CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Differences between chimpanzee and baboon gastrointestinal parasite communities.

Cross-species infection among humans, chimpanzees (Pan troglodytes) and baboons (Papio spp.) is potentially a significant public health issue in Africa, and of concern in the conservation of P. troglodytes. However, to date, no statistical comparisons have been made between the prevalence, richness and composition of parasite communities in sympatric populations of baboons and P. troglodytes. We compared parasite communities in sympatric P. troglodytes and Papio papio living in a wilderness site, in the Republic of Senegal, West Africa. We asked whether, in the absence of humans, there are significant differences between these hosts in their interactions with gastrointestinal parasites. We tested whether host, location, or time of collection accounted for variation in prevalence, richness and community composition, and compared prevalence across six studies. We concluded that, despite being closely related, there are significant differences between these two hosts with respect to their parasite communities. At our study site, prevalence of Balantidium, Trichuris and Watsonius was higher in P. papio. Papio papio harboured more parasites per host, and we found evidence of a positive association between Trichuris and Balantidium in P. troglodytes but not P. papio.

Arboreal nesting as anti-predator adaptation by savanna chimpanzees (Pan troglodytes verus) in southeastern Senegal.

Chimpanzees (Pan troglodytes) make nests for resting and sleeping, which is unusual for anthropoid primates but common to all great apes. Arboreal nesting has been linked to predation pressure, but few studies have tested the adaptive nature of this behavior. We collected data at two chimpanzee study sites in southeastern Senegal that differed in predator presence to test the hypothesis that elevated sleeping platforms are adaptations for predator defense. At Assirik in the Parc National du Niokolo-Koba, chimpanzees face four species of large carnivore, whereas at Fongoli, outside national park boundaries, humans have exterminated almost all natural predators. We quantified the availability of vegetation at the two sites to test the alternative hypothesis that differences in nesting reflect differences in habitat structure. We also examined possible sex differences in nesting behavior, community demographic differences, seasonality and nest age differences as variables also potentially affecting nest characteristics and nesting behavior between the two sites. Chimpanzees at Fongoli nested at lower heights and farther apart than did chimpanzees at Assirik and sometimes made nests on the ground. The absence of predators outside of the national park may account for the differences in nest characteristics at the two sites, given the similarities in habitat structure between Fongoli and Assirik. However, Fongoli chimpanzees regularly build arboreal nests for sleeping, even under minimal predation pressure, and this requires explanation.

Etho-archaeology of manual laterality: well digging by wild chimpanzees.

We present the first indirect test of manually lateralized behaviour in non-human primates, based on wells dug for drinking water by wild chimpanzees (Pan troglodytes schweinfurthii). Apes at Toro-Semliki Wildlife Reserve, in Uganda, dig bimanually in sandy riverbeds, leaving behind paired piles of excavated sand. The volumes of left- versus right-side piles do not differ, suggesting a lack of behavioural laterality, but this needs to be verified by further, direct observational data.

Ant fishing by wild chimpanzees is not lateralised.

Right-dominant handedness is unique and universal in Homo sapiens, suggesting that it is a highly derived trait. Our nearest living relations, chimpanzees, show lateralised hand preference when using tools, but not when otherwise manipulating objects. We report the first contrary data, that is, non-lateralised tool-use, for ant fishing as done in the Mahale Mountains of Tanzania. Unlike nut cracking, termite fishing, and fruit pounding, as seen elsewhere, in which most individuals are either significantly or wholly left- or right-biassed, ant fishers are mostly ambilateral. The clue to this exception lies in arboreality; all other patterns of chimpanzee elementary technology are done on the ground. Arboreal tool use usually requires not only that one hand be used to hold the tool, but also that the other hand gives postural support. When the supporting hand is fatigued, then it must be relieved by the other. Terrestrial tool use entails no such trading off. To test the hypothesis, we compared frequency of hand changing with the incidence of major hand support, and found them to be significantly positively correlated. The evolutionary transition from arboreality to terrestriality may have been a key enabler for the origins of human laterality.

Bilateral asymmetry in the limb bones of the chimpanzee (Pan troglodytes).

There is much debate in behavioral primatology on the existence of population-level handedness in chimpanzees. The presence or absence of functional laterality in great apes may shed light on the origins of human handedness and on the evolution of cerebral asymmetry. The plasticity of long bone diaphyses in response to mechanical loading allows the functional interpretation of differences in cross-sectional geometric. While left-right asymmetry in upper limb diaphyseal morphology is a known property in human populations, it remains relatively unexplored in apes. We studied bilateral asymmetry in 64 skeletons of wild-caught chimpanzee using the humerus, second metacarpal, and femur. The total subperiosteal area (TA) of the diaphyses was measured at 40% of maximum humeral length and at the midshaft of the metacarpals and femora using external silicone molds. Overall, the TA values of the left humeri were significantly greater than the right, indicating directional asymmetry. This effect was even greater when the magnitude of difference in TA between each pair of humeri was compared. The right second metacarpals showed a tendency toward greater area than did the left, but this did not reach statistical significance. The lack of asymmetry in the femur serves as a lower limb control, and suggests that the upper limb results are not a product of fluctuating asymmetry. These findings imply behavioral laterality in upper limb function in chimpanzees, and suggest a complementary relationship between precision and power.

Genotyping aids field study of unhabituated wild chimpanzees.

Prolonged habituation times for wild great apes delay the collection of behavioral and environmental data, sometimes for years. However, genotyping of noninvasively collected feces can provide useful socioecological information in the meantime. We tested this premise on an unhabituated wild population of western chimpanzees (Pan troglodytes verus) at Mont Assirik, Senegal. Genotyping yielded information on kinship, group size, party size and composition, sex ratio, and ranging.

Survey of savanna chimpanzees (Pan troglodytes verus) in Southeastern Sénégal.

A survey of the western subspecies of chimpanzee (Pan troglodytes verus) was conducted from 1 February to 9 April 2000 in Sénégal, West Africa, by the Miami Assirik Pan Project (MAPP). In addition to the Assirik area of the Parc National du Niokolo Koba (PNNK), areas south and east of the park were surveyed. Nests made by chimpanzees were used to estimate chimpanzee distribution and densities. Within the PNNK, chimpanzees were estimated to occur at an average of 0.13 individuals/km(2). Chimpanzee nests were recorded in nine of 10 locales surveyed outside of the PNNK, as well as within the park. Data on 994 nests made by chimpanzees were recorded outside the PNNK, while 736 nests were recorded inside the park. Nest density in areas surveyed outside the PNNK, such as Bandafassi, Tomboronkoto, and Segou, was comparable to that of Assirik in habitats where nests were concentrated (i.e., evergreen gallery forest). The purpose of MAPP was to initiate long-term research of chimpanzees in southeastern Sénégal, as a follow-up to the Stirling African Primate Project (SAPP) of the 1970s. We sought to replicate the standards set by the SAPP project, except when technological innovations allowed improvement in data collection procedures (e.g., the global positioning system (GPS)).

Manual laterality in anvil use: wild chimpanzees cracking Strychnos fruits.

Wild chimpanzees (Pan troglodytes schweinfurthii) at Gombe National Park, Tanzania, smash open the hard-shelled fruits of Strychnos spp. on anvils of stone or woody vegetation. In this food-processing task, most of the apes show exclusive use of one hand or the other, that is, strong individual hand preferences. Such extreme laterality of manual functioning corresponds to Level 3 on a five-level descriptive model of lateralisation that appears to reflect the increasingly skillful demands of object manipulation. There is precise congruence in laterality between anvil use and another subsistence task involving elementary technology-termite fishing-in almost all cases.

The inductive properties of mesoderm suggest that the neural crest cells are specified by a BMP gradient.

We have analyzed the role of mesoderm in the induction of the neural crest in Xenopus using expression of neural plate (Xsox-2) and neural crest (Xslug and ADAM). Conjugation experiments using different kinds of mesoderm together with embryonic dissection experiments suggest that the dorsolateral mesoderm is capable of specifically inducing neural crest cells. Neural crest markers can be induced in competent ectoderm at varying distances from the inducing mesoderm, with dorsal tissue inducing neural crest at a distance while dorsolateral tissue only induces neural crest directly in adjacent ectoderm. The results suggest that dorsal mesoderm has a high level of inducer and dorsolateral mesoderm has a lower level, consistent with a inductive gradient. We explored the possible role of BMP and noggin in the generation of such a hypothetical gradient and found that: (1) progressively higher levels of BMP activity are sufficient for the specification of neural plate, neural crest, and nonneural cells, respectively; (2) progressively higher levels of noggin are able to induce neural crest at greater distances from the source of inducer; and (3) modification of the levels of BMP activity causes induction of the neural crest in absence of neural plate, suggesting independent induction of these two tissues. We propose a model in which a gradient of BMP activity is established in the ectoderm by interaction between BMP in the ectoderm and BMP inhibitors in the mesoderm. Neural crest is induced when a threshold level of BMP is attained in the ectoderm. The dorsolateral mesoderm produces either BMP inhibitors or a specific neural crest inducer, with low BMP activity inducing neural plate while high BMP activity induces epidermis.

Inhibition of mesoderm formation by follistatin.

Mesoderm induction requires interaction between cells of the animal and vegetal hemispheres of the embryo. Several molecules have been proposed as candidates for mesoderm-inducing signals, with activin a particularly strong candidate. However, it has not been possible to inhibit mesoderm formation in vivo by specifically blocking activin action. Follistatin is able to inhibit the action of activin but not that of the mature region of Vg1, a member of the transforming growth factor beta family. Follistatin therefore provides a useful tool for distinguishing between signalling by these two factors. We have overexpressed Xenopus follistatin mRNA and analysed the expression of several mesodermal markers. Our results show an inhibition of mesodermal formation by follistatin in a concentration-dependent manner, showing the requirement of activin for mesodermal induction.

Methodology of motor skill and laterality: new test of hand preference in Macaca nemestrina.

Ten female pig-tailed macaques (Macaca nemestrina) were tested for hand preference and hand skill (i.e., speed of performance and error rate). The experimental task was naturalistic, calling for adaptive manual skills and fine manipulation: the monkeys had to remove small food rewards embedded in a vertical array, and precision opposition of thumb and forefinger was needed to extract each pellet. Each monkey was tested 10 times on 10 different days. The results indicated individual hand preference rather than population-level handedness; however, a tendency toward right predominance was found. The results on hand skill showed a relation between error rate and hand preference, as the preferred hand made fewer errors. A different and unexpected finding was obtained when skill was evaluated in terms of speed of performance: in adult subjects the left hand was quicker than the right. Therefore, different kinds of skill showed different patterns in relation to hand preference.

Splenic implant in the jejunum: radiographic and pathologic findings.

We report a patient in whom barium studies and computed tomography revealed an intramural mass in the jejunum that consisted pathologically of ectopic splenic tissue. Because the patient had a prior splenectomy, the lesion probably represented splenosis rather than an accessory spleen. When intramural lesions are detected on barium studies in patients who have had prior abdominal trauma or splenectomy, 99mTc-tagged, heated-red blood cell scintigraphy may be performed to confirm the diagnosis, thereby eliminating the need for surgery in these patients.

Independent effects of fiber and protein on colonic luminal ammonia concentration.

The potential interactive effects of protein and fiber on cecal and colonic surface areas, colonic luminal ammonia concentrations, luminal pH and blood indices of nitrogen metabolism were tested using two levels of protein (8% and 24%) and two types of fiber (8% pectin or cellulose). Pectin supplementation resulted in larger cecal surface areas and longer large intestines than those of rats fed fiber-free or cellulose-supplemented diets. All high protein diets resulted in total large bowel luminal ammonia (NH3 + NH4+) concentrations that were twice as high as their low protein counterparts (P less than 0.05). The effect of fiber on ammonia concentration depended on the fiber type. In the distal colon, pectin-fed animals had three times the ammonia concentration of the fiber-free animals, and 4-5 times the ammonia concentration of the cellulose-fed animals (P less than 0.001). Blood urea nitrogen values were higher in the high protein than in the low protein groups (P less than 0.05), and highest in the high protein/pectin animals (P less than 0.01). This study clearly demonstrates that luminal ammonia concentration is dependent upon both protein level and fiber type, and that a fermentable fiber (pectin), rather than decreasing colonic ammonia concentrations, actually increases them several-fold.