam (20 mg) for 7 days. Temazepam did not alter the circadian phase of melatonin secretion (the Dim Light Melatonin Onset, the timing of the peak of secretion), the total melatonin secretion nor the sensitivity of melatonin secretion to suppression by full spectrum light. This is an important negative finding which suggests that the short half-life benzodiazepine hypnotic temazepam does not confound tests of light sensitivity or melatonin phase.

Alcohol use and interpersonal violence: alcohol detected in homicide victims.

To characterize the relationship between alcohol use and homicide victimization, we used data from the Los Angeles City Police Department and the Los Angeles Medical Examiner's Office to study 4,950 victims of criminal homicides in Los Angeles in the period 1970-79. Alcohol was detected in the blood of 1,883 (46 per cent) of the 4,092 victims who were tested. In 30 per cent of those tested, the blood alcohol level was greater than or equal to 100 mg/100 ml, the level of legal intoxication in most states. Blood alcohol was present most commonly in victims who were male, young, and Latino, categories where rates have been increasing at an alarming pace. Alcohol was also detected most commonly in victims killed during weekends, when homicides occurred in bars or restaurants, when homicides resulted from physical fights or verbal arguments, when victims were friends or acquaintances of offenders, and when homicides resulted from stabbings. The evidence for alcohol use by homicide victims focuses attention on the need for controlled epidemiologic studies of the role played by alcohol as a risk factor in homicide and on the importance of considering situational variables in developing approaches to homicide prevention.

Placental prostacyclin production in normal and toxemic pregnancies.

Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. Because toxemia is characterized by increased vasoconstriction frequently associated with increased platelet aggregation and reduced uteroplacental blood flow, a deficiency in prostacyclin production during pregnancy could contribute to the development of toxemia. Placentally produced prostacyclin could have both local effects on the uteroplacental vasculature and systemic effects because prostacyclin, unlike the other prostaglandins, is not extensively metabolized by the lungs. Fresh human term placentas were obtained immediately after delivery from 12 normal and 12 toxemic (blood pressure greater than or equal to 140/90 mm Hg, urinary protein greater than 0.3 gm/24 hours) pregnancies. Tissues (300 mg) were incubated in a sterile manner in 5 ml of Dulbecco's Modified Eagle's Medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide in a metabolic shaker. Samples were collected at 8, 20, 32, and 48 hours and analyzed for prostacyclin by radioimmunoassay of its stable metabolite, 6-keto-prostaglandin F1 alpha. Prostacyclin production was significantly decreased in toxemic placental tissue compared with normal placental tissue (2.72 +/- 0.49 versus 7.22 +/- 0.44 pg/mg/hr, mean +/- SE, p less than 0.01). In both normal and toxemic placentas, prostacyclin production was inhibited by indomethacin (5 or 50 mumol/L) and not affected (p greater than 0.10) by arachidonic acid (5 or 100 mumol/L). Lowering the oxygen concentration from 95% to 20% significantly (p less than 0.01) decreased prostacyclin production in normal but not toxemic placentas. Prostacyclin production rates in the amnion and chorion were not affected (p greater than 0.10) by toxemia. The amniotic and chorionic prostacyclin production rates were not different from each other (p greater than 0.10) and were only one seventh of the normal placental production rate. These data indicate that placental prostacyclin production is decreased in toxemia; therefore, this vasoactive prostaglandin may be involved in the causation and the associated hypertension and coagulation abnormalities of this disorder.

Plasma exchange in acute renal allograft rejection. A controlled trial.

A controlled trial was carried out to assess the value of intensive plasma exchange in 27 renal transplant recipients with clinical and histological evidence of acute vascular rejection. In addition to standard immunosuppression, 13 patients received plasma exchange on six consecutive days at a mean exchange volume of 40.6 ml/kg of body weight each day using an intermittent cell separator. A further 14 patients received standard immunosuppression only. In addition, 10 patients exchanged prior to the controlled trial have been studied. Analysis of short-term benefit, as evidenced by a reduction in serum creatinine, and by subsequent graft survival revealed no significant difference in these parameters between the two groups in the controlled trial. This regimen of plasma exchange has not, therefore, been shown to modify acute renal allograft rejection.

Homicide followed by suicide: Los Angeles, 1970-1979.

A study of 104 homicide-followed-by-suicide events in Los Angeles during 1970-1979 are reported and compared, in part, to the findings of D.J. West for Wales and England, 1954-1961. Variables discussed are age, ethnicity, sex distribution of both offenders and victims, relationship between them, methods by which victims were killed, alcohol content in victims and offenders, suicide notes, depression, and physical illness.

The paraureteric diverticulum in childhood.

The clinical features and the results of surgical treatment in 27 children with a paraureteric diverticulum treated between 1969 and 1979 were reviewed. The condition is commoner in males. Vesicoureteric reflux and double ureters were associated findings and together with the diverticulum accounted for the high incidence of urinary infection as a presenting feature. In only 2 patients with the diverticulum seen on excretion urography, but micturating cystography confirmed the diagnosis in 24 patients. Conservative treatment with continuous chemotherapy is satisfactory when the diverticulum is small and prior to the development of vesicoureteric reflux. In the later stages, excision of the diverticulum and reimplantation of the contiguous ureter is the surgical treatment of choice.

The interrelationship between paraureteric diverticula, vesicoureteric reflux and duplication of the pelvicaliceal collecting system: a family study.

The incidence of a bifid pelvicaliceal system, vesicoureteric reflux, its sequelae and paraureteric diverticulum was determined in the patients and siblings of 22 patients with a paraureteric diverticulum. The results support the hypothesis that there is a direct genetic relationship between a paraureteric diverticulum, duplication of the pelvicaliceal system and vesicoureteric reflux. This suggests that the vesicoureteric reflux associated with a parauretic diverticulum is primary and related to lateral ectopia of the ureteric orifice. This syndrome complex may be inherited by multiple genes producing a cumulative effect, thus determining the length of the intravesical ureter, or by an autosomal dominant gene of variable penetrance.