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Objectives: The appearance of external auditory exostoses archaeologically has been attributed to aquatic activities in middle latitudes. However, recent clinical research implicates low sea surface temperatures, especially below a threshold of 19°C, as a stronger predictor of ear exostosis development than latitude. Here, we examine the frequency of external auditory exostoses in human remains from nine pre-Columbian archaeological sites in Panama, representing individuals from a warm, tropical region., Materials and Methods: External auditory exostoses were recorded as present when an abnormal bony growth was observed macroscopically within the ear canal. The presence of exostoses was compared by right and left side, geographical region, sex, and degree of stenosis., Results: A total of 125 adult individuals made up the observable sample analyzed in this study. Exostoses were observed in seven males and one female. All individuals affected by this pathology were excavated from mortuary contexts along the Gulf of Panama-a region characterized by intense cold water upwelling in the dry season., Discussion: This study suggests that external auditory exostoses in pre-Columbian Panama affected individuals involved in habitual aquatic activities in the cold, upwelled waters of the Gulf of Panama. These activities appear to be almost exclusively dominated by male individuals. Ethnohistorical and archaeological records point to marine shell resource acquisition by deep-water diving as the activity driving exostosis development in pre-Columbian Panama., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

We present a rare case of primary bone cancer principally affecting the right humerus of a skeleton from the pre-Columbian site of Cerro Brujo (1265-1380 CE) in Bocas del Toro, on the Caribbean coast of Panamá, excavated in the early 1970s. The humerus contains a dense, calcified sclerotic mass with associated lytic lesions localized around the midshaft of the diaphysis. Evidence of systemic inflammation and anemia, likely caused by the cancer, are visible in the form of severe porotic hyperostosis of the cranial vault and bilateral periosteal reactions in the tibiae. Differential diagnosis and future probes of the tumor are discussed. A tooth from the individual yielded a radiocarbon date 150 years later than those of the domestic occupation at the site. Given that it was the only formal burial recovered from the site, and as the individual had such a visible, painful, and rare pathology, this likely constitutes a ritual burial., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Transitions between the marine and freshwater macrohabitat have occurred repeatedly in the evolution of teleost fishes. For example, ariid catfishes have moved from freshwater to marine environments, and vice versa. Opercles, a skeletal feature that has been shown to change during such transitions, were subjected to 2D geometric morphometric analyses in order to investigate evolutionary shape changes during habitat transition in ariid catfishes and to test the influence of habitat on shape changes. A mtDNA marker, which proved useful in previous studies, was used to verify species identities. It greatly improved the assignment of specimens to a species, which are difficult to assign by morphology alone. The application of a mtDNA marker confirmed the occurrence of Notarius biffi in Central America, South of El Salvador. Molecular identification together with principal component analysis (PCA) and further morphological inspection of neurocrania indicated the existence of a cryptic species within Bagre pinnimaculatus. Principal component (PC) scores of individual specimens clustered in morphospace by genus rather than by habitat. Strong phylogenetic structure was detected using a permutation test of PC scores of species means on a phylogenetic tree. Calculation of Pagel's λ suggested that opercle shape evolved according to a Brownian model of evolution. Yet canonical variate analysis (CVA) conducted on the habitat groups showed significant differences in opercle shapes among freshwater and marine species. Overall, opercle shape in tropical American Ariidae appears to be phylogenetically constrained. This verifies the application of opercle shape as a taxonomic tool for species identification in fossil ariid catfishes. At the same time, adaptation to freshwater habitats shows characteristic opercle shape trajectories in ariid catfishes, which might be used to detect habitat preferences in fossils.

Background: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing., Methods: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine., Results: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]., Conclusions: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets., (© The Author 2015. Published by Oxford University Press on behalf of the American Association for Public Opinion Research.)

Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDEs), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE; however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO-A VT (an index of MAO-A density) was measured using [(11)C]harmine positron emission tomography (PET) in 42 subjects with MDEs secondary to major depressive disorder and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC was analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F(2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F(2,38)=5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. As MAO-A creates oxidative stress, facilitates apoptosis, and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms.

Objective: To address the gaps between need and access, and between treatment guidelines and their implementation for mental illness, through capacity building of front-line health workers., Methods: Following a learning needs assessment, work-based continuing education courses in evidence-supported psychotherapies were developed for front-line workers in underserviced community settings. The 5-hour courses on the fundamentals of cognitive-behavioural therapy, interpersonal psychotherapy, motivational interviewing, and dialectical behaviour therapy each included videotaped captioned simulations, interactive lesson plans, and clinical practice behaviour reminders. Two courses, sequentially offered in 7 underserviced settings, were subjected to a mixed methods evaluation. Ninety-three nonmedical front-line workers enrolled in the program. Repeated measures analysis of variance was used to assess pre- and postintervention changes in knowledge and self-efficacy. Qualitative data from 5 semistructured focus groups with 25 participants were also analyzed., Results: Significant pre- and postintervention changes in knowledge (P < 0.001) were found in course completers. Counselling self-efficacy improved in participants who took the first course offered (P = 0.001). Dropouts were much less frequent in peer-led, small-group learning than in a self-directed format. Qualitative analysis revealed improved confidence, morale, self-reported practice behaviour changes, and increased comfort in working with difficult clients., Conclusion: This work-based, multimodal, interactive, interprofessional curriculum for knowledge translation of psychotherapeutic techniques is feasible and helpful. A peer-led group format is preferred over self-directed learning. Its application can build capacity of front-line health workers in helping patients who suffer from common mental disorders.

Objective: Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD., Methods: The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using chi(2) test, transmission disequilibrium test, and pedigree-based association. SNP rs1556314 was also genotyped in our case-control sample set comprised of 184 BD and 195 healthy Caucasian subjects., Results: The SNP rs1556314 in exon 11 was significantly associated with bipolar disorder type I (BD-I) (p = 0.011, p(permutation) = 0.015) in the case-control dataset and in the family design (p = 0.018, p(permutation) = 0.052, TDTPHASE). Interestingly, the C-T-A haplotype of SNPs rs1618355, rs933151, and rs749909 was significantly associated with early age at onset in BD-I families., Conclusion: Significant association of TRPM2 genetic variants with BD in case-control and family datasets further supports a role for TRPM2 in the pathogenesis of this disorder. Overtransmission of the G allele of rs1556314 at exon 11 of TRPM2 in BD-I but not bipolar disorder type II (BD-II) further supports different genetic contributions to the pathogenesis of these bipolar phenotypes.

Background: The nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non-Japanese populations and, if so, their relationship to altered basal intracellular Ca(2+) ([Ca(2+)](B)) in BLCL from BD patients., Methods: Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent. The 5'-nuclease allelic discrimination TaqMan assay was used to detect selected single nucleotide polymorphisms (SNPs) in promoter, introns and 3'UTR regions, spanning the NDUFV2 gene. NDUFV2 mRNA levels and [Ca(2+)](B) in BLCLs were determined., Results: The A allele of the NDUFV2 SNP rs1156044 was significantly associated (Bonferroni-corrected) with BD (p = 0.013) but differed in allele (rs1156044 G allele) from that previously reported as associated with BD. There was a trend for elevated BLCL [Ca(2+)](B) associated with SNP rs977581 in BD patients, but NDUFV2 mRNA levels in BLCLs did not differ between patients and controls, nor represented genotypes., Conclusions: While genetic variants of NDUFV2 may increase risk for BD, the role of its altered expression and the link to intracellular Ca(2+) abnormalities in BD remains equivocal.

The Central American isthmus was a major dispersal route for plant taxa originally brought under cultivation in the domestication centers of southern Mexico and northern South America. Recently developed methodologies in the archaeological and biological sciences are providing increasing amounts of data regarding the timing and nature of these dispersals and the associated transition to food production in various regions. One of these methodologies, starch grain analysis, recovers identifiable microfossils of economic plants directly off the stone tools used to process them. We report on new starch grain evidence from Panama demonstrating the early spread of three important New World cultigens: maize (Zea mays), manioc (Manihot esculenta), and arrowroot (Maranta arundinacea). Maize starch recovered from stone tools at a site located in the Pacific lowlands of central Panama confirms previous archaeobotanical evidence for the use of maize there by 7800-7000 cal BP. Starch evidence from preceramic sites in the less seasonal, humid premontane forests of Chiriquí province, western Panama, shows that maize and root crops were present by 7400-5600 cal BP, several millennia earlier than previously documented. Several local starchy resources, including Zamia and Dioscorea spp., were also used. The data from both regions suggest that crop dispersals took place via diffusion or exchange of plant germplasm rather than movement of human populations practicing agriculture.

Chili peppers (Capsicum spp.) are widely cultivated food plants that arose in the Americas and are now incorporated into cuisines worldwide. Here, we report a genus-specific starch morphotype that provides a means to identify chili peppers from archaeological contexts and trace both their domestication and dispersal. These starch microfossils have been found at seven sites dating from 6000 years before present to European contact and ranging from the Bahamas to southern Peru. The starch grain assemblages demonstrate that maize and chilies occurred together as an ancient and widespread Neotropical plant food complex that predates pottery in some regions.

Estuarine and coastal transformation is as old as civilization yet has dramatically accelerated over the past 150 to 300 years. Reconstructed time lines, causes, and consequences of change in 12 once diverse and productive estuaries and coastal seas worldwide show similar patterns: Human impacts have depleted >90% of formerly important species, destroyed >65% of seagrass and wetland habitat, degraded water quality, and accelerated species invasions. Twentieth-century conservation efforts achieved partial recovery of upper trophic levels but have so far failed to restore former ecosystem structure and function. Our results provide detailed historical baselines and quantitative targets for ecosystem-based management and marine conservation.

Objective: To identify the determinants of practice location and of outreach consultation of recently graduated psychiatrists., Methods: We surveyed 153 psychiatrists who graduated from the University of Toronto Department of Psychiatry between January 1990 and June 2002 (response rate 51%), on the basis of a self-administered mail questionnaire. The survey assessed factors that influenced practice location and outreach consultation, such as demographics, links to practice communities, and outreach experiences, including rural or northern electives as a resident., Results: Professional variables were rated as the most important factors in choosing a practice location. Variables such as age or sex were not significantly associated with location. Nine percent reported working in communities of less than 100,000, and only 1% practised in Northern Ontario. Eighteen percent practised in the same location where they were born or raised. Forty-four percent had rural or northern experience as a resident but almost exclusively in the form of short, fly-in consultation electives. Twenty-four percent indicated that they provide outreach consultation. Psychiatry residents who participated in outreach electives were 10 times as likely as those who did not participate to continue outreach as a consultant., Conclusion: Although early exposure to rural or northern medicine leads to significantly greater continued involvement in outreach activities after graduation, our findings suggest the need for more long-term, on-site residency training opportunities in rural and remote areas.

Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD., ((c) 2005 Wiley-Liss, Inc.)

Background: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy., Methods: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)])., Results: At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events., Conclusions: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Elevated basal intracellular calcium (Ca(2+)) levels ([Ca(2+)](B)) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca(2+) homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca(2+) signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca(2+) homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N=26) and healthy subjects (N=17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca(2+)](B), lysophosphatidic acid (LPA)-stimulated Ca(2+) mobilization ([Ca(2+)](S)), and thapsigargin-induced store-operated Ca(2+) entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca(2+)](B) (F=8.47; p=0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca(2+)](S) and SOCE were significantly reduced (F=11.1, p=0.002 and F=8.36, p=0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca(2+)](B) in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca(2+) mobilization in BLCLs suggests that modulation of intracellular Ca(2+) homeostasis may be important to the therapeutic action of lithium.

Finding measures that can assess areas of expected program impact, provide valid results, and be easily integrated into routine program practices is a significant challenge. This paper is intended to assist program staff by providing an accessible inventory of measures appropriate for routine monitoring of the status and outcome of individuals using mental health outpatient and community programs. The inventory is not exhaustive, but rather includes examples of solid measures for assessing outcomes in four key domains--symptoms, functioning, quality of life, and satisfaction. These can provide a core of information, to which measurement of more in-depth issues can be added to address specific concerns.

Degradation of coral reef ecosystems began centuries ago, but there is no global summary of the magnitude of change. We compiled records, extending back thousands of years, of the status and trends of seven major guilds of carnivores, herbivores, and architectural species from 14 regions. Large animals declined before small animals and architectural species, and Atlantic reefs declined before reefs in the Red Sea and Australia, but the trajectories of decline were markedly similar worldwide. All reefs were substantially degraded long before outbreaks of coral disease and bleaching. Regardless of these new threats, reefs will not survive without immediate protection from human exploitation over large spatial scales.

Background: Catatonic symptoms have been associated with mixed mania in the older psychiatric literature, however, to date no systematic studies have been performed to assess their frequency in these patients., Method: Ninety-nine patients with bipolar disorder manic or mixed episode were assessed for the presence of catatonia., Results: Thirty-nine patients fulfilled criteria for mixed mania of whom 24 were catatonic. Among the patients with pure mania, only three were catatonic. Eighteen catatonic patients with mixed mania required admission to the acute care unit (ACU)., Limitations: Our findings only apply to severely ill patients with mixed mania who require ACU admission. Nevertheless, it is important to know, that the likelihood of overlooking catatonia in less severely ill patients with mixed mania is low and that it does not need to be routinely assessed on a general ward., Conclusions: Catatonia is frequent in mania and linked to the mixed episode. Catatonia in mixed mania is likely to be found among the severely ill group of patients with mixed mania, who require emergency treatment.

Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca(2+)](B)) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle couples to intracellular Ca(2+) mobilization, these two putative endophenotypes may be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca(2+)](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12). IMPA2 mRNA levels were significantly lower in BLCLs from male BD-I patients with high [Ca(2+)](B) (n = 6) compared with healthy male subjects (n = 5) (-52%, P = 0.013), male BD-I patients with normal BLCL [Ca(2+)](B) (n = 8) (-42%, P = 0.003) and female BD-I patients with high [Ca(2+)](B) (n = 6) (-59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca(2+)](B) in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.

Background: As altered storage-operated calcium (Ca(2+)) entry (SOCE) may affect Ca(2+) homeostasis in bipolar disorder (BD), we determined whether changes occur in the expression of TRPC7 and SERCA2s, proteins implicated or known to be involved in SOCE, in B lymphoblast cell lines (BLCLs) from BD-I patients and comparison subjects., Methods: mRNA levels were determined in BLCL lysates from BD-I, BD-II, and major depressive disorder patients, and healthy subjects by comparative reverse transcriptase-polymerase chain reaction, and BLCL basal intracellular Ca(2+) concentration ([Ca(2+)]B) was determined by ratiometric spectrophotometry using Fura-2, in aliquots of the same cell lines, at 13-16 passages in culture., Results: TRPC7 mRNA levels were significantly lower in BLCLs from BD-I patients with high BLCL [Ca(2+)]B compared with those showing normal [Ca(2+)]B (-33%, p =.017) and with BD-II patients (-48%, p =.003), major depressive disorder patients (-47%, p =.049) and healthy subjects (-33%, p =.038). [Ca(2+)]B also correlated inversely with TRPC7 mRNA levels in BLCLs from the BD-I group as a whole (r = -.35, p =.027)., Conclusions: Reduced TRPC7 gene expression may be a trait associated with pathophysiological disturbances of Ca(2+) homeostasis in a subgroup of BD-I patients.

Quality of life is used to assess the overall impact of medical treatments from the patient's perspective. Because depression affects a person's ability to function at work and at home, the evaluation of various treatments must include an assessment of patients' physical, social and psychological status. This paper classifies and evaluates a variety of widely used health-related quality-of-life questionnaires that have potential value as outcome measures in the treatment of depression. The paper also outlines how these measures have been beneficial in the assessment of depressed patients. They reveal differences between patients with depression and control groups, are sensitive to change in status during treatment, have predictive value for outcome measures and provide additional information about timelines for improvement in psychosocial functioning, which may occur at a different rate than changes in other depressive symptoms. Despite the limitations of these questionnaires, they provide an important additional dimension to the evaluation of treatment with antidepressant medications.

Background: Although bipolar disorder is associated with substantial levels of disability, efforts to investigate the correlates of impairment have been meagre., Methods: Sixty-one euthymic patients with a diagnosis of bipolar disorder were administered a variety of quality of life measures, including a measure of community functioning entitled the Occupational Performance Questionnaire (OPQ). This measure included a Community Functioning Scale (CFS) that provides a rating of adaptive level of functioning that was compared with other clinical and functional indices., Results: The OPQ was found responsive to the assessment of community functioning among euthymic patients, as about one third of the patients did not meet the criteria for adequate level of community functioning. Moreover, a positive history for alcoholism or alcohol abuse and reported current levels of high anxiety were associated with the impairment in community functioning., Limitations: This study relied on self-report data derived from a measure of community functioning developed specifically for this study., Conclusion: Despite the preliminary nature of these findings, further investigation of the functional impairments associated with bipolar disorder is needed.

Objective: To examine the relationship between number of episodes and inter-episode functioning in bipolar disorder., Method: Sixty-four euthymic subjects with bipolar affective disorder completed the Medical Outcomes Questionnaire Short Form and the Global Assessment of Functioning Scale. Goodness-of-fit models were used to define the relation between episode number and level of function., Results: Non-linear logarithmic and power relations best described the association between number of episodes and outcome. Number of past depressions was a stronger determinant of outcome than past manias., Conclusion: Strategies to minimize the number of episodes experienced by patients with bipolar illness must be pursued aggressively if function is to be maintained, with particular attention given to minimizing episodes of depression.

Objective: To determine the frequency of obsessive-compulsive disorder (OCD) in inpatient subjects with bipolar disorder (BD) and to examine the clinical characteristics of BD subjects with OCD., Method: The sample consisted of 143 inpatient subjects with DSM-III-R BD-I and BD-NOS (BD-II), recovered from a current episode of either depression or mania. Demographic and clinical variables were obtained on the day of admission. Current comorbid conditions including OCD were determined by the Structured Clinical Interview for DSM-III-R Ifollowing recovery from the acute affective episode., Results: The frequency of current OCD was 7% (N = 10). All BD subjects with OCD were BD-II, were male, and had a diagnosis of current dysthymia. They had fewer episodes and a higher incidence of prior suicide attempts than bipolar subjects without OCD. None of the bipolar subjects with OCD fulfilled criteria for cyclothymia., Conclusions: Our findings suggest that BD-II, OCD, dysthymia, and suicidality cluster together in some subjects with BD. We discuss the clinical implications of our findings.

Intrauterine administration of the 5-lipoxygenase inhibitor nordihydroguariaretic acid (NDGA; 5 mg, bid) on Days 9-14 of the ovine estrous cycle (estrus = Day 0) delayed luteolysis and extended the duration of the estrous cycle (20+/-1, SD, vs. 16+/-1 days; P < 0.01). In control ewes, plasma concentrations of 13,14,dihydro-15-keto prostaglandin F2alpha increased significantly (P < 0.001) following i.v. administration of oxytocin (10 i.u.) on Day 14; in the nordihydroguariaretic acid-treated ewes, however, there was no such increase. In addition, concentrations of endometrial oxytocin receptors were significantly less (P < 0.01) in the nordihydroguariaretic acid-treated ewes (218+/-60 vs. 579+/-66 fmol/mg tissue). These results suggest that 5-lipoxygenase products of arachidonate metabolism may be involved in the control of ovine luteal function.

Metalloproteinases are members of a family of proteinases that remodel the extracellular matrix throughout the body. To test the hypothesis that metalloproteinases are regulated by gonadotropin-induced changes during follicular growth, rats were injected with eCG (20 IU, s.c.), and ovaries and serum were collected at the time of eCG administration (0 h) and at 6, 12, 24, 36, or 48 h later for analysis of metalloproteinase mRNA expression, metalloproteinase activity, and steroidogenesis. Serum estradiol levels increased from 18.9 pg/ml at 0 h to 503.8 pg/ml at 48 h. Analysis of mRNA expression was performed for collagenase-3, 72-kDa gelatinase, and 92-kDa gelatinase (n = 3-4). For collagenase-3, eCG stimulated a 32-fold increase in collagenase-3 mRNA at 48 h after eCG injection as compared to that in ovaries collected at the time of eCG administration (i.e., 0-h control). The mRNA levels for 72-kDa gelatinase were 2.8-fold compared to 0 h at 36 h after eCG treatment and returned to control levels by 48 h after gonadotropin treatment. Levels of the 92-kDa mRNA expression peaked at 24 h (4. 2-fold compared to 0 h) and returned to control levels by 36 h. Gel zymography revealed 3 gelatinolytic bands corresponding to the gelatinases of approximately 72 kDa, 92 kDa, and 105 kDa. Analysis of metalloproteinase activity as the degradation of collagen or gelatin per ovary showed an increase in gelatinolytic and collagenolytic activity between 12 and 48 h after eCG treatment. In summary, these findings demonstrate that the gonadotropin induction of folliculogenesis results in changes in the metalloproteinases that may be responsible for extracellular matrix remodeling associated with follicular growth.

Objective: To assess the family-of-origin characteristics of patients with bipolar disorder relative to those of control subjects., Method: Fifty-six euthymic patients meeting research diagnostic criteria for bipolar disorder and 21 control subjects completed the Family Environment Scale (FES) for the family they grew up with., Results: The 2 groups showed strikingly similar profiles on 10 indices of family functioning or structure., Conclusions: The results do not support the hypothesis that specific family attributes contribute to the development of bipolar disorder.

Intrauterine administration of nordihydroguaiaretic acid (5 mg, bid. NDGA), an inhibitor of the enzyme 5-lipoxygenase, on days 10-14 of the oestrous cycle, maintained luteal function and delayed oestrus in the ewe. The duration (mean +/- SD) of the oestrous cycle in the treatment group (n = 4) was 24 +/- 1 days, which was significantly (P < 0.001) longer than that of 16 +/- 1 days in vehicle-treated controls (n = 4); plasma progesterone concentrations were also significantly (P < 0.01) higher in the treatment group. On days 13 and 14 of the cycle (oestrus = Day 0) in the control group large pulses of 13,14-dihydro-15-keto prostaglandin F2alpha (PGFM) were evident, with mean (+/- SD) maximum concentrations of 232.5 +/- 66 and 415 +/- 309 pg ml(-1), respectively. In the treatment group, however, concentrations of PGFM were below detection level (< 50 pg ml(-1)). Similarly, in the control group, oxytocin release was highly pulsatile, with mean (+/- SD) peak concentrations of 21.8 +/- 5 and 18.5 +/- 6 pg ml(-1) on days 13 and 14, respectively; these were significantly (P < 0.01) higher than values of 7.6 +/- 3 and 6.1 +/- 3 pg ml(-1) in NDGA-treated ewes, where pulses were of relatively low amplitude. These results suggest that 5-lipoxygenase products of arachidonic acid metabolism may be involved in the positive feedback mechanism between luteal oxytocin and uterine PGF2alpha during luteolysis in the ewe.

The effects of close intra-arterial infusion of acetylcholine and adrenalin on ovarian secretion of progesterone and oxytocin were examined on Day 10 of the estrous cycle in goats (estrus = Day 0). Acetylcholine (15 micrograms/min) was without effect, but adrenalin (10 micrograms/min) significantly (P < 0.001) raised both progesterone and oxytocin concentrations in ovarian vein plasma. These results show that luteal hormone secretion is enhanced in the goat by beta-adrenergic stimulation and suggest that, as in the sheep and cow, there may be neuroendocrine involvement in the regulation of caprine luteal function.

Background: The importance of gender on the course and outcome in bipolar disorder (BD) has been widely acknowledged. The limited data suggest that the prevalence is similar between sexes but that the course of illness may be different. This study investigated gender differences in a clinic sample of patients with BD including a measure of subjects' perception of well-being and functioning., Methods: Euthymic outpatients attending a mood disorders clinic were systematically assessed. Measurements obtained included SADS-LV, Hamilton Depression Ratings scores, Young Mania Rating scores, and Medical Outcome Survey Short Form 20 items and Global Assessment of Functioning., Results: Women with BD have a later onset of mania, are more likely to have a rapid cycling course, experience mixed episodes, experience more depressive episodes and report more overall impairment in all MOS subscale scores with significant impairment in physical health and pain., Conclusions: Further investigation and replication of these differences need to be addressed including non-euthymic patients and during a longer period of systematic follow-up.

The effect of an intra-luteal injection of the 5-lipoxygenase (5-LO) inhibitor BWA4C (2 mg in 50 microl DMSO) on the secretion of oxytocin (OT) from the corpus luteum in response to a close-arterial infusion of prostaglandin (PG)-F2alpha (5 ng min(-1)) was examined in anaesthetised sheep. Within 30 minutes of administration both basal (pre-infusion) and PGF2alpha-stimulated OT release into the posterior vena cava were significantly (P<0.01) reduced. These results are consistent with the proposition that 5-LO products of arachidonic acid may modulate OT secretion from the ovine corpus luteum.

The effects of jugular infusions of adrenalin and the beta-adrenergic receptor antagonist propranolol on plasma concentrations of progesterone and oxytocin were examined at 2 different stages of the caprine estrous cycle. Adrenalin (25 micrograms.kg-1h-1) significantly (P < 0.05) increased oxytocin secretion on Day 3 and Day 10 of the cycle (estrus = Day 0); progesterone concentrations were significantly (P < 0.05) elevated on Day 10 alone. Propranolol had no effect on progesterone secretion yet significantly (P < 0.05) reduced oxytocin concentrations on Day 3. These results suggest that there may be neuroendocrine involvement in the regulation of luteal oxytocin secretion in the goat.

The aim of the study was to compare psychotic and nonpsychotic bipolar patients on demographic and outcome measures. Sixty two patients with bipolar disorder were divided into groups on the basis of psychosis during an index episode of mania. Groups were compared on demographic, clinical and outcome measures. Psychotic patients were more symptomatic during the index episode, but they did not differ from nonpsychotic patients on ratings of function and well being when euthymic. Psychosis occurring within the context of an exacerbation of mania does not seem to predict a poorer outcome when patients return to the euthymic state. A limitation of the present study is that it involves short-term outcome, but the data can be used to inform patients and family about the possibility of full recovery even in the psychotic form of mania.

The objective was to assess the extent and pattern of illness intrusiveness, one measure of quality of life, in subjects with bipolar disorder (BD) and to determine whether specific illness variables had influenced the degree of intrusiveness experienced. To compare findings from BD subjects relative to published findings for subjects with chronic medical conditions. The study involved the administration of a self-report assessment tool to euthymic outpatients with BD attending a university based hospital clinic. Of the 155 eligible participants, 112 completed a standardized psychiatric interview (SADS-L) and 87 of these met study criteria for euthymia and were approached to participate in the study. Sixty-eight completed self-report measures were returned. The main outcome measure was the Illness Intrusiveness Rating Scale (IIRS) which was analysed along with a composite measure of life events. It resulted that individuals' with BD experience significant illness intrusiveness into a number of life domains even after controlling for negative life events. Factors such as type of BD, the presence of a depressive episode in the preceding year and current Hamilton depression rating scale score contributed to the total illness intrusiveness. The degree of total illness intrusiveness experienced by individuals with BD was similar to that of subjects with multiple sclerosis and greater than subjects with end stage renal disease and rheumatoid arthritis. It seems apparent that quality of life, as determined by illness intrusiveness, is compromised in subjects with BD even during periods of euthymia. BD is at least as intrusive as several chronic medical conditions. Those with a type II BD report greater impairment in all domains compared with type I. Future research should determine specific psychosocial interventions aimed at reducing the impact of BD.

The purpose of this study was to examine personality differences among three different Axis I disorders-recovered patients with unipolar depression (n = 62), euthymic patients with bipolar disorder (n = 34), and patients with schizophrenia in the residual phase of their illness (n = 41) using the five-factor model of personality (FFM). The dimensions of the FFM-Neuroticism (N), Extraversion (E), Openness (O), Agreeableness (A), and Conscientiousness (C)-were measured with composite scores derived from the NEO Personality Inventory (NEO PI) and the Revised NEO Personality Inventory (NEO PI-R). While no group differences emerged on N or C, the bipolar patients scored significantly higher on the Positive Emotion facet (subscale) of E than the unipolar patients. The schizophrenic patients scored lower on the Feelings, Values and Actions facets of O than did the unipolar and bipolar patients. The unipolar patients scored higher on A than the schizophrenic patients.

We examined differences between personality characteristics of euthymic bipolar disorder patients (BD) (n = 34) and recovered unipolar depressed patients (UD) (n = 74) using the taxonomy of the Five-Factor Model of personality (FFM) as measured by composite scales derived from the NEO Personality Inventory (NEO PI) and the revised NEO PI (NEO PI-R). Euthymic BD patients scored significantly higher on the Openness (O) dimension and the Positive Emotions facet of the E dimension than did recovered UD patients. For O, euthymic BD patients scored higher on the Feelings facet. These results suggest not only that euthymic BD patients are more likely to experience positive affects than recovered UD patients, but also that euthymic BD patients are more receptive to their positive and negative feelings than are recovered UD patients.

Two brief patient-rated scales, the Internal State Scale (ISS) and the Self-Report Manic Inventory (SRMI), have been shown to reliably diagnose mania. In the current study we further evaluated the utility of these scales relative to each other and to the observer-rated Young Mania Rating Scale (YMRS), for quantifying the severity of manic/hypomanic symptoms cross-sectionally and over time, in 20 patients with rapid-cycling bipolar disorder. The self-report scales correlated well with each other and with the YMRS, but each covered a somewhat different domain of the manic syndrome. The SRMI and the ISS were more sensitive than the YMRS to the mood fluctuations in the euthymic to hypomanic range observed in our subjects. Used in tandem, the two self-report scales may find application in clinical research with outpatients with bipolar disorder, and as an adjunct to clinical monitoring in this patient population.

Sixty-eight euthymic outpatients diagnosed with bipolar disorder according to Research Diagnostic Criteria, based on structured assessment, completed the 20-item short form of the Medical Outcomes Study (MOS) questionnaire (SF-20). Patients' mean scores on the 6 SF-20 subscales fell within or below the range of mean scores reported for patients with chronic medical illness and major depression in the MOS. Thus, BD, even in clinical remission, is associated with marked reductions in self-reported functioning and well-being, confirming the importance of the disorder as a major public health problem, meriting substantial resources for research and treatment.

Objective: The authors examined the prevalence of binge eating disorder (BED), partial binge eating syndrome, and night binge eating syndrome in subjects with bipolar disorder (BD)., Method: Sixty-one subjects in whom BD was established using DSM-III-R criteria received a semistructured clinical interview including a detailed description of binge eating behavior and of night binge eating. Frequencies were compared to prevalence estimates in community samples., Results: Eight subjects (13%) met DSM-IV criteria for the diagnosis of BED. An additional 15 subjects (25%) exhibited a partial binge eating syndrome. These two otherwise identical groups of binge eaters were separated only by the DSM-IV frequency criterion. The rates found were higher than rates found in community samples. Ten subjects reported night binge eating in addition to their usual binge eating behavior. This occurred consistently between 2:00 and 4:00 a.m., Conclusions: Possible underlying mechanisms for the high frequency of binge eating among bipolar subjects are discussed including a model of serotonin-mediated self-modulation of mood. The finding of two groups of binge eaters separated only by the frequency criterion raises questions as to whether the frequency criterion as presently defined in DSM-IV is valid or should be modified.

Serum Mg2+ has been implicated in the symptom severity and pathophysiology of mood disorders. Furthermore, the recent findings of blunted signalling through the G-protein-coupled adenylyl cyclase (AC) pathway in major depressive disorder (MDD) and the importance of Mg2+ in G-protein/AC function led us to reexamine in a large sample whether serum Mg2+ concentrations were decreased in MDD patients. In 145 drug-free MDD patients compared with 2 control groups: (a) patients with bipolar disorder (n = 33) and (b) non-mood-disordered patients (n = 47), there were no differences in Mg2+ levels or Ca2+/Mg2+ ratios. Neither of these measures differed when comparing responders and nonresponders to antidepressant treatment.

The harm avoidance (HA) personality dimension has been hypothesized to be a vulnerability factor for unipolar depression (UD) but not for bipolar disorder (BD). The reported difference on HA scores between these diagnostic groups may have been compromised by the assessment of BD patients who had not fully recovered. To test the diagnostic specificity of elevated HA scores and to elucidate whether assumptions about differences between patients with UD or BD might be attributed to the lingering effects of mood state, the Tridimensional Personality Questionnaire (TPQ) was administered to recovered patients with either BD or UD and a nonpatient comparison group. Both patient groups scored higher on the HA dimension than the nonpatient comparison group, but the patient groups did not differ from one another on this dimension. Moreover, novelty seeking (NS) scores were elevated in subjects with BD compared with both UD patients and nonpatient subjects. These results suggest that high HA scores may be associated with a mood disorder diagnosis, whereas high NS scores may be associated with the BD subtype.

The comorbidity of OCD and bipolar disorder has not been systematically examined. Therefore, we determined the frequency of patients meeting DSM-III criteria for OCD syndrome in a sample of 149 inpatients with DSM-III major affective disorder who had received a clinically reviewed structured diagnostic interview. The frequency of OCD syndrome was not significantly different between subjects with major depression (35.2%, n = 105) and bipolar disorder (35.1%, n = 37). This suggests that OCD is equally common in bipolar as in unipolar patients.

Prostaglandin (PG)F2 alpha, in the dose range 1-10(4) nM, failed to elicit oxytocin secretion in vitro from ovine luteal tissue on day 12 of the estrous cycle (estrus = Day 0), during a 60 minute period. Preincubation of luteal slices for 6 hours prior to treatment suggested that tissue desensitization due to the release of endogenous prostaglandins by tissue preparation is not responsible for this lack of response. However, in luteal tissue collected on day 6 of the ovine estrous cycle, PGF2 alpha stimulated oxytocin release in a dose-dependent manner. This apparent change in sensitivity of the ovine corpus luteum in vitro may be due to a combination of a reduction in the luteal oxytocin available for release and saturation of PGF2 alpha receptors in the more mature tissue.

The relationship between Grade II subclinical hypothyroidism and mixed affective states were examined in a cohort of 66 patients with bipolar affective disorder. The overall frequency of Grade II subclinical hypothyroidism was 20%. There was no difference in frequency of subclinical hypothyroidism or in mean thyroid hormone levels between the mixed state and non-mixed-state group.

Intrauterine administration of nordihydroguaiaretic acid (NDGA) will maintain luteal function in sheep and also suppress the release of both oxytocin and prostaglandin F2 alpha (PGF2 alpha) suggesting that 5-lipoxygenase products of arachidonic acid may be involved in ovine luteolysis. During luteolysis, uterine PGF2 alpha is considered to be the major stimulus for the secretion of luteal oxytocin, and we report the effects of 5-lipoxygenase inhibition, via intrauterine NDGA administration, on the ability of PGF2 alpha to effect such secretion. In the NDGA-treated ewes, luteal function was maintained and oestrus delayed, the duration of the oestrous cycle (20 +/- 1 days; mean +/- S.D.; n = 9) being significantly (P < 0.01) longer than in intact controls (15 +/- 1 days, n = 4). Jugular infusions of PGF2 alpha did not stimulate luteal secretion of oxytocin, the effects being comparable with those in ovariectomized ewes. In intact ewes receiving intrauterine infusions of vehicle only, PGF2 alpha produced marked increases in luteal secretion of oxytocin. Also, preinfusion or basal concentrations of oxytocin in this group of ewes (6.6 +/- 1.9 pg/ml) were significantly (P < 0.01) greater than in either the NDGA-treated (3.1 +/- 1.1 pg/ml) or ovariectomized (3.0 +/- 0.6 pg/ml) ewes. The results suggest involvement of 5-lipoxygenase products of arachidonic acid in the release of oxytocin from the ovine corpus luteum.

Increased peripheral plasma concentrations of testosterone were detected in goats on days 13 and 14 of the oestrous cycle (oestrus = day 0), at the onset of luteolysis. Subcutaneous administration of spironolactone (10 mg kg-1 day-1) on days 10 to 19 inhibited the increases in testosterone, delayed luteolysis and suppressed plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha and oxytocin. These results suggest that testosterone of follicular or luteal origin, possibly via aromatisation to oestrogens, is needed to expedite luteolysis and induce oestrus in the goat.

Adrenaline (10(-6)-10(-4)M), serotonin (10(-6)-10(-4)M), and several other potential steroidogenic agonists failed to enhance either basal or LH-stimulated progesterone production from dispersed caprine luteal cells from Day 10 of the estrous cycle. The caprine corpus luteum (CL) would appear to be more refractory to exogenous stimulation than either the ovine or bovine CL.