Proprioception and muscle torque deficits in children with hypermobility syndrome.

OBJECTIVES: Sensorimotor deficits such as impaired joint proprioception and muscle weakness have been found in association with hypermobility syndrome (HMS) in adults. HMS is more common in children than adults, yet such deficits have not been adequately investigated in paediatric populations. It is therefore uncertain as to what sensorimotor deficits are present in children with HMS. This study investigated knee joint proprioception and muscle torque in healthy children and those with HMS. METHODS: Thirty-seven healthy children (mean age +/- s.d. = 11.5 +/- 2.6 yrs) and 29 children with HMS (mean age +/- s.d. = 11.9 +/- 1.8 yrs) participated in this study. Knee joint kinaesthesia (JK) and joint position sense (JPS) were measured, with the absolute angular error (AAE) calculated as the absolute difference between the target and perceived angles. Knee extensor and flexor muscle torque was assessed and normalized to body mass. Mann-Whitney U-tests were performed to compare JK, JPS and muscle torque between the two groups. RESULTS: Children with HMS had significantly poorer JK and JPS compared with the controls (both P < 0.001). Knee extensor and flexor muscle torque was also significantly reduced (both P < 0.001) in children with HMS compared with their healthy counterparts. CONCLUSIONS: The findings of this study demonstrated that knee joint proprioception was impaired in children with HMS. They also had weaker knee extensor and flexor muscles than healthy controls. Clinicians should be aware of these identified deficits in children with HMS, and a programme of proprioceptive training and muscle strengthening may be indicated.

Separation of A- versus C-nociceptive inputs into spinal-brainstem circuits.

This study was designed to determine the organization of nociceptive inputs with different behavioral significance into spinal-brainstem circuits in the rat. Induction of Fos protein was used to localize spinal dorsal horn and hypothalamic neurons activated by noxious heating of the hind paw dorsum at rates known to preferentially activate C- or A-heat nociceptors. This was combined with retrograde transport of cholera toxin subunit B from the dorsolateral/lateral- (DL/L-) or the ventrolateral- (VL-) periaqueductal gray (PAG) in order to map the organization of A- and C-fiber input to spinal-brainstem circuits. The majority of dorsal horn heat-activated neurons were located in laminae I and II. A significantly larger proportion of C-fiber-activated neurons projected to the VL-PAG (P<0.05) compared with its DL/L-sector. In contrast, there was no columnar separation in the projections of A-fiber-activated neurons. However, a significantly greater proportion of A-fiber-activated neurons (P<0.05) were retrogradely labeled from the DL/L-PAG, when compared with C-fiber-activated neurons. A large proportion (25-50%) of A- and C-fiber-activated neurons in the lateral spinal nucleus projected to the PAG. A-fiber-activated neurons were found throughout the rostral hypothalamus but those projecting to the PAG were focused in the lateral area of the anterior hypothalamus (LAAH), from where approximately 20% projected to the VL-PAG, which was significantly more than to the DL/L PAG (P<0.05). We hypothesize that the organization of A- versus C-fiber inputs to the PAG enables the coordination of coping strategies appropriate to meet the demands imposed by these different noxious stimuli. Hypothalamic-PAG projections activated by A-fiber inputs did not reflect this level of organization and we suggest that this may relate to their role in thermoregulation as opposed to autonomic responses to particular nociceptive inputs.

Asymmetric binding of the high-affinity Q(H)(*)(-) ubisemiquinone in quinol oxidase (bo3) from Escherichia coli studied by multifrequency electron paramagnetic resonance spectroscopy.

Ubiquinone-2 (UQ-2) selectively labeled with (13)C (I =(1)/(2)) at either the position 1- or the 4-carbonyl carbon is incorporated into the ubiquinol oxidase bo(3) from Escherichia coli in which the native quinone (UQ-8) has been previously removed. The resulting stabilized anion radical in the high-affinity quinone-binding site (Q(H)(*)(-)) is investigated using multifrequency (9, 34, and 94 GHz) electron paramagnetic resonance (EPR) spectroscopy. The corresponding spectra reveal dramatic differences in (13)C hyperfine couplings indicating a strongly asymmetric spin density distribution over the quinone headgroup. By comparison with previous results on labeled ubisemiquinones in proteins as well as in organic solvents, it is concluded that Q(H)(*)(-) is most probably bound to the protein via a one-sided hydrogen bond or a strongly asymmetric hydrogen-bonding network. This observation is discussed with regard to the function of Q(H) in the enzyme and contrasted with the information available on other protein-bound semiquinone radicals.

A new facile method for spin-labeling of oligonucleotides.

A new facile method for spin-labeling suitable for DNA and RNA oligonucleotides is presented. The nitroxide 3-ethenyl-2,2,5,5-tetramethyl-pyrrolin-1-yloxy was directly introduced during automated solid-phase synthesis by a Pd(0) cross coupling reaction. The main advantages of this procedure are the small amount of spin-label needed for the derivatisation of the oligonucleotide and the high coupling efficiency on the solid phase.

Mutations in both sides of the photosystem I reaction center identify the phylloquinone observed by electron paramagnetic resonance spectroscopy.

The core of photosystem I (PS1) is composed of the two related integral membrane polypeptides, PsaA and PsaB, which bind two symmetrical branches of cofactors, each consisting of two chlorophylls and a phylloquinone, that potentially link the primary electron donor and the tertiary acceptor. In an effort to identify amino acid residues near the phylloquinone binding sites, all tryptophans and histidines that are conserved between PsaA and PsaB in the region of the 10th and 11th transmembrane alpha-helices were mutated in Chlamydomonas reinhardtii. The mutant PS1 reaction centers appear to assemble normally and possess photochemical activity. An electron paramagnetic resonance (EPR) signal attributed to the phylloquinone anion radical (A(1)(-)) can be observed either transiently or after illumination of reaction centers with pre-reduced iron-sulfur clusters. Mutation of PsaA-Trp(693) to Phe resulted in an inability to photo-accumulate A(1)(-), whereas mutation of the analogous tryptophan in PsaB (PsaB-Trp(673)) did not produce this effect. The PsaA-W693F mutation also produced spectral changes in the time-resolved EPR spectrum of the P(700)(+) A(1)(-) radical pair, whereas the analogous mutation in PsaB had no observable effect. These observations indicate that the A(1)(-) phylloquinone radical observed by EPR occupies the phylloquinone-binding site containing PsaA-Trp(693). However, mutation of either tryptophan accelerated charge recombination from the terminal Fe-S clusters.

Pulsed EPR spectroscopy: biological applications.

Pulsed electron paramagnetic resonance (EPR) methods such as ESEEM, PELDOR, relaxation time measurements, transient EPR, high-field/high-frequency EPR, and pulsed ENDOR, have been used successfully to investigate the local structure and dynamics of paramagnetic centers in biological samples. These methods allow different contributions to the EPR spectra to be distinguished and can help unravel complicated EPR spectra consisting of overlapping resonance lines, as are often found in disordered protein samples. The basic principles, specific potentials, technical requirements, and limitations of these advanced EPR techniques will be reviewed together with recent applications to metal centers, organic radicals, and spin labels in proteins.

QH*- ubisemiquinone radical in the bo3-type ubiquinol oxidase studied by pulsed electron paramagnetic resonance and hyperfine sublevel correlation spectroscopy.

The high-affinity QH ubiquinone-binding site in the bo(3) ubiquinol oxidase from Escherichia coli has been characterized by an investigation of the native ubiquinone radical anion QH(*-) by pulsed electron paramagnetic resonance (EPR) spectroscopy. One- and two-dimensional electron spin-echo envelope modulation (ESEEM) spectra reveal strong interactions of the unpaired electron of QH(*-) with a nitrogen nucleus from the surrounding protein matrix. From analysis of the experimental data, the (14)N nuclear quadrupolar parameters have been determined: kappa = e(2)qQ/4h = 0.93 MHz and eta = 0.50. This assignment is confirmed by hyperfine sublevel correlation (HYSCORE) spectroscopy. On the basis of a comparison of these data with those obtained previously for other membrane-protein bound semiquinone radicals and model systems, this nucleus is assigned to a protein backbone nitrogen. This result is discussed with regard to the location and potential function of QH in the enzyme.

Chlorophyll and carotenoid radicals in photosystem II studied by pulsed ENDOR.

The stable carotenoid cation radical (Car(*+)) and chlorophyll cation radical (Chl(Z)(*+)) in photosystem II (PS II) have been studied by pulsed electron nuclear double resonance (ENDOR) spectroscopy. The spectra were essentially the same for oxygen-evolving PS II and Mn-depleted PS II. The radicals were generated by illumination given at low temperatures, and the ENDOR spectra were attributed to Car(*)(+) and Chl(Z)(*+) on the basis of their characteristic behavior with temperature as demonstrated earlier [Hanley et al. (1999) Biochemistry 38, 8189-8195]: i.e., (a) the Car(*)(+) alone was generated by illumination at < or =20 K, while Chl(Z)(*+) alone was generated at 200 K, and (b) warming of the sample containing the Car(*+) to 200 K resulted in the loss of the signal attributable to Car(*+) and its replacement by a spectrum attributable to the Chl(Z)(*+). A map of the hyperfine structure of Car(*+) in PS II and in organic solvent was obtained. The largest observed hyperfine splitting for Car(*+) in either environment was in the order of 8-9 MHz. Thus, the spin density on the cation is proposed to be delocalized over the carotenoid molecule. The pulsed ENDOR spectrum of Chl(Z)(*)(+) was compared to that obtained from a Chl a cation in frozen organic solvent. The hyperfine coupling constants attributed to the beta-protons at position 17 and 18 are well resolved from Chl(Z)(*+) in PS II (10. 8 and 14.9 MHz) but not in Chl a(*+) in organic solvent (12.5 MHz). This suggests a more defined conformation of ring IV with respect to the rest of the tetrapyrrole ring plane of Chl(Z)(*+) than Chl a(*+) probably induced by the protein matrix.

Electron paramagnetic resonance studies of zinc-substituted reaction centers from Rhodopseudomonas viridis.

The primary quinone acceptor radical anion Q(A)(-)(*) (a menaquinone-9) is studied in reaction centers (RCs) of Rhodopseudomonas viridis in which the high-spin non-heme Fe(2+) is replaced by diamagnetic Zn(2+). The procedure for the iron substitution, which follows the work of Debus et al. [Debus, R. J., Feher, G., and Okamura, M. Y. (1986) Biochemistry 25, 2276-2287], is described. In Rps. viridisan exchange rate of the iron of approximately 50% +/- 10% is achieved. Time-resolved optical spectroscopy shows that the ZnRCs are fully competent in charge separation and that the charge recombination times are similar to those of native RCs. The g tensor of Q(A)(-)(*) in the ZnRCs is determined by a simulation of the EPR at 34 GHz yielding g(x) = 2.00597 (5), g(y) = 2.00492 (5), and g(z) = 2.00216 (5). Comparison with a menaquinone anion radical (MQ(4)(-)(*)) dissolved in 2-propanol identifies Q(A)(-)(*) as a naphthoquinone and shows that only one tensor component (g(x)) is predominantly changed in the RC. This is attributed to interaction with the protein environment. Electron-nuclear double resonance (ENDOR) experiments at 9 GHz reveal a shift of the spin density distribution of Q(A)(-)(*) in the RC as compared with MQ(4)(-)(*) in alcoholic solution. This is ascribed to an asymmetry of the Q(A) binding site. Furthermore, a hyperfine coupling constant from an exchangeable proton is deduced and assigned to a proton in a hydrogen bond between the quinone oxygen and surrounding amino acid residues. By electron spin-echo envelope modulation (ESEEM) techniques performed on Q(A)(-)(*) in the ZnRCs, two (14)N nuclear quadrupole tensors are determined that arise from the surrounding amino acids. One nitrogen coupling is assigned to a N(delta)((1))-H of a histidine and the other to a polypeptide backbone N-H by comparison with the nuclear quadrupole couplings of respective model systems. Inspection of the X-ray structure of Rps. viridis RCs shows that His(M217) and Ala(M258) are likely candidates for the respective amino acids. The quinone should therefore be bound by two H bonds to the protein that could, however, be of different strength. An asymmetric H-bond situation has also been found for Q(A)(-)(*) in the RC of Rhodobacter sphaeroides. Time-resolved electron paramagnetic resonance (EPR) experiments are performed on the radical pair state P(960)(+) (*)Q(A)(-)(*) in ZnRCs of Rps. viridis that were treated with o-phenanthroline to block electron transfer to Q(B). The orientations of the two radicals in the radical pair obtained from transient EPR and their distance deduced from pulsed EPR (out-of-phase ESEEM) are very similar to the geometry observed for the ground state P(960)Q(A) in the X-ray structure [Lancaster, R., Michel, H. (1997) Structure 5, 1339].

Effects of copper and zinc ions on photosystem II studied by EPR spectroscopy.

The effect of Zn(2+) or Cu(2+) ions on Mn-depleted photosystem II (PS II) has been investigated using EPR spectroscopy. In Zn(2+)-treated and Cu(2+)-treated PS II, chemical reduction with sodium dithionite gives rise to a signal attributed to the plastosemiquinone, Q(A)(*)(-), the usual interaction with the non-heme iron being lost. The signal was identified by Q-band EPR spectroscopy which partially resolves the typical g-anisotropy of the semiquinone anion radical. Illumination at 200 K of the unreduced samples gives rise to a single organic free radical in Cu(2+)-treated PS II, and this is assigned to a monomeric chlorophyll cation radical, Chl a(*)(+), based on its (1)H-ENDOR spectrum. The Zn(2+)-treated PS II under the same conditions gives rise to two radical signals present in equal amounts and attributed to the Chl a(*)(+) and the Q(A)(*)(-) formed by light-induced charge separation. When the Cu(2+)-treated PS II is reduced by sodium ascorbate, at >/=77 K electron donation eliminates the donor-side radical leaving the Q(A)(*)(-) EPR signal. The data are explained as follows: (1) Cu(2+) and Zn(2+) have similar effects on PS II (although higher concentrations of Zn(2+) are required) causing the displacement of the non-heme Fe(2+). (2) In both cases chlorophyll is the electron donor at 200 K. It is proposed that the lack of a light-induced Q(A)(*)(-) signal in the unreduced Cu(2+)-treated sample is due to Cu(2+) acting as an electron acceptor from Q(A)(*)(-) at low temperature, forming the Cu(+) state and leaving the electron donor radical Chl a(*)(+) detectable by EPR. (3) The Cu(2+) in PS II is chemically reducible by ascorbate prior to illumination, and the metal can therefore no longer act as an electron acceptor; thus Q(A)(*)(-) is generated by illumination in such samples. (4) With dithionite, both the Cu(2+) and the quinone are reduced resulting in the presence of Q(A)(*)(-) in the dark. The suggested high redox potential of Cu(2+) when in the Fe(2+) site in PS II is in contrast to the situation in the bacterial reaction center where it has been shown in earlier work that the Cu(2+) is unreduced by dithionite. It cannot be ruled out however that Q(A)-Cu(2+) is formed and a magnetic interaction is responsible for the lack of the Q(A)(-) signal when no exogenous reductant is present. With this alternative possibility, the effects of reductants would be explained as the loss of Cu(2+) (due to formation of Cu(+)) leading to loss of the Cu(2+) from the Fe(2+) site due to the binding equilibrium. The quite different binding and redox behavior of the metal in the iron site in PS II compared to that of the bacterial reaction center is presumably a further reflection of the differences in the coordination of the iron in the two systems.

Direct evidence for a tyrosine radical in the reaction of cytochrome c oxidase with hydrogen peroxide.

Cytochrome c oxidase (COX) catalyzes the reduction of oxygen to water, a process which is accompanied by the pumping of four protons across the membrane. Elucidation of the structures of intermediates in these processes is crucial for understanding the mechanism of oxygen reduction. In the work presented here, the reaction of H(2)O(2) with the fully oxidized protein at pH 6.0 has been investigated with electron paramagnetic resonance (EPR) spectroscopy. The results reveal an EPR signal with partially resolved hyperfine structure typical of an organic radical. The yield of this radical based on comparison with other paramagnetic centers in COX was approximately 20%. Recent crystallographic data have shown that one of the Cu(B) ligands, His 276 (in the bacterial case), is cross-linked to Tyr 280 and that this cross-linked tyrosine is ideally positioned to participate in dioxygen activation. Here selectively deuterated tyrosine has been incorporated into the protein, and a drastic change in the line shape of the EPR signal observed above has been detected. This would suggest that the observed EPR signal does indeed arise from a tyrosine radical species. It would seem also quite possible that this radical is an intermediate in the mechanism of oxygen reduction.

A systematic survey of conserved histidines in the core subunits of Photosystem I by site-directed mutagenesis reveals the likely axial ligands of P700.

The Photosystem I complex catalyses the transfer of an electron from lumenal plastocyanin to stromal ferredoxin, using the energy of an absorbed photon. The initial photochemical event is the transfer of an electron from the excited state of P700, a pair of chlorophylls, to a monomer chlorophyll serving as the primary electron acceptor. We have performed a systematic survey of conserved histidines in the last six transmembrane segments of the related polytopic membrane proteins PsaA and PsaB in the green alga Chlamydomonas reinhardtii. These histidines, which are present in analogous positions in both proteins, were changed to glutamine or leucine by site-directed mutagenesis. Double mutants in which both histidines had been changed to glutamine were screened for changes in the characteristics of P700 using electron paramagnetic resonance, Fourier transform infrared and visible spectroscopy. Only mutations in the histidines of helix 10 (PsaA-His676 and PsaB-His656) resulted in changes in spectroscopic properties of P700, leading us to conclude that these histidines are most likely the axial ligands to the P700 chlorophylls.

ESEEM study of the phyllosemiquinone radical A1.- in 14N- and 15N-labeled photosystem I.

The phyllosemiquinone radical of the photosystem I reaction center has been studied by electron spin echo envelope modulation (ESEEM) spectroscopy. A comparative analysis of ESEEM data of the semiquinone in 14N- and 15N-labeled PSI and numerical simulations demonstrate the existence of two protein nitrogen nuclei coupled to the semiquinone. One of the 14N couplings is characterized by a quadrupolar coupling constant e2qQ/4h of 0.77 MHz, an asymmetry parameter eta of 0.18, and a hyperfine coupling tensor with an almost pure isotropic hyperfine coupling, i.e. (Axx, Ayy, Azz) = (1.3, 1.3, 1.5 MHz). The second nitrogen coupling is characterized by a quadrupolar coupling constant e2qQ/4h of 0.45 MHz, an asymmetry parameter eta of 0.85, and a weak hyperfine coupling tensor with a dominant anisotropic part, i.e. (Axx, Ayy, Azz) = (-0.2, -0.2, 1.5 MHz). On the basis of a comparison of the 14N-ESEEM data with 14N-NQR and 14N-ESEEM data from the literature, the first coupled nitrogen is assigned to the indole nitrogen of a tryptophan residue. The coupling of the second nitrogen is much weaker and therefore more difficult to assign. However, the simulated spectrum best describes an amino nitrogen of a histidine, although the amide group of an asparagine or glutamine cannot be ruled out. The possible origins of teh nitrogen hyperfine coupling are discussed in terms of the amino acid residues thought to be close to the semiquinone in PSI.

Orientation of the phylloquinone electron acceptor anion radical in photosystem I.

The photosynthetic reaction center of photosystem I (PS I) contains a phylloquinone molecule (A1) which acts as a transient electron acceptor. In PS I form the cyanobacterium Synechocystis PCC 6803 under reducing conditions, we have photoaccumulated an EPR signal assigned to the phylloquinone radical anion. The phylloquinone EPR spectrum has been studied in oriented multilayers of PS I using EPR at 9 GHz. In addition, the phyllosemiquinone spectrum has been obtained at 283 GHz using high-field, high-frequency EPR spectroscopy. From the orientation dependence of the spectrum at 9 GHz and the resolved g values obtained at 283 GHz, the phyllosemiquinone ring plane was determined to be almost perpendicular to the membrane (76 degrees) while the oxygen-oxygen (O-O) axis of the quinone was found to make an approximate 63 degrees angle to the membrane plane. The orientation of the ring plane is similar to that determined for the quinone electron acceptor (QA) in the purple bacterial reaction center, while the orientation of the O-O axis is significantly different. The new orientation information, when taken with data in the literature, allows the position of the phylloquinone in the reaction center to be better defined.

Cognitive therapy and recovery from acute psychosis: a controlled trial. I. Impact on psychotic symptoms.

BACKGROUND: The application of cognitive therapy (CT) to psychosis is currently being developed in the UK. This paper reports a trial of CT in acute psychosis with the objective of hastening the resolution of positive symptoms and reducing residual symptoms. METHOD: Of 117 patients with acute non-affective psychosis, 69 satisfied inclusion criteria and 40 proceeded to stratified randomisation. The experimental intervention involving individual and group CT was compared with a group receiving matched hours of therapist input providing structured activities and informal support; routine pharmacotherapy was provided by clinicians blind to group allocation. Patients were monitored weekly using self-report and mental state assessments during admission and over the subsequent nine months. RESULTS: Both groups showed a decline in positive symptoms but this was more marked in the CT group (P < 0.001). At 9 months 5% of the CT group, v.56% of the control group, showed moderate or severe residual symptoms. CONCLUSION: CT appears to be a potent adjunct to pharmacotherapy and standard care for acute psychosis. Issues concerning internal and external validity of the study and opportunities for further research are discussed.

Cognitive therapy and recovery from acute psychosis: a controlled trial. II. Impact on recovery time.

BACKGROUND: A trial of CT in acute psychosis conducted by the authors has shown a significant impact on the rate and degree of recovery of positive symptoms, the focus of the intervention. This paper seeks to determine whether these effects generalise to other features of acute psychosis including dysphoria, insight and "low level' psychotic thinking which were not directly targeted. METHOD: Measures of dysphoria, insight and psychotic thinking were taken over a six-month period following presentation for acute psychosis. Using survival analysis, time to recovery from psychosis using three definitions of increasing stringency was compared between the CT and control group. RESULTS: CT was associated with a 25-50% reduction in recovery time depending on the definition used. CONCLUSION: The impact of the CT intervention extended beyond positive symptoms to include insight, dysphoria and "low level' psychotic thinking. Nevertheless this kind of "clinical' recovery required a median of 20 weeks to complete. Implications for clinical models of acute care are discussed.

EPR and ENDOR investigation of the primary electron acceptor radical anion QA.- in iron-depleted photosystem II membrane fragments.

Photosystem II (PS II) membrane fragments were treated with trypsin at pH = 7.4 followed by incubation with o-phenanthroline and lithium perchlorate. This procedure removes and/or decouples the non-heme Fe2+ associated with the quinones QA and QB in the PS II reaction center (RC). Treatment of such samples (referred to as iron-depleted) with sodium dithionite or illumination in the presence of dichlorophenol indophenol (DCIP) and sodium ascorbate yielded EPR spectra similar to those of the plastoquinone-9 (PQ-9) radical anion generated in organic solvents. Q-band EPR yielded the principal values of the g-tensor for PQ-9.- in 2-propanol and QA.- in PS II. Electron nuclear double resonance (ENDOR) experiments were performed both on PQ-9.- in vitro and on QA.- in the iron-depleted PS II samples. For the former a complete set of isotropic 1H hyperfine coupling constants and hyperfine tensors of the two methyl groups and the alpha-proton were obtained. On the basis of H/D exchange experiments two different hydrogen bonds could be detected in frozen solution that are formed between the carbonyl oxygens of the radical and protons from the surrounding solvent molecules. The hydrogen bond distances were estimated using the point-dipole model. 1H-ENDOR spectra of QA.- in iron-depleted PS II samples have been measured in buffers made in H2O and D2O. The spectrum in deuterated buffer allowed the determination of two different methyl group hyperfine tensors. Differences detected between the spectra in protonated and deuterated buffer reveal the hyperfine tensors of two exchangeable protons belonging to hydrogen bonds between the oxygens of QA and specific protein residues. The assignment of these hydrogen bonds in PS II is discussed and compared with the situation found in the bacterial reaction center.

Prediction of outcome following a first episode of schizophrenia. A follow-up study of Northwick Park first episode study subjects.

BACKGROUND: Although previous studies have attempted to identify predictors of outcome in schizophrenia, few have prospectively studied first episode patients for an adequate follow-up period. METHOD: The psychopathological predictors of outcome were investigated in a subgroup of 51 subjects, originally included in the Northwick Park study of first episode schizophrenia who were followed up 7.3 years (s.d. 1.1, range 5.3-10.3) after first admission in the Harrow study. Forty-four subjects (24 men, 20 women) were traced. Outcome measures were time to first readmission, occupational level and total duration of hospital admission at five years after first admission. RESULTS: A survival analysis of time to first relapse revealed that the presence of subjective feelings of depression (CATEGO syndrome SD) during the first admission was associated with early relapse while the presence of depressive delusions (CATEGO syndrome DD) and higher educational attainment protected against early relapse. Total duration of hospitalisation at five years after first onset was positively associated with the presence of CATEGO syndromes SD and OD (biological features of depression) and negatively associated with female sex. Poor occupational outcome was not significantly associated with any psychopathological predictors. CONCLUSIONS: Our findings challenge the conventional view that symptoms of depression are associated with better outcome in schizophrenia.

A self-report Insight Scale for psychosis: reliability, validity and sensitivity to change.

Lack of insight is a frequent concomitant of psychosis and has traditionally been viewed as a binary, all or none phenomenon. Recent conceptualization has formulated insight as a continuum representing the juxtaposition of 3 factors--awareness of illness, need for treatment and attribution of symptoms. Measurement of insight has been exclusively based on interview; this method does not easily lend itself to frequent repeated measurement and requires interrater reliability to be established. A self-report Insight Scale is presented, and evidence in support of its reliability, validity and sensitivity is provided that includes a sample of 30 patients monitored during recovery from an acute psychosis. The scale is a quick and acceptable measure that may find application in investigations of acute care, cognitive therapy of psychotic symptoms and as a method of augmenting clinical judgements of insight.

Early intervention in schizophrenia.

The management of schizophrenia may be characterised by two paradigms. The first approaches the schizophrenias as episodic relapsing disorders, where treatment is provided through both acute (crisis) care and to achieve prophylaxis. The second paradigm, sometimes arising from a failure of the first, is of "rehabilitation", involving amelioration of disabilities, occasionally within a framework of relative asylum. We would propose a third paradigm of "early intervention", involving a combination of medical and psychosocial interventions targeted at young, vulnerable people with the aim of preventing or limiting likely social, psychological and mental deterioration. Vigorous intervention early in the course of illness, early recognition and treatment of relapse and the promotion of psychological adjustment to psychotic illness are proposed as key elements of this third paradigm.