Postcranial evidence of late Miocene hominin bipedalism in Chad.

Bipedal locomotion is one of the key adaptations that define the hominin clade. Evidence of bipedalism is known from postcranial remains of late Miocene hominins as early as 6 million years ago (Ma) in eastern Africa1-4. Bipedality of Sahelanthropus tchadensis was hitherto inferred about 7 Ma in central Africa (Chad) based on cranial evidence5-7. Here we present postcranial evidence of the locomotor behaviour of S. tchadensis, with new insights into bipedalism at the early stage of hominin evolutionary history. The original material was discovered at locality TM 266 of the Toros-Ménalla fossiliferous area and consists of one left femur and two, right and left, ulnae. The morphology of the femur is most parsimonious with habitual bipedality, and the ulnae preserve evidence of substantial arboreal behaviour. Taken together, these findings suggest that hominins were already bipeds at around 7 Ma but also suggest that arboreal clambering was probably a significant part of their locomotor repertoire.

Management of depression in patients with schizophrenia spectrum disorders: a critical review of international guidelines.

OBJECTIVES: Depression is a frequent but potentially treatable clinical dimension in patients with schizophrenia spectrum disorders (PWS). However, there is a lack of consensual recommendations regarding the optimal strategy to manage depression in PWS. In this study, we aimed to compare the various proposed strategies to define a core set of valid care recommendations for depression management in PWS. METHODS: After a systematic search of the literature, the methodological quality of 10 international guidelines from four continents was compared using a validated guideline appraisal instrument (AGREE II). Key recommendations for the management of depression in PWS were subsequently reviewed and discussed. RESULTS: The methodological quality of the guidelines was heterogeneous. Although all guidelines proposed pharmacotherapy, psychosocial interventions were a minor concern. Waiting for antipsychotic effects mostly was recommended during the acute phase of schizophrenia. During the postpsychotic phase of the illness, a switch to a second-generation antipsychotic and/or the adjunction of an antidepressant were the primary recommendations. Cognitive behavioural therapy and other medications were considered with strong variations. CONCLUSIONS: Further studies are needed to strengthen the level of evidence for antidepressive approaches in PWS. The inclusion of PWS as stakeholders is also considered to be a major issue for future guideline development.

Fossil birds of the Kibish Formation.

The Kibish Formation has yielded a small collection of bird fossils, which are identified here as belonging to five species in four different families: Pelecanidae (pelicans), Anhingidae (darters), Ardeidae (herons) and Phasianidae (gamefowl). Two species of pelicans are identified: Pelecanus cf. P. onocrotalus, and P. aff. P. rufescens. The darter is referrable to Anhinga melanogaster. The heron is identifiable as Ardea sp., and the gamefowl as Numidinae indet. (guineafowl). Pelecanus cf. P. onocrotalus is represented by, among other remains, a well-preserved partial skull. Four of the birds are thus referrable to extant taxa that provide some paleoenvironmental clues for Member I of the Kibish Formation. The two species of pelican, the darter, and the heron indicate the presence of local freshwater bodies, a lake or a slow river, supporting resources of fish. The guineafowl is poorly informative ecologically, but probably excludes the notion that the local terrestrial landscape was treeless.

Automation of metabolic stability studies in microsomes, cytosol and plasma using a 215 Gilson liquid handler.

A 215 Gilson liquid handler was used to automate enzymatic incubations using microsomes, cytosol and plasma. The design of automated protocols are described. They were based on the use of 96 deep well plates and on HPLC-based methods for assaying the substrate. The assessment of those protocols was made with comparison between manual and automated incubations, reliability and reproducibility of automated incubations in microsomes and cytosol. Examples of the use of those programs in metabolic studies in drug research, i.e. metabolic screening in microsomes and plasma were shown. Even rapid processes (with disappearance half lives as low as 1 min) can be analysed. This work demonstrates how stability studies can be automated to save time, render experiments involving human biological media less hazardous and may be improve inter-laboratory reproducibility.

In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative.

N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]- phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) has been selected from a chemical program aimed at identifying an optimized inhibitor of multidrug resistance (MDR). The potency of GF120918 is assessed by dose-dependent sensitization of CHRC5, OV1/DXR and MCF7/ADR cells to the cytotoxicity of doxorubicin and vincristine respectively: GF120918 fully reverses multidrug resistance at 0.05 to 0.1 microM and is half maximally active at 0.02 microM. The spectrum of drugs sensitized by GF120918 coincides with those having the classical MDR phenotype. In CHRC5 cells, 0.01-0.1 microM GF120918 enhances the uptake of [3H]daunorubicin and blocks the efflux from preloaded cells. It is also shown that GF120918 is still active several hours after being taken away from the culture medium showing that it is not, like verapamil, effluxed rapidly by P-glycoprotein. GF120918 effectively competes with [3H]azidopine for binding P-glycoprotein, pointing to this transport membrane protein as its likely site of action. After i.v. administration to mice, GF120918 penetrates thoroughly various organs that have a tissue level/blood level ratio above 10. It is eliminated from organs and blood with a half-time of approximately 2.7 h. It is well absorbed after p.o. administration. In mice implanted i.p. with the MDR P388/Dox tumor, a single i.v. or p.o. dose of GF120918 restores sensitivity of the tumor to a single i.p. dose (5 mg/kg) of doxorubicin administered 1 h later. A statistically significant effect is observed at 1 mg/kg GF120918 i.v. and maximal effect is reached at 5 mg/kg. Similarly, whereas neither drug alone is effective, GF120918 (10 mg/kg i.p.) associated with doxorubicin (5 mg/kg i.p.) inhibits the growth of the moderately MDR C26 tumor implanted s.c. as assessed by tumor size at day 19. GF120918 does not modify significantly the distribution or the elimination of doxorubicin in mice ruling out the possibility that the antitumor effects seen might be explained by pharmacokinetic interactions.

Use of hepatocyte cultures for preliminary metabolism and cytotoxicity studies of a new anti-hypertensive agent, oxaminozoline.

1. Adult rat hepatocytes co-cultured with rat liver epithelial cells were used to evaluate chronic cytotoxicity of a new alpha 2 agonist, oxaminozoline (S-3341-3) compared to that of clonidine. The same maximum non-toxic concentration (25 micrograms per ml of medium) was found for both drugs after a daily treatment for 12 days. 2. Oxaminozoline metabolism was analysed in short-term hepatocyte cultures. Four metabolites resulting from oxidation or hydrolysis of the parent drug were identified. Three of the metabolites were identical to those reported in vivo. The presence of an additional minor metabolite in culture may be due to the higher metabolic rate of the drug in this model system.

Pharmacokinetics of almitrine bismesylate: studies in patients.

Many pharmacokinetic studies have been undertaken following both intravenous and oral administration in diseased patients after acute or chronic administration. Studies were carried out on COLD patients (IV and PO routes), patients with renal insufficiency (PO route) and patients with hepatic insufficiency (PO route). Plasma almitrine bismesylate assays are performed by a simple, sensitive and specific technique using a thermoionic nitrogen detector. Pharmacokinetic results obtained are compared to those obtained on healthy volunteers and discussed in terms of absorption, distribution and elimination. Results show that for the same administered dose, pharmacokinetic profile in COLD patients is close to the pharmacokinetic profile obtained on healthy volunteers. After six months' treatment the levels are not dependent on the subject's age or weight. In patients with renal insufficiency total plasma clearance is unchanged, mean steady state levels will be the same as normal patients and almitrine bismesylate can be administered in renal subjects without a change in dosage. In patients with liver insufficiency results are more variable. Some subjects have the same profile as healthy volunteers but absorption is diminished in others. Regarding the variability in kinetics and potential for impaired elimination, almitrine bismesylate should be titrated carefully in hepatic insufficiency.