Gonadotrophins modulate hormone secretion and steady-state mRNA levels for activin receptors (type I, IIA, IIB) and inhibin co-receptor (betaglycan) in granulosa and theca cells from chicken prehierarchical and preovulatory follicles

Ovarian follicle development is regulated through endocrine and local mechanisms. Increasing evidence indicates roles for transforming growth factor beta superfamily members, including inhibins and activins. We recently identified divergent expression of mRNAs encoding activin receptors (ActR) and inhibin co-receptor betaglycan in chicken follicles at different stages of maturation. Here, we compare the actions of LH and FSH (0, 1, 10, 100 ng/ml) on levels of mRNA for ActRI, ActRIIA, ActRIIB and betaglycan in chicken granulosa and theca cells (GC and TC) from preovulatory (F1) and prehierarchical (6-8 mm) follicles. The expression of mRNAs for LH-R and FSH-R and production of inhibin A, oestradiol and progesterone were also quantified. FSH decreased ActRIIB and ActRI mRNA levels in 6-8 mm GC, whereas LH increased the mRNA levels. Both LH and FSH enhanced ActRIIA (5- and 8.5-fold) and betaglycan mRNA expression (2- and 3.5-fold) in 6-8 mm GC. In 6-8 mm TC, LH and FSH both increased the betaglycan mRNA level (7- and 3.5-fold respectively) but did not affect ActRI, ActRIIA and ActRIIB transcript levels. In F1 GC, both LH and FSH stimulated ActRI (2- and 2.4-fold), ActRIIB (3.2- and 2.7-fold) and betaglycan (7- and 4-fold) mRNA levels, while ActRIIA mRNA was unaffected. In F1 TC, LH and FSH reduced ActRIIA (35-50%) and increased (4.5- and 7.6-fold) betaglycan mRNA, but had no effect on ActRI and ActRIIB transcript levels. Results support the hypothesis that expression of ActR and betaglycan are differentially regulated by gonadotrophins during follicle maturation in the hen. This may represent an important mechanism for fine-tuning follicle responsiveness to local and systemic activins and inhibins.

Differential expression of mRNAs encoding co-receptor (betaglycan) and activin type-I preovulatory and prehierarchical follicles of the putative inhibin and type-II receptors in the laying hen ovary

Ovarian follicle development is primarily regulated by an interplay between the pituitary gonadotrophins, LH and FSH, and ovary-derived steroids. Increasing evidence implicates regulatory roles of transforming growth factor-beta (TGF beta) superfamily members, including inhibins and activins. The aim of this study was to identify the expression of mRNAs encoding key receptors of the inhibin/activin system in ovarian follicles ranging from 4 mm in diameter to the dominant F1 follicle (similar to 40 turn). Ovaries were collected (n=16) from inid-sequence hens maintained on a long-day photoschedule (16h of light:8 h of darkness). All follicles removed were dissected into individual granulosa and thecal layers. RNA was extracted and cDNA synthesized. Real-time quantitative PCR was used to quantify the expression of niRNA encoding betaglycan, activin receptor (ActR) subtypes (type-I, -IIA and -IIB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH); receptor expression data were normalized to GAPDH expression. Detectable levels of ActRI, -IIA and -IIB and the inhibin co-receptor (betaglycan) expression were found in all granulosa and thecal layers analysed. Granulosa ActRI mRNA peaked (P < 0(.)05) in 8-9(.)9 mm follicles, whereas ActRIIA rose significantly from 6-7(.)9 mm to 8-9(.)9 nun, before filling to F3/2; levels then rose sharply (3-fold) to F1 levels. Granulosa betaglycan niRNA expression rose 3-fold from 4-5(.)9 min to 8-9(.)9 mm, before falling 4-fold to F3/2; levels then rose sharply (4-fold) to F1 levels. ActRIIB levels did not vary significantly during follicular development. Thecal ActRI mRNA expression was similar from 4-7(.)9 mm then decreased significantly to a nadir at the F4 position, before increasing 2-fold to the F1 (P < 0(.)05). Although thecal ActRIIB and -IIA expression did not vary significantly from 4 nim to F3, ActRIIB expression increased significantly (2-fold) from F3 to F1 and ActIIA, increased 22-fold from F2 to F1 (P < 0(.)05). Thecal betaglycan fell to a nadir at F6 after follicle selection; levels then increased significantly to F2, before filling similar to 50% in the F I. In all follicles studied expression of betaglycan and ActRI (granulosa: 1-0(.)65, P < 0-001, n=144/group; theca: r=0(.)49, P < 0-001, n=144/group) was well correlated. No significant correlations were identified between betaglycan and ActRIIA or -IIB. Considering all follicles analysed, granulosa mRNA expression of betaglycan, ActRI ActRIIA and ActRIIB were all significantly lower than in corresponding thecal tissue (betaglycan, 11(.)4-fold; ActRIIB, 5(.)1-fold; ActR(.) 3-8-fold: ActRIIA, 2(.)8-fold). The co-localization of type-I and -II activin receptors and betaglycan on granulosa and thecal cells are consistent with a local auto/paracrine role of inhibins and activins in modulating ovarian follicle development, selection and progression in the domestic fowl.

PtdIns(5)P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection

The virulence factor IpgD, delivered into nonphagocytic cells by the type III secretion system of the pathogen Shigella flexneri, is a phosphoinositide 4-phosphatase generating phosphatidylinositol 5 monophosphate (PtdIns(5) P). We show that PtdIns(5) P is rapidly produced and concentrated at the entry foci of the bacteria, where it colocalises with phosphorylated Akt during the first steps of infection. Moreover, S. flexneri-induced phosphorylation of host cell Akt and its targets specifically requires IpgD. Ectopic expression of IpgD in various cell types, but not of its inactive mutant, or addition of short-chain penetrating PtdIns(5) P is sufficient to induce Akt phosphorylation. Conversely, sequestration of PtdIns(5) P or reduction of its level strongly decreases Akt phosphorylation in infected cells or in IpgD-expressing cells. Accordingly, IpgD and PtdIns(5) P production specifically activates a class IA PI 3-kinase via a mechanism involving tyrosine phosphorylations. Thus, S. flexneri parasitism is shedding light onto a new mechanism of PI 3-kinase/Akt activation via PtdIns(5) P production that plays an important role in host cell responses such as survival.

Methylene spacer-regulated structural variation in cobalt(II/III) complexes with bridging acetate and Salen- or Salpn-type Schiff-base ligands

Two linear, trinuclear mixed-valence complexes, [Co-II{(mu-L-1)(mu-OAc)Co-III (OAc)}(2)] (1) and [Co-II(mu-L-2) (mu-OAc)Co-III(OAc)}(2)] (2) and two mononuclear Con' complexes [Co-III{L-3)(OAc)] (3), and [Co-III {L-4}(OAc)] (4) were prepared and the molecular structures of 1, 2 and 4 elucidated on the basis of X-ray crystallography [OAc = Acetate ion, H2L1 = H(2)Salen 1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene, H2L2 H2Me2-Salen = 2,7-bis(2-hydroxyphenyl)-2,6-diazaocta-2,6-diene, H2L3 = H(2)Salpn = 1,7-bis(2-hydroxyphenyl)-2,6-diazahepta1,6-diene, H2L4 = H(2)Me(2)Salpn = 2,8-bis(2-hydroxyphenyl)3,7-diazanona-2,7-dienel. In complexes I and 2, the acetate groups show both monodentate and bridging bidentate coordination modes, whereas chelating bidentate acetate is present in 4. The terminal (CoN2O4)-N-III centres in 1 and 2 exhibit uniform facial arrangements of both non-bridged N2O and bridging O-3 donor sets and the Co-II centre is coordinated to six (four phenoxo and two acetato) oxygen atoms of the bridging ligands. The effective magnetic moment at room temperature corresponds to the presence of high-spin Coll in both 1 and 2. The complexes 1 and 2 are thus Co-III(S = 0)Co-II(S = 3/2)-Co-II(S = 0) trimers. Complexes 3 and 4 are monomeric and diamagnetic containing low-spin Co-III(S = 0) with chelating tetradentate Schiff base and bidentate acetate. Calculations based on DFT rationalise the formation of trinuclear or monomiclear complexes. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).

Synthesis and evaluation of a solid supported molecular tweezer type receptor for cholesterol

A new macroporous stationary phase bearing 'tweezer' receptors that exhibit specificity for cholesterol has been constructed from rigid multifunctional vinylic monomers derived from 3,5-dibromobenzoic acid, propargyl alcohol and cholesterol. The synthesis of the novel tweezer monomer that contains two cholesterol receptor arms using palladium mediated Sonogashira methodologies and carbonate couplings is reported. The subsequent co-polymerisation of this tweezer monomer with a range of cross-linking agents via a 'pseudo' molecular imprinting approach afforded a diverse set of macroporous materials. The selectivity and efficacy of these materials for cholesterol binding was assessed using a chromatographic screening process. The optimum macroporous stationary phase material composition was subsequently used to construct monolithic solid phase extraction columns for use in the selective extraction of cholesterol from multi-component mixtures of structurally related steroids.

Development of novel brush-type chiral stationary phases based on terpenoid selectors: HPLC evaluation and theoretical investigation of enantioselective binding interactions

The terpenoid chiral selectors dehydroabietic acid, 12,14-dinitrodehydroabietic acid and friedelin have been covalently linked to silica gel yielding three chiral stationary phases CSP 1, CSP 2 and CSP 3, respectively. The enantiodiscriminating capability of each one of these phases was evaluated by HPLC with four families of chiral aromatic compounds composed of alcohols, amines, phenylalanine and tryptophan amino acid derivatives and beta-lactams. The CSP 3 phase, containing a selector with a large friedelane backbone is particularly suitable for resolving free alcohols and their derivatives bearing fluorine substituents, while CSP 2 with a dehydroabietic architecture is the only phase that efficiently discriminates 1, 1'-binaphthol atropisomers. CSP 3 also gives efficient resolution of the free amines. All three phases resolve well the racemates of N-trifluoracetyl and N-3,5-dinitrobenzoyl phenylalanine amino acid ester derivatives. Good enantioseparation of beta-lactams and N-benzoyl tryptophan amino acid derivatives was achieved on CSP 1. In order to understand the structural factors that govern the chiral molecular recognition ability of these phases, molecular dynamics simulations were carried out in the gas phase with binary diastereomeric complexes formed by the selectors of CSP 1 and CSP 2 and several amino acid derivatives. Decomposition of molecular mechanics energies shows that van der Waals interactions dominate the formation of the diastereomeric transient complexes while the electrostatic binding interactions are primarily responsible for the enantioselective binding of the (R)- and (S)-analytes. Analysis of the hydrogen bonds shows that electrostatic interactions are mainly associated with the formation of N-(HO)-O-...=C enantio selective hydrogen bonds between the amide binding sites from the selectors and the carbonyl groups of the analytes. The role of mobile phase polarity, a mixture of n-hexane and propan-2-ol in different ratios, was also evaluated through molecular dynamics simulations in explicit solvent. (c) 2006 Elsevier Ltd. All rights reserved.

Synthesis, reactivity, and X-ray crystal structure of some mixed-ligand oxovanadium(V) complexes: first report of binuclear oxovanadium(V) complexes containing 4,4 '-Bipyridine type bridge

Reaction of the tridentate ONO Schiff-base ligand 2-hydroxybenzoylhydrazone of 2-hydroxybenzoylhydrazine (H2L) with VO(acac)(2) in ethanol medium produces the oxoethoxovanadium(V) complex [VO(OEt)L] (A), which reacts with pyridine to form [VO(OEt)L center dot(py)] (1). Complex 1 is structurally characterized. It has a distorted octahedral O4N2 coordination environment around the V(V) acceptor center. Both complexes A and 1 in ethanol medium react with neutral monodentate Lewis bases 2-picoline, 3-picoline, 4-picoline, 4-amino pyridine, imidazole, and 4-methyl imidazole, all of which are stronger bases than pyridine, to produce dioxovanadium(V) complexes of general formula BH[VO2L]. Most of these dioxo complexes are structurally characterized, and the complex anion [VO2L](-) is found to possess a distorted square pyramidal structure. When a solution/suspension of a BH[VO2L] complex in an alcohol (ROH) is treated with HCl in the same alcohol, it is converted into the corresponding monooxoalkoxo complex [ O(OR)L], where R comes from the alcohol used as the reaction medium. Both complexes A and 1 produce the 4,4'-bipyridine-bridged binuclear complex [VO(OEt)L](2)(mu-4,4'-bipy) (2), which, to the best of our knowledge, represents the first report of a structurally characterized 4,4'-bipyridine-bridged oxovanadium(V) binuclear complex. Two similar binuclear oxovanadium(V) complexes 3 and 4 are also synthesized and characterized. All these binuclear complexes (2-4), on treatment with base B, produce the corresponding mononuclear dioxovanadium(V) complexes (5-10).

Using bargaining-game theory for negotiating concession period for BOT-type contract

This paper extends the build-operate-transfer (BOT) concession model (BOTCcM) to a new method for identifying a concession period by using bargaining-game theory. Concession period is one of the most important decision variables in arranging a BOT-type contract, and there are few methodologies available for helping to determine the value of this variable. The BOTCcM presents an alternative method by which a group of concession period solutions are produced. Nevertheless, a typical weakness in using BOTCcM is that the model cannot recommend a specific time span for concessionary. This paper introduces a new method called BOT bargaining concession model (BOTBaC) to enable the identification of a specific concession period, which takes into account the bargaining behavior of the two parties concerned in engaging a BOT contract, namely, the investor and the government concerned. The application of BOTBaC is demonstrated through using an example case.

Differential expression of mRNAs encoding co-receptor (betaglycan) and activin type-I preovulatory and prehierarchical follicles of the putative inhibin and type-II receptors in the laying hen ovary

Ovarian follicle development is primarily regulated by an interplay between the pituitary gonadotrophins, LH and FSH, and ovary-derived steroids. Increasing evidence implicates regulatory roles of transforming growth factor-beta (TGF beta) superfamily members, including inhibins and activins. The aim of this study was to identify the expression of mRNAs encoding key receptors of the inhibin/activin system in ovarian follicles ranging from 4 mm in diameter to the dominant F1 follicle (similar to 40 turn). Ovaries were collected (n=16) from inid-sequence hens maintained on a long-day photoschedule (16h of light:8 h of darkness). All follicles removed were dissected into individual granulosa and thecal layers. RNA was extracted and cDNA synthesized. Real-time quantitative PCR was used to quantify the expression of niRNA encoding betaglycan, activin receptor (ActR) subtypes (type-I, -IIA and -IIB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH); receptor expression data were normalized to GAPDH expression. Detectable levels of ActRI, -IIA and -IIB and the inhibin co-receptor (betaglycan) expression were found in all granulosa and thecal layers analysed. Granulosa ActRI mRNA peaked (P < 0(.)05) in 8-9(.)9 mm follicles, whereas ActRIIA rose significantly from 6-7(.)9 mm to 8-9(.)9 nun, before filling to F3/2; levels then rose sharply (3-fold) to F1 levels. Granulosa betaglycan niRNA expression rose 3-fold from 4-5(.)9 min to 8-9(.)9 mm, before falling 4-fold to F3/2; levels then rose sharply (4-fold) to F1 levels. ActRIIB levels did not vary significantly during follicular development. Thecal ActRI mRNA expression was similar from 4-7(.)9 mm then decreased significantly to a nadir at the F4 position, before increasing 2-fold to the F1 (P < 0(.)05). Although thecal ActRIIB and -IIA expression did not vary significantly from 4 nim to F3, ActRIIB expression increased significantly (2-fold) from F3 to F1 and ActIIA, increased 22-fold from F2 to F1 (P < 0(.)05). Thecal betaglycan fell to a nadir at F6 after follicle selection; levels then increased significantly to F2, before filling similar to 50% in the F I. In all follicles studied expression of betaglycan and ActRI (granulosa: 1-0(.)65, P < 0-001, n=144/group; theca: r=0(.)49, P < 0-001, n=144/group) was well correlated. No significant correlations were identified between betaglycan and ActRIIA or -IIB. Considering all follicles analysed, granulosa mRNA expression of betaglycan, ActRI ActRIIA and ActRIIB were all significantly lower than in corresponding thecal tissue (betaglycan, 11(.)4-fold; ActRIIB, 5(.)1-fold; ActR(.) 3-8-fold: ActRIIA, 2(.)8-fold). The co-localization of type-I and -II activin receptors and betaglycan on granulosa and thecal cells are consistent with a local auto/paracrine role of inhibins and activins in modulating ovarian follicle development, selection and progression in the domestic fowl.

Analysis of chain and blood group type and branching pattern of sialylated oligosaccharides by negative ion electrospray tandem mass spectrometry

We previously reported sequence determination of neutral oligosaccharides by negative ion electrospray tandem mass spectrometry on a quadrupole-orthogonal time-of-flight instrument with high sensitivity and without the need of derivatization. In the present report, we extend our strategies to sialylated oligosaccharides for analysis of chain and blood group types together with branching patterns. A main feature in the negative ion mass spectrometry approach is the unique double glycosidic cleavage induced by 3-glycosidic substitution, producing characteristic D-type fragments which can be used to distinguish the type 1 and type 2 chains, the blood group related Lewis determinants, 3,6-disubstituted core branching patterns, and to assign the structural details of each of the branches. Twenty mono- and disialylated linear and branched oligosaccharides were used for the investigation, and the sensitivity achieved is in the femtomole range. To demonstrate the efficacy of the strategy, we have determined a novel complex disialylated and monofucosylated tridecasaccharide that is based on the lacto-N-decaose core. The structure and sequence assignment was corroborated by :methylation analysis and H-1 NMR spectroscopy.

Dissociating mere exposure and repetition priming as a function of word type

The mere exposure effect is defined as enhanced attitude toward a stimulus that has been repeatedly exposed. Repetition priming is defined as facilitated processing of a previously exposed stimulus. We conducted a direct comparison between the two phenomena to test the assumption that the mere exposure effect represents an example of repetition priming. In two experiments, having studied a set of words or nonwords, participants were given a repetition priming task (perceptual identification) or one of two mere exposure (affective liking or preference judgment) tasks. Repetition printing was obtained for both words and nonwords, but only nonwords produced a mere exposure effect. This demonstrates a key boundary for observing the mere exposure effect, one not readily accommodated by a perceptual representation systems (Tulving & Schacter, 1990) account, which assumes that both phenomena should show some sensitivity to nonwords and words.

Effect of changing the amount and type of fat and carbohydrate on insulin sensitivity and cardiovascular risk: the RISCK (Reading, Imperial, Surrey, Cambridge, and Kings) trial

Background: Insulin sensitivity (Si) is improved by weight loss and exercise, but the effects of the replacement of saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) or carbohydrates of high glycemic index (HGI) or low glycemic index (LGI) are uncertain. Objective: We conducted a dietary intervention trial to study these effects in participants at risk of developing metabolic syndrome. Design: We conducted a 5-center, parallel design, randomized controlled trial [RISCK (Reading, Imperial, Surrey, Cambridge, and Kings)]. The primary and secondary outcomes were changes in Si (measured by using an intravenous glucose tolerance test) and cardiovascular risk factors. Measurements were made after 4 wk of a high-SFA and HGI (HS/HGI) diet and after a 24-wk intervention with HS/HGI (reference), high-MUFA and HGI (HM/HGI), HM and LGI (HM/LGI), low-fat and HGI (LF/HGI), and LF and LGI (LF/LGI) diets. Results: We analyzed data for 548 of 720 participants who were randomly assigned to treatment. The median Si was 2.7 × 10−4 mL · μU−1 · min−1 (interquartile range: 2.0, 4.2 × 10−4 mL · μU−1 · min−1), and unadjusted mean percentage changes (95% CIs) after 24 wk treatment (P = 0.13) were as follows: for the HS/HGI group, −4% (−12.7%, 5.3%); for the HM/HGI group, 2.1% (−5.8%, 10.7%); for the HM/LGI group, −3.5% (−10.6%, 4.3%); for the LF/HGI group, −8.6% (−15.4%, −1.1%); and for the LF/LGI group, 9.9% (2.4%, 18.0%). Total cholesterol (TC), LDL cholesterol, and apolipoprotein B concentrations decreased with SFA reduction. Decreases in TC and LDL-cholesterol concentrations were greater with LGI. Fat reduction lowered HDL cholesterol and apolipoprotein A1 and B concentrations. Conclusions: This study did not support the hypothesis that isoenergetic replacement of SFAs with MUFAs or carbohydrates has a favorable effect on Si. Lowering GI enhanced reductions in TC and LDL-cholesterol concentrations in subjects, with tentative evidence of improvements in Si in the LF-treatment group. This trial was registered at clinicaltrials.gov as ISRCTN29111298.

A hydrogen-1 nuclear magnetic resonance, mass spectral and extended Hückel study of some olefin complexes of rhodium(I) and iridium(I) and the crystal and molecular structure of η4-2,4-dimethylpenta-1,4-diene(η5-formylcyclopentadienyl)rhodium(I)

A 1H NMR study of monosubstituted η-cyclopentadienyl-rhodium(I) complexes of type LLRh(C5H4X) and -iridium(I) complexes of type L2Ir(C5H4X) (L = ethene, LL = 1,3- or 1,5-diolefin; X = C(C6H5)3, CHO, or COOCH3) has been carried out. For complexes of both metals in which the neutral ligand is ethene or a non-conjugated diolefin the NMR spectra of the cyclopentadienyl protons are unusual in that H(2), H(5) resonate to high field either at room temperature or below. The corresponding NMR spectra for the cyclopentadienyl ring protons of complexes where the neutral ligand is a conjugated diene are, with one exception, normal. A single crystal X-ray structural analysis of (η4-2,4-dimethylpenta-1,4-diene)(η5-formylcyclopentadienyl)rhodium(I) (which exhibits an abnormal 1H NMR spectrum) reveals substantial localisation of electron density in the C(3)C(4) Cp ring bond (1.283(33) Å) which may be consistent with a contribution from an ‘allyl-ene’ rotamer to the ring—metal bonding scheme. An extended Hückel calculation with self consistent charge iteration was performed on this complex. The results predict a greater Mulliken overlap population for the C(3)C(4) bond in the cyclopentadienyl ring and show that the localisation is dependent on both the Cp ring substituent and the nature of the diolefin. The mass spectral fragmentation patterns of some representative diene complexes of iridium(I) and rhodium(I) are presented.

Comparison of the rheology of mozzarella-type curd made from buffalo and cows’ milk

Curd rheology and calcium distribution in buffalo and cows’ milk, were compared at their natural pH and during acidification (pH 6.5–5.6). Buffalo milk displays a curd structure and rheology different from that of cows’ milk and the casein-bound calcium, as well as the contents of fat, protein and calcium, are also higher. Due to these higher amounts of casein-bound calcium, the overall curd strength with buffalo milk (as indicated by the dynamic moduli) was higher, at similar pH values, than those of equivalent gels produced from cows’ milk. The curd rheology was adversely affected at lower pH (5.8–5.6) in both of the milk types, due to the loss of casein-bound calcium from casein micelles. The degree of solubilisation of calcium in buffalo milk during acidification is quite different from that observed in cows’ milk with a lower proportion of the calcium being solubilised in the former. The maximum curd firmness was obtained at pH 6.0 in both milk types. For both species, these rheological and micellar changes were qualitatively the same but quantitatively different, due to the different milk compositions.

Effective elements of cognitive behaviour therapy for psychosis: results of a novel type of subgroup analysis based on principal stratification

Background. Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology. Method. The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization. Results. Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective. Conclusions. Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment.