Heating events in the nascent solar system recorded by rare earth element isotopic fractionation in refractory inclusions.

Equilibrium condensation of solar gas is often invoked to explain the abundance of refractory elements in planets and meteorites. This is partly motivated, by the observation that the depletions in both the least and most refractory rare earth elements (REEs) in meteoritic group II calcium-aluminum-rich inclusions (CAIs) can be reproduced by thermodynamic models of solar nebula condensation. We measured the isotopic compositions of Ce, Nd, Sm, Eu, Gd, Dy, Er, and Yb in eight CAIs to test this scenario. Contrary to expectation for equilibrium condensation, we find light isotope enrichment for the most refractory REEs and more subdued isotopic variations for the least refractory REEs. This suggests that group II CAIs formed by a two-stage process involving fast evaporation of preexisting materials, followed by near-equilibrium recondensation. The calculated time scales are consistent with heating in events akin to FU Orionis- or EX Lupi-type outbursts of eruptive pre-main-sequence stars.

Self, Voices and Embodiment: A Phenomenological Analysis.

OBJECTIVE: The primary aim of this study was to examine first-person phenomenological descriptions of the relationship between the self and Auditory Verbal Hallucinations (AVHs). Complex AVHs are frequently described as entities with clear interpersonal characteristics. Strikingly, investigations of first-person (subjective) descriptions of the phenomenology of the relationship are virtually absent from the literature. METHOD: Twenty participants with psychosis and actively experiencing AVHs were recruited from the University of Illinois at Chicago. A mixed-methods design involving qualitative and quantitative components was utilized. Following a priority-sequence model of complementarity, quantitative analyses were used to test elements of emergent qualitative themes. RESULTS: The qualitative analysis identified three foundational constructs in the relationship between self and voices: 'understanding of origin,' 'distinct interpersonal identities,' and 'locus of control.' Quantitative analyses further supported identified links of these constructs. Subjects experienced their AVHs as having identities distinct from self and actively engaged with their AVHs experienced a greater sense of autonomy and control over AVHs. DISCUSSION: Given the clinical importance of AVHs and emerging strategies targeting the relationship between the hearer and voices, our findings highlight the importance of these relational constructs in improvement and innovation of clinical interventions. Our analyses also underscore the value of detailed voice assessments such as those provided by the Maastricht Interview are needed in the evaluation process. Subjects narratives shows that the relational phenomena between hearer and AVH(s) is dynamic, and can be influenced and changed through the hearers' engagement, conversation, and negotiation with their voices.

A 20-year multi-follow-up of hallucinations in schizophrenia, other psychotic, and mood disorders.

BACKGROUND: Hallucinations are a major aspect of psychosis and a diagnostic feature of both psychotic and mood disorders. However, the field lacks information regarding the long-term course of hallucinations in these disorders. Our goals were to determine the percentage of patients with hallucinations and the relationship between hallucinations and recovery, and work attainment. Method The present study was a prospective evaluation of the 20-year trajectory of hallucinations in 150 young patients: 51 schizophrenia, 25 schizoaffective, 25 bipolar with psychosis, and 49 unipolar depression. The patients were studied at an index phase of hospitalization for hallucinations, and then reassessed longitudinally at six subsequent follow-ups over 20 years. RESULTS: The longitudinal course of hallucinations clearly differentiated between schizophrenia and bipolar disorder with psychosis, and suggested some diagnostic similarities between schizophrenia and schizoaffective disorder, and between bipolar disorder and schizoaffective disorder and depression. Frequent or persistent hallucinatory activity over the 20-year period was a feature of 40-45% of schizophrenia patients. The early presence of hallucinations predicted the lack of future periods of recovery in all patients. Increased hallucinatory activity was associated with reduced work attainment in all patients. CONCLUSIONS: This study provides data on the prospective longitudinal course of hallucinations, which were previously unavailable to the field, and are one of the key features of psychosis in major psychiatric disorders. This information on the clinical course of major psychiatric disorders can inform accurate classification and diagnosis.

Clamping renal artery alone produces less ischemic damage compared to clamping renal artery and vein together in two animal models: near-infrared tissue oximetry and quantitation of 8-isoprostane levels.

PURPOSE: To investigate renal ischemia injury during renal hilar clamping (artery alone versus clamping artery/vein together) by evaluating ischemic damage via two different modalities in animal models-near-infrared tissue oximetry and 8-isoprostane levels. METHODS: Near-infrared renal oximetry measurements of Yorkshire swines (n = 4; 8 renal units) subject to hilar clamping were obtained at baseline, during warm ischemia (15- and 30-min trials) and after unclamping. Quantitation of 8-isoprostane levels is the second technique of quantitating interstitial fluid collected from a dialysis catheter placed through renal parenchyma of male Sprague-Dawley rats (n = 50) subject to hilar clamping during preclamp, clamp (either 15 or 30 min of hilum clamping), and post-clamp. RESULTS: N ear-infrared tissue oximetry. In the 15-min trial, oxygen saturation decreased 6× faster with artery alone compared to artery/vein clamped together. In the 30-min trial, the decrease was 5× faster. Recovery of oxygen saturation with only artery clamped occurred more than 2× faster in the 15- and 30-min periods. Isoprostane. For 15-min clamp times, 8-isoprostane levels in the artery alone group demonstrated a 1.54 decrease in the artery clamped alone group (p = 0.006) versus artery/vein together: preclamp (11.47 and 11.63 pg/mL/g), clamp (14.61 and 17.70 pg/mL/g), and post-clamp (14.26 and 22.04 pg/mL/g). CONCLUSIONS: Renal ischemia injury from clamping the renal artery alone was significantly less than clamping artery/vein together demonstrated in two different techniques. Recovery of oxygen saturation was twofold faster, and mean post-clamp 8-isoprostane levels demonstrated a 1.54-fold decrease with clamping renal artery alone compared to clamping artery/vein together.

Comparative analysis of encephalization in mammals reveals relaxed constraints on anthropoid primate and cetacean brain scaling.

There is a well-established allometric relationship between brain and body mass in mammals. Deviation of relatively increased brain size from this pattern appears to coincide with enhanced cognitive abilities. To examine whether there is a phylogenetic structure to such episodes of changes in encephalization across mammals, we used phylogenetic techniques to analyse brain mass, body mass and encephalization quotient (EQ) among 630 extant mammalian species. Among all mammals, anthropoid primates and odontocete cetaceans have significantly greater variance in EQ, suggesting that evolutionary constraints that result in a strict correlation between brain and body mass have independently become relaxed. Moreover, ancestral state reconstructions of absolute brain mass, body mass and EQ revealed patterns of increase and decrease in EQ within anthropoid primates and cetaceans. We propose both neutral drift and selective factors may have played a role in the evolution of brain-body allometry.

An exploratory analysis of factors associated with weight change in a 16-week trial of oral vs. orally disintegrating olanzapine: the PLATYPUS study.

BACKGROUND: We conducted exploratory analyses of the data from a multinational, randomised study to identify factors associated with weight change after 16 weeks of treatment with standard olanzapine tablets (SOT) or sublingual orally disintegrating olanzapine (ODO). METHODS: One hundred and forty nine outpatients who gained weight during prior SOT therapy were enrolled into the study and treated with ODO (N = 84) or SOT (N = 65). Exploratory analyses were conducted with the subset of compliant patients (ODO: n = 60; SOT: n = 47). RESULTS: The decrease in the rate of weight gain at the end of study therapy (change from baseline) was greater in the ODO group than the SOT group (-0.59 kg/week vs. -0.38 kg/week, p = 0.0246). Age was negatively associated with weight change (p = 0.0203) in both treatment groups combined: patients gained 0.7 kg less for every 10 years of age. The least squares mean weight gain was lower with ODO than SOT in male patients (0.35 kg vs. 3.04 kg, p = 0.061), but not female patients and in American patients (0.55 kg vs. 6.21 kg, p < 0.0001), but not Canadian or Mexican patients. CONCLUSIONS: Although not conclusive, these data suggest that ODO may be a reasonable treatment option for some patients who gain weight with SOT. Further research is required to confirm these findings.

Reinvestigation of the direct two-proton decay of the long-lived isomer 94Ag(m) [0.4 s, 6.7 MeV, (21+)].

An attempt to confirm the reported direct one-proton and two-proton decays of the (21+) isomer at 6.7(5) MeV in 94Ag has been made. The 0.39(4) s half-life of the isomer permitted use of a helium-jet system to transport reaction products from the 40Ca + (nat)Ni reaction at 197 MeV to a low-background area; 24 gas DeltaE-(Si)E detector telescopes were used to identify emitted protons down to 0.4 MeV. No evidence was obtained for two-proton radioactivity with a summed energy of 1.9(1) MeV and a branching ratio of 0.5(3)%. Two groups of one-proton radioactivity from this isomer had also been reported; our data confirm the lower energy group at 0.79(3) MeV with its branching ratio of 1.9(5)%.

A randomized controlled trial of the effect of sublingual orally disintegrating olanzapine versus oral olanzapine on body mass index: the PLATYPUS Study.

BACKGROUND: Patients with schizophrenia and bipolar disorder have frequently reported weight gain during olanzapine treatment. Previous studies have observed a decrease in weight gain, or weight loss, in patients switching from standard olanzapine tablets (SOT) to orally disintegrating olanzapine (ODO) tablets. The primary objective of this study was to investigate the change in body mass index (BMI) in patients who had previously gained weight with SOT and continued with this therapy during the study period, compared with those patients who switched to ODO during the study period. METHODS: This was a 16-week, multicentre, randomized, double-blind, double-dummy, study of outpatients diagnosed with schizophrenia, schizoaffective disorder, related psychotic disorder or bipolar disorder, who were taking 5-20 mg SOT daily. Patients continued treatment with 5-20 mg olanzapine in a flexible single daily dose, and were randomized to either receive sublingual ODO plus an oral placebo, or sublingual placebo plus SOT. RESULTS: No statistically significant between group differences in mean change from baseline in BMI, weight or waist circumference were observed. Analysis of change in body weight from baseline, by pre-specified category (no change, loss of >or=1.5 kg, gain of >or=1.5 kg), revealed a significant difference between groups, favoring ODO patients, who also experienced a significant reduction in subjective appetite and better treatment compliance, compared to patients in the SOT group. CONCLUSIONS: In this study, patients treated with ODO experienced a similar mean change in BMI and weight from baseline, to those patients treated with SOT.

XPD gene polymorphism and host characteristics in the association with cutaneous malignant melanoma risk.

We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9-2.5 for 312Asn; OR=1.3, 95% CI=0.8-2.1 for 751Gln, adjusted for age, gender, dysplastic naevi and pigmentation characteristics). However, XPD variants were associated with increased risk in older (>50 years) subjects (OR=3.4, 95% CI=1.6-7.3 for 312Asn; OR=2.3, 95% CI=1.1-4.9 for 751Gln). The 751Gln allele was associated with elevated melanoma risk among subjects without dysplastic naevi (OR=2.6, 95% CI=1.1-6.4). Subjects with low tanning ability and XPD variants exhibited a nonsignificant increase of melanoma risk (OR=2.3, 95% CI=0.7-7.0 for 312Asn; OR=3.0, 95% CI=1.0-8.8 for 751Gln). DNA repair capacity was slightly decreased in subjects carrying 751Gln alleles. XPD variants may modify melanoma risk in subjects with specific host characteristics, such as older age, lack of dysplastic naevi or low tanning ability.

A self-assessment program for multidisciplinary mental health teams.

OBJECTIVE: The authors describe a self-assessment training program for multidisciplinary mental health teams that was developed in a public multihospital system, the process of implementing the training at a state psychiatric hospital, and a measurement instrument, the Scale for Leadership Assessment and Team Evaluation (SLATE), which they have used for self-assessment of multidisciplinary teams and which is currently being studied. They assessed whether changes in team self-assessments could be seen after the training program. METHODS: A total of 102 mental health professionals from 12 inpatient units representing the disciplines of psychiatry, psychology, nursing, social work, and occupational and activity therapy completed the SLATE before and after participation in a training program that consisted primarily of team self-assessment in the context of treatment planning sessions. The training program included structured feedback, didactics, consultation, and videotaping of sessions. Aggregate data were used to compare mean item scores for the SLATE overall and for its four subscales (team, psychiatrist, participation, and treatment plan) at baseline and after the training. RESULTS: Scores increased significantly for the overall SLATE and for all four subscales, indicating improved team functioning in the areas addressed. The increase in mean score was greatest for the subscale that assessed the leadership of the psychiatrist. CONCLUSIONS: Treatment planning sessions can be used successfully by multidisciplinary mental health teams to examine team functioning in various areas in a self-assessment model. Participation in a training program that included videotaping of sessions, consultation, and structured attention to team functioning was associated with improved ratings of team functioning.

Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype.

Recent molecular epidemiological studies have identified polymorphisms in the XPD gene that are associated with increased risk of brain gliomas and head, neck, lung, and skin cancers. However, the functional significance of these polymorphic variants in altering cell processes such as cell cycle checkpoints, DNA repair, and apoptosis is uncertain. We have cloned the XPD variants Lys751Gln, Asp312Asn, and Lys751Gln-Asp312Asn into a pcDNA-3.1-expression vector. Using these constructs, we did not find any detectable difference in either in vitro binding with wild-type p53 or in DNA repair proficiency as measured by host cell reactivation assay. We then genotyped 34 different lymphoblastoid cell lines from six Centre d'Etude du Polymorphisme Humaine (CEPH)/Utah pedigree families and a CEPH/French pedigree family for polymorphisms at codons 751 and 312 and assessed their apoptotic response after either UV or ionized radiation exposure. The lymphoblastoid cell lines with homozygous or heterozygous Asp at codon 312 have similar apoptotic rates, whereas cell lines with homozygous Asn at codon 312 showed a 2.5-fold increased response to UV (P = 0.005; Student's t test). This is the first report known to us of a functional polymorphism in a gene involved in DNA damage-induced apoptosis. However, the presence of Lys or Gln at codon 751 did not influence the apoptotic response to UV. The diminished apoptotic response of cells containing the 312 Asp allele could both allow the survival and selective clonal expansion of carcinogen-damaged cells and be a mechanistic explanation for the increased risk of cancer at diverse tissue sites.

Polymorphisms of the DNA repair gene XPD: correlations with risk of basal cell carcinoma revisited.

The XPD gene product has a dual function in basal transcription and in nucleotide excision repair. We have previously reported that two polymorphisms in the gene, one silent mutation in codon 156 of exon 6 and one giving rise to a Lys-->Gln substitution in codon 751 of exon 23, showed signs of being associated with basal cell carcinoma in a Scandinavian study group of psoriasis patients and non-psoriatics with and without basal cell carcinoma [Dybdahl, Vogel, Frentz, Wallin and Nexø (1999) Cancer Epidemiol. Biomark. Prev., 8, 77-81]. In both polymorphisms, the CC genotype appeared to be protective against basal cell carcinoma. Here, we have genotyped an American study group of basal cell carcinoma patients and controls without skin cancer for the two polymorphisms. In addition, we studied an A-->G polymorphism in codon 312 of exon 10, which results in an Asp-->Asn substitution in a conserved region of XPD. In the whole study group, subjects carrying the AA and AC genotype in exon 6 were at 1.9-fold higher risk of basal cell carcinoma (P = 0.062, CI 0.96-3.75). If only subjects without a family history of non-melanoma skin cancer were included, subjects carrying AA or AC genotype were at 3.3-fold higher risk of basal cell carcinoma (P = 0.007, CI 1.35-8.18). Among subjects with a family history of non-melanoma skin cancer, subjects with an AG or AA genotype in codon 312 of exon 10 were at 5.25-fold increased risk of basal cell carcinoma (P = 0.027, CI 1.15-23.93). A protective effect of the CC genotype in exon 23 could not be confirmed. Cases with a family history of skin cancer had statistically significantly different allele frequencies of the polymorphisms in exon 6 and exon 10 from cases without family history of non-melanoma skin cancer. Our results indicate that the exon 6(A) allele is a risk factor in basal cell carcinoma.

Mammalian subunit IV isoforms of cytochrome c oxidase.

Cytochrome c oxidase (COX) contains ten nuclear encoded subunits, three of them known to show tissue isoforms in mammals. We have now found a fourth isoform, for subunit IV, in human, rat and mouse (COX IV-2). Comparison of the two human isoform genes shows a similar structural organization, including an overall size of about 8 kb, the presence of five exons, and the initiation of translation in the second exon, consistent with formation by gene duplication. Also consistent is the higher identity of precursor peptides of 78% within the new IV-2 isoform (average in the three species) compared to 44% average identity with the IV-1 isoform. Northern analysis and quantitative PCR with human and rat tissues show high IV-2 expression in adult lung and lower expression in all other tissues investigated, including fetal lung. In contrast, the IV-1 isoform is ubiquitously expressed. In situ hybridizations were performed to localize isoform transcripts in rat lung. Both isoforms are found in similar ratios in most lung cell types except for smooth muscle and respiratory epithelium, which have a IV-2 and a IV-1 preference, respectively. Structural modeling of the IV-2 isoform from human, based on the bovine crystal data, produces a conformation in which two of three conserved cysteine groups, exclusively present in the mammalian IV-2 isoform, are in close proximity. The formation of a cysteine bond and the implications for function of these sequence differences for subunit IV, which plays a pivotal role in COX regulation, are discussed.

Evolution of nuclear- and mitochondrial-encoded subunit interaction in cytochrome c oxidase.

Mitochondrial DNA (mtDNA)-encoded proteins function in eukaryotes as subunits of respiratory complexes that also contain nuclear DNA (nDNA)-encoded subunits. The importance of functional interactions between mtDNA- and nDNA-encoded proteins was previously demonstrated by testing the survivability of cybrid cells or individuals containing nDNA and mtDNA from different populations or species. This report focuses on the multisubunit respiratory complex cytochrome c oxidase (COX), made up of both mtDNA-encoded and nDNA-encoded subunits. A combination of evolutionary and crystallographic data is employed to determine whether rates of nonsynonymous substitutions have been higher, the same, or lower for residues in close proximity that are encoded by a different genome (nDNA or mtDNA). This determination is performed by simply taking the ratio, called the interaction ratio i, of the nonsynonymous substitution rate of the close-contact residues to the nonsynonymous substitution rate of the noncontact residues. We assume that the close-contact residues (which are more likely to interact) are functionally important and that, therefore, amino acid replacements among these residues cannot escape the scrutiny of natural selection. i = 1 indicates that the close-contact residues have been under neither greater purifying selection nor greater positive selection than the noncontact residues as a specific consequence of their being encoded by separate genomes. i < 1 indicates that the close-contact residues have been under greater purifying selection but less positive selection than have the noncontact residues. Conversely, i > 1 indicates that the close-contact residues have been under less purifying but greater positive selection than have the noncontact residues. i < 1 may be referred to as a constraining interaction; i.e., the close-contact residues compared with the noncontact residues appear to be under greater structural-functional constraints. On the other hand, i > 1 may be referred to as an optimizing interaction; i.e., apparently many different amino acid replacements are required to optimize this subunit's interaction with the other subunit. A major finding is that the nDNA-encoded residues in close physical proximity to mtDNA-encoded residues evolve more slowly than the other nuclear-encoded residues (and thus display a constraining interaction), whereas the mtDNA-encoded residues in close physical proximity to nDNA-encoded residues evolve more rapidly than the other mitochondrial-encoded residues (and thus display an optimizing interaction). A possible reason for this striking difference between the nuclear- and mitochondrial-encoded COX subunits in how their functional interaction evolves is discussed.

Molecular evolution of aerobic energy metabolism in primates.

As part of our goal to reconstruct human evolution at the DNA level, we have been examining changes in the biochemical machinery for aerobic energy metabolism. We find that protein subunits of two of the electron transfer complexes, complex III and complex IV, and cytochrome c, the protein carrier that connects them, have all undergone a period of rapid protein evolution in the anthropoid lineage that ultimately led to humans. Indeed, subunit IV of cytochrome c oxidase (COX; complex IV) provides one of the best examples of positively selected changes of any protein studied. The rate of subunit IV evolution accelerated in our catarrhine ancestors in the period between 40 to 18 million years ago and then decelerated in the descendant hominid lineages, a pattern of rate changes indicative of positive selection of adaptive changes followed by purifying selection acting against further changes. Besides clear evidence that adaptive evolution occurred for cytochrome c and subunits of complexes III (e.g., cytochrome c(1)) and IV (e.g., COX2 and COX4), modest rate accelerations in the lineage that led to humans are seen for other subunits of both complexes. In addition the contractile muscle-specific isoform of COX subunit VIII became a pseudogene in an anthropoid ancestor of humans but appears to be a functional gene in the nonanthropoid primates. These changes in the aerobic energy complexes coincide with the expansion of the energy-dependent neocortex during the emergence of the higher primates. Discovering the biochemical adaptations suggested by molecular evolutionary analysis will be an exciting challenge.

Molecular evolution of cytochrome c oxidase subunit I in primates: is there coevolution between mitochondrial and nuclear genomes?

Phylogenetic analyses carried out on cytochrome c oxidase (COX) subunit I mitochondrial genes from 14 primates representing the major branches of the order and four outgroup nonprimate eutherians revealed that transversions and amino acid replacements (i.e., the more slowly occurring sequence changes) contained lower levels of homoplasy and thus provided more accurate information on cladistic relationships than transitions (i.e., the more rapidly occurring sequence changes). Several amino acids, each with a high likelihood of functionality involving the binding of cytochrome c or interaction with COX VIII, have changed in Anthropoidea, the primate suborder grouping New World monkey, Old World monkey, ape, and human lineages. They are conserved in other mammalian lineages and in nonanthropoid primates. Maximum-likelihood ancestral COX I nucleotide sequences were determined utilizing a near most parsimonious branching arrangement for the primate sequences that was consistent with previously hypothesized primate cladistic relationships based on larger and more diverse data sets. Relative rate tests of COX I mitochondrial sequences showed an elevated nonsynonymous (N) substitution rate for anthropoid-nonanthropoid comparisons. This finding for the largest mitochondrial (mt) DNA-encoded subunit is consistent with previous observations of elevated nonsynonymous substitution/synonymous substitution (S) rates in primates for mt-encoded COX II and for the nuclear-encoded COX IV and COX VIIa-H. Other COX-related proteins, including cytochrome c and cytochrome b, also show elevated amino acid replacement rates or N/S during similar time frames, suggesting that this group of interacting genes is likely to have coevolved during primate evolution.