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This study's purpose was to develop a reliable and valid self-report questionnaire, the Child-Adolescent Suicidal Potential Index (CASPI), to screen for risk for suicidal behavior in children and adolescents. Four hundred twenty-five child and adolescent psychiatric patients and nonpatients completed the CASPI and other research instruments to rate suicidal and assaultive behavior and symptoms of depression, anxiety, and hopelessness. The 30-item CASPI involves 3 factors (anxious-impulsive depression, suicidal ideation or acts, family distress) that contributed to a unidimensional 2nd-order factor accounting for 59% of the total variance. Internal consistency (alpha) for the total score was .90, and test-retest reliability (ICC) for the total score was .76. Total score distinguished between children and adolescents with different severity of psychopathology and different levels of suicidal and assaultive behavior. Each of the 3 factors had different contributions to discriminating between levels of suicidal status. CASPI total score of 11 distinguished suicidal ideation or acts from nonsuicidal behavior, with sensitivity 70% and specificity 65%. CASPI total score positively correlated with symptom severity of depression, anxiety, and hopelessness.

Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Up-regulation of SREBP-1 also occurred in livers of Sprague-Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.

The vulnerability of streptozotocin (STZ)-induced diabetic rats to cold stress has been established. One of the elements controlling body temperature is thermogenesis, in which uncoupling protein (UCP) is known to play an important role. We have examined UCP2 and UCP3 expressions in brown adipose tissue (BAT), white adipose tissue (WAT), and skeletal muscle (MSL) during the acute and chronic phases of STZ-induced diabetes in rats. The long-term effect and the effect of insulin treatment thereafter were also unexplored previously and are examined in this study. In the acute phase of diabetes (2.5 days after STZ injection), UCP2 gene expression in BAT, WAT, and MSL, and UCP3 expression in the muscle were significantly increased. In the chronic phase of diabetes (21 days after STZ injection), UCP2 and UCP3 expression in the MSL were restored to the control levels without insulin supplementation. UCP2 in BAT and WAT remained high in the chronic phase, whereas UCP3 expression in BAT and WAT, which did not change in the acute phase, was significantly decreased. Insulin supplementation restored UCP2 expression in BAT and WAT, but over-corrected UCP3 in WAT above the control and did not affect UCP3 expression in BAT. Insulin supplementation depressed UCP3 expression in the MSL below control. These results indicate that the effects of STZ-induced diabetes on UCPs gene expression are tissue-specific as well as dependent on the duration of diabetes.

One hundred seven community-dwelling elderly patients with Alzheimer disease were enrolled in a study to evaluate the characteristics specific to the patients' and caregivers' situations that are associated with behavioral disturbances and to examine how these disturbances are related to caregiving stress. The frequencies of the disturbance were assessed by using the Troublesome Behavior Scale according to its three categories, agitation, hyperactivity, and miscellaneous. The patients' characteristics found to contribute most to their own behavioral disturbances were visual and speech function, activities of daily living, years of education, cognitive function, and sex, whereas the caregivers' characteristics contributing to these disturbances were duration of caregiving, age of caregiver, and relationship to the patient. In addition, a mutual relation among the three categories was found. Among the three categories, agitation was most strongly related to the caregivers' psychologic health status rated by use of the General Health Questionnaire. Behavioral disturbance as a whole was the only predictor of the patient's institutionalization within 2 years after baseline examination. Thus, behavioral disturbances were found to be influenced by the personal characteristics and situational circumstances of both the patient and caregiver, influencing, in turn, the caregivers' psychologic health status.

The authors examined the cognitive profiles of 104 older adults with major depression and empirically identified three subgroups with distinct patterns of cognitive impairment. The entire sample demonstrated memory impairment relative to age-standardized scores, distributed equally across the three cognitive subgroups. One-third of subjects displayed either executive impairment or attentional deficits. The subgroup with executive dysfunction had greater behavioral disability. Identification of executive impairment in depressed older adults may facilitate intervention for disturbances in planning, sequencing, organizing, and abstracting. Demonstrating the presence of subtypes of cognitive impairments in older adults may provide the basis for further investigation of mechanisms of late-life depression and the pathophysiology of antidepressant response. The association of behavioral disability with executive dysfunction can initiate an inquiry into the biology of functional impairment ultimately linking biological research to studies of treatment effectiveness.

Background: This study investigated the relationship of executive and memory impairment to relapse, recurrence, and course of residual depressive symptoms and signs after remission of geriatric major depression., Methods: Fifty-eight elderly subjects remitted from major depression received continuation nortriptyline treatment (plasma levels 60-150 ng/mL) for 16 weeks and then were randomly assigned to either nortriptyline maintenance therapy or placebo for up to 2 years. Diagnosis was made using the Research Diagnostic Criteria and the DSM-IV criteria after an interview using the Schedule for Affective Disorders and Schizophrenia. Executive dysfunction and memory were assessed with the Dementia Rating Scale, disability and social support were rated with the Philadelphia Multiphasic Instrument, and medical burden was assessed with the Cumulative Illness Rating Scale., Results: Abnormal initiation and perseveration scores, but not memory impairment, were associated with relapse and recurrence of geriatric depression and with fluctuations of depressive symptoms in the whole group and in subjects who never met criteria for relapse or recurrence during the follow-up period. Memory impairment, disability, medical burden, social support, and history of previous episodes did not significantly influence the outcome of depression in this sample., Conclusions: Executive dysfunction was found to be associated with relapse and recurrence of geriatric major depression and with residual depressive symptoms. These observations, if confirmed, will aid clinicians in identifying patients in need of vigilant follow-up. The findings of this study provide the rationale for investigation of the role of specific prefrontal pathways in predisposing or perpetuating depressive syndromes or symptoms in elderly patients.

The principal aim of this study was to investigate possible neurophysiological underpinnings of self-injurious behavior in women with borderline personality disorder (BPD). Pain report and EEG power spectrum density during a laboratory pain procedure, a 4-min 10 degrees C cold pressor test (CPT), were compared among four groups; female inpatients with BPD who do (BPD-P group, n = 22) and do not (BPD-NP group, n = 19) report pain during self-injury, female inpatients with major depression (n = 15), and normal women (n = 20). The BPD-NP group reported less pain intensity during the CPT compared to the other groups. Total absolute theta power was significantly higher in the BPD-NP group compared to the Depressed (P = 0.0074) and Normal (P = 0.0001) groups, with a trend toward being significantly higher compared to the BPD-P group (P = 0.0936). Dissociative Experience Scale scores were significantly higher in the BPD-NP group compared to the Depressed and Normal groups (maximum P = 0.0004), and significantly higher in the BPD-P group compared to the Normal group (P = 0.0016). Beck Depression Inventory and Sheehan Patient Rated Anxiety Scale scores were significantly lower in the Normal group compared to all patient groups. Theta activity was significantly correlated with pain rating (Pearson partial r = -0.43, P = 0.0001) and Dissociative Experiences Scale score (Pearson partial r = 0.32, P = 0.01).

Background: The aim of this study was to find clinical characteristics that can identify elderly patients with depression at risk for suicidal ideation and to determine their prognosis., Method: Suicidal ideation, past suicidal behavior, severity of depression, cognitive impairment, medical burden, disability, and social support were studied in 354 patients with depression aged 61 to 93 years. The patients had in-person evaluations every 6 months and telephone evaluations for a mean of 1.8 years (SD, 2.2)., Results: During the index episode, suicidal ideation was predicted by previous suicide attempts with serious intent (odds ratio [OR], 2.82; 95% confidence interval [CI], 1.37-5.80), severity of depression (OR, 1.09; 95% CI, 1.03-1.16), and poor social support (OR, 1.77; 95% CI, 1.18-2.65). Suicide attempts during the year prior to entry were reported by patients with a severe index episode (OR, 1.05; 95% CI, 1.00-1.11), impaired instrumental activities of daily living (OR, 0.78; 95% CI, 0.67-0.93), and limited impairment in activities of daily living (OR, 1.53; 95% CI, 1.10-2.14). At the initial evaluation, severity of depression, previous attempts, and seriousness of suicidal intent during previous attempts predicted the course of suicidal ideation (concordance correlation, 0.78). During follow-up, contemporaneous severity of depression was the most important determinant of suicidal ideation over time (concordance correlation, 0.88)., Conclusions: Elderly individuals with severe depression, history of suicide attempts with serious intent, and poor social support are most likely to have suicidal ideation and should be targeted for appropriate interventions. Severity of depression is the strongest predictor of the course of suicidal ideation.

The aim of the present study was to determine the longitudinal course of behavioral disturbances and to examine whether these disturbances are stage dependent during the course of Alzheimer disease (AD). One hundred seven community-dwelling patients with probable AD were assessed up to six times annually by using a validated and reliable rating scale, the Troublesome Behavior Scale, for assessing the frequencies of behavioral disturbances. The subjects were divided into three groups according to their baseline global function as assessed by the Clinical Dementia Rating (CDR; 1 = mild, 2 = moderate, 3 = severe). At the end of the 5-year observation period, 31 subjects were still active participants, 52 had died, 20 lived in institutions, and 4 had stopped participating. The patterns of their behavioral disturbance changes depended to a considerable extent on the baseline severity of the illness. The behavioral disturbance frequencies generally peaked at the CDR 2 stage and followed a downward trend thereafter. Considerable individual variations in the disturbance frequencies during the course of the illness were observed. Knowing the behavioral course of AD will enable clinicians to better counsel families and appraise the results of treatments for behavioral symptoms.

Serum alpha(1)-acid glycoprotein (AAG) reportedly can increase with age in the normal population, especially among women. In 33 patients with unipolar major depression or bipolar disorder, serum AAG was measured by age. The authors noted a positive association with age, particularly in depressed female patients (n=18; r(s)=0.61; P<0.01). The authors discuss implications for drug pharmacokinetics. Investigation of AAG in mood disorders needs to take age and sex into consideration.

To determine whether the depletion of body fat caused by adenovirus-induced hyperleptinemia is mediated via the hypothalamus, we used as a "bioassay" for hypothalamic leptin activity the hypothalamic expression of a leptin-regulated peptide, cocaine- and amphetamine-regulated transcript (CART). The validation of this strategy was supported by the demonstration that CART mRNA was profoundly reduced in obese rats with impaired leptin action, whether because of ablation of the ventromedial hypothalamus (VMH) or a loss-of-function mutation in the leptin receptor, as in Zucker diabetic fatty rats. We compared leptin activity in normal rats made hyperleptinemic by adenovirus-leptin treatment (43 +/- 9 ng/ml, cerebrospinal fluid leptin 100 pg/ml) with normal rats made hyperleptinemic by a 60% fat intake (19 +/- 4 ng/ml, cerebrospinal fluid leptin 69 +/- 22 pg/ml). CART was increased 5-fold in the former and 2-fold in the latter, yet in adenovirus-induced hyperleptinemia, body fat had disappeared, whereas in high-fat-fed rats, body fat was abundant. Treatment of the high-fat-fed rats with adenovirus-leptin further increased their hyperleptinemia to 56 +/- 6 ng/ml without changing CART mRNA or food intake, indicating that leptin action on hypothalamus had not been increased. Nevertheless, their body fat declined 36%, suggesting that an extrahypothalamic mechanism was responsible. We conclude that in diet-induced obesity body-fat depletion by leptin requires supraphysiologic plasma concentrations that exceed the leptin-transport capacity across the blood-brain barrier.

Human chorionic gonadotropin (hCG) exhibits molecular heterogeneity in both its protein and carbohydrate moieties. This communication describes changes in hCG isoforms detected directly in clinical samples. These isoforms, quantified in blood or urine specimens, show a progression of change throughout normal pregnancy. Early pregnancy produces a type of hCG that resembles, in terms of immunoreactivity, a major form of hCG excreted in choriocarcinoma. The isoforms predominate for the first 5-6 weeks of gestation and then diminish, being replaced with the hCG isoforms which predominate throughout the remainder of pregnancy. The alteration in hCG isoform content occurs in both blood and urine. The progression of isoforms is best delineated by calculating the change in the ratio of the two forms, as many hCG assays either do not detect or fail to discriminate among these isoforms. An analogous pattern of hCG isoforms was observed in patients with in vitro fertilization pregnancies. hCG isolated from the pituitary displayed binding characteristics similar to those of the hCG derived from normal pregnancy urine. The early pregnancy hCG isoforms appear to have a differential expression in normal pregnancy as opposed to pregnancies which will not carry to term, suggesting that a determination of the relative balance of hCG isoforms may have diagnostic application in predicting pregnancy outcome.

In geriatric patients with major depression (N=15), the authors compared response to treatment with nortriptyline as it relates to brain morphology assessed by computed tomography. There was a significant negative association between ventricle-brain ratio and response to nortriptyline (rs=-0.63; P=0.015).

Background: Decreased dopamine beta-hydroxylase (DBH) activity has been reported in unipolar psychotic depression. DBH comparisons between elderly delusional and nondelusional depressives and controls and determination of whether pretreatment group differences persist have not been reported. Our objective was to compare DBH activity in elderly delusional major depressives with that of nondelusional depressives and normal control subjects before and after hospital treatment., Methods: Enzyme activity was assessed after hospital admission. A subsample had predischarge assessments. Treatment was not controlled but accounted for in analyses. Electroconvulsive therapy subjects were medication-free for posttreatment assays., Results: Baseline and predischarge DBH assays were lower in subjects with delusional depression than in either comparison group. Despite high intraindividual correlation, treatment was associated with significant increases in activity in the clinical groups., Conclusions: Patients with late-life delusional depression have lower DBH activity before and after hospital treatment than age-matched nondelusional patients or normal controls.

Diabetic rats have a deficiency in their heart ATP concentrations, and although the mechanism remains to be elucidated, this deficiency may involve increased uncoupling of oxidative phosphorylation. To investigate whether heart uncoupling proteins (UCPs) are subject to transcriptional regulation in diabetes, we examined changes in UCP mRNA expression in the heart of streptozotocin-induced diabetic (STZ-DM) rats. Heart UCP3 mRNA expression significantly increased by 9.4-fold in STZ-DM rats, while levels of UCP2 mRNA expression were not significantly altered. Insulin supplementation in STZ-DM rats returned UCP3 mRNA concentrations to control levels. The expression of UCP3 mRNA was similarly elevated in the heart of fasted rats, which also have hypoinsulinemia and hyper-free fatty acidemia but, unlike the STZ-DM rats, are hypoglycemic. Since hyperinsulinemia alone was previously reported to not affect UCP3 gene expression in the muscle, these results indicate that hyper-free fatty acidemia is a potent enhancer of UCP3 gene expression in the diabetic rat heart. Interestingly, we found no changes in UCP3 mRNA levels in Zucker fatty (fa/fa) rats with excessive chronic hyper-free fatty acidemia, which suggests that upregulation of heart UCP3 mRNA may depend on an acute change in free fatty acid concentrations rather than on their sustained elevation. High-energy ATP deficiencies in the diabetic rat heart may primarily result from proton leakage due to the upregulation of UCP3 expression.

A family of uncoupling proteins (UCPs), free fatty acid anion transporters, plays a crucial role in energy homeostatic thermoregulation. Tumor necrosis factor-alpha (TNF-alpha), a member of the cytokine family, is well known as an endogenous pyrogen. To evaluate the interaction of TNF-alpha with UCPs in thermogenesis, effects of TNF-alpha on rat UCP gene expression were examined in intrascapular brown adipose tissue (BAT), epididymal white adipose tissue (WAT) and soleus muscle (Muscle). Administration of TNF-alpha elevated rectal temperature by 0.7 degree C as well as serum leptin which peaked at 6 h, compared with saline controls. BAT UCP1 mRNA expression was increased by 1.2-fold at 6 h after the TNF-alpha treatment and decreased by 0.8-fold at 16 h after the treatment. In contrast to UCP1 expression in BAT, UCP2 mRNA expressions in BAT, WAT, and Muscle was increased to reach maximum levels of 1.3-, 1.6- and 1.8-fold, respectively, at 16 h after the treatment. UCP3 mRNA in Muscle, but not in BAT or WAT, was exclusively up-regulated by 1.7-fold at 16 h after the treatment. These results indicate that TNF-alpha up-regulates UCP gene expression differentially and tissue dependently, and add novel insights into thermogenesis under conditions of malignancy and inflammation.

We report the development and characterization of an IRMA for the direct measurement of nicked human chorionic gonadotropin (hCGn) in blood and urine. hCGn derived from a reference preparation of hCG used as an immunogen elicits monoclonal antibodies (mAbs) with enhanced recognition of human luteinizing hormone epitopes. The most specific assay for pregnancy hCGn is an IRMA composed of one mAb to choriocarcinoma-derived hCGn (C5) and a second mAb developed from immunization with normal-pregnancy hCGn. This assay was used to evaluate hCGn profiles in normal, in vitro fertilization, Down syndrome, and ectopic pregnancies. In all pregnancies, hCGn was usually present in much lower concentrations than the non-nicked hCG isoform. Our results suggest that some form of physical separation from the overwhelming quantities of non-nicked hCG present in clinical specimens will be required before accurate immunochemical estimations of hCGn can be made.

Background: The cytokine tumour necrosis factor (TNF) alpha has been reported to induce metabolic abnormalities such as anorexia and thermogenesis. To investigate functional modulators of uncoupling protein-2 (UCP2) gene expression, we examined the effects of TNF-alpha on UCP2 mRNA expression in rats., Methods: Mature male Wistar King A (WKA) rats at 10-11 weeks of age were treated with recombinant human TNF-alpha at a dose of 0.6 nmol 100 g-1 body weight by intraperitoneal administration., Results: TNF-alpha treatment induced an increase in UCP2 mRNA expression in broadly distributed tissues including brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle, and an elevation of ob gene mRNA expression in WAT. After the TNF-alpha treatment, an increase in plasma leptin concentration occurred in an ob gene-dependent manner, accompanied by an anorectic effect., Conclusion: The present results provide evidence for a new regulatory loop involving TNF-alpha and UCP2, and add novel insights into the regulatory mechanisms of energy homeostasis.

Early pregnancy loss (EPL), detected by patterns of human chorionic gonadotrophin (hCG) in urine, is the biomarker employed in investigations of the impact of personal, workplace or environmental reproductive toxins on human fertility. An issue central to these studies is what, in terms of urinary hCG expression, constitutes an EPL. This report describes the urinary molecular forms of hCG expressed in menstrual cycles in which a normal pregnancy was conceived, or an EPL occurred, or no apparent conception occurred. Qualitative and significant quantitative differences in the expression of hCG-associated analytes were found between normal pregnancy cycles and EPL cycles. Discriminant analysis calculation based on mole fractions of the different hCG-associated molecules afforded 91 per cent and 80 per cent correct classification of clinical pregnancy cycles and EPL cycles, respectively. Although hCG-associated molecules unique to either EPL or normal pregnancy were not found, what is thought to be an early form of hCG is expressed both at a high frequency and at a significantly higher concentration in early normal pregnancy when compared with EPL. The relative absence of this molecule very early in pregnancy may signal a pregnancy loss.

Background: This study reports relationships between suicidal behavior and its risk factors in prepubertal children and whole blood and platelet serotonin-related measures., Methods: Seventy-five prepubertal psychiatric inpatients including 23 (30.7%) nonsuicidal, 32 (42.7%) with suicidal ideation, and 20 (26.6%) with a suicide attempt were compared to 35 normal prepubertal controls with regard to platelet serotonin content, serotonin-amplified platelet aggregation, and whole blood tryptophan., Results: Mean whole blood tryptophan content was significantly lower among inpatient children with a recent suicide attempt than among normal controls or inpatients with suicidal ideation (F = 3.94, df = 3.54, p < or = .01). Inpatient children with a mood disorder had significantly higher platelet serotonin content than inpatients without a mood disorder (F = 3.86, df = 2.80, p < or = .03). Racial/ethnic differences were also observed for inpatients and normal controls, with whites having significantly lower levels of platelet serotonin (expressed as ng/mL blood or ng/10(9) platelets) than blacks or Latinos. Blacks had significantly higher levels of whole blood tryptophan than other racial/ethnic groups., Conclusions: The results suggest that whole blood tryptophan and platelet serotonin content should be studied for their predictive validity as risk factors for suicidal behavior in youth while controlling for racial/ethnic differences.

In our previous studies patients with schizophrenia and their parents had less frequent eye fixations and a more limited area of inspection than normal controls while freely viewing stationary S-shaped figures. The present study attempted to discriminate schizophrenics from non-schizophrenics using exploratory eye movements. Two groups (A and B) were formed, each comprising 30 schizophrenic and 70 non-schizophrenic subjects (10 each of patients with depression, methamphetamine psychosis, alcohol psychosis, anxiety disorder, temporal lobe epilepsy, frontal lobe lesions and healthy normal controls). Discriminant analysis was performed on group A to obtain a discriminant. The validity of applying this discriminant to group B was investigated. By focussing on exploratory eye movements, schizophrenics could be discriminated from non-schizophrenics with a sensitivity of 76.7% and a specificity of 81.4%. These results show that exploratory eye movements are a useful discriminator for schizophrenia.

Standard family history and family study methods were used with 650 first- and 1174 second-degree biological relatives of 133 adolescents who were studied initially 6 to 8 years ago. They included 69 prepubertal children considered at risk for suicidal behavior and 64 prepubertal children selected from the community. This study aimed to identify relationships between family psychopathology and adolescents' lifetime history of suicidal states. Family discord, suicide attempts of mother, and substance abuse of mothers and fathers were significantly more prevalent among adolescents with lifetime history of a suicide attempt. Mothers' and fathers' substance abuse was associated with adolescents' lifetime history of suicidal ideation. Results highlight importance of evaluating and treating family psychopathology to reduce risk for youth suicidal states.

Objective: The purpose of this study was to determine if P300 latency is prolonged in geriatric depression and if longer P300 latency and deficits in initiation and errors of perseveration in depressed elderly patients are related to risk factors for vascular disease., Method: Geriatric patients with unipolar depression (N = 43) and elderly comparison subjects (N = 24) were assessed for depressive symptoms, cognitive functions, risk factors for vascular disease, and P300 latency., Results: Depressed elderly patients had longer P300 latency than normal elderly subjects. In the depressed patients, P300 latency was related to deficits in initiation and errors in perseveration. Risk factors for vascular disease were associated not only with P300 latency but also with deficits in initiation and errors in perseveration., Conclusions: Functional impairment of the cortico-striato-pallido-thalamo-cortical pathways from vascular disease, implicated in late-life depressive disorders, may explain not only deficits in initiation and errors in perseveration but also longer P300 latency in depressed elderly patients. These results are preliminary and need further examination with brain imaging and more sensitive neuropsychological measures.

X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HHG). Mutations of the DAX1 gene have been reported in patients with AHC and HHG. We found a novel DAX1 mutation in our patient. Sequence analysis of the patient's DAX1 demonstrated a 1-bp (G) deletion at codon 49 in exon 1. The mutation shifts the reading frame, resulting in completely different amino acid sequences from codon 49 to the premature stop codon at 84. The G was present at this position in the sequences of the father and 2 younger brothers. Direct sequence and single-strand conformation polymorphism analyses of polymerase chain reaction fragments revealed that the mutation at codon 49 was heterozygously present in the mother's DAX1 gene. The codon 84 is located in the first half of the DNA binding domain, and the mutation site is closer to the N-terminus than those in previously reported cases. The onset of adrenal insufficiency in the neonatal period as seen in our patient has also been reported in other patients with different DAX1 mutations, especially in a patient with DAX1 protein lacking 11 amino acids at the C-terminus. Therefore, it is less likely that position of termination codons correlate to clinical manifestations.

We isolated rat UCP2 cDNA, which has been proposed to play an important role in mammalian thermogenesis and body weight regulation. The nucleotide sequence of the cDNA revealed that the rat UCP2 protein is composed of 309 amino acid residues, and is 99% and 95% identical to the mouse and human proteins, respectively. The molecular weight of rat UCP2, calculated from the predicted amino acid sequence, was 33,369, and the UCP2 protein of this size was detected when the cDNA was expressed in vitro. Northern blot analysis revealed that the corresponding mRNA is approximately 1.7 kb in size, and is expressed in a variety of rat organs, with predominant expression in the heart, lung and spleen. UCP2 mRNA levels in the heart, liver, muscle and epididymal adipose tissue of Zucker fatty (fa/fa) rats were comparable to those in the lean littermates, while ob mRNA level markedly increased in the epididymal adipose tissue of Zucker (fa/fa) rats.

Evidence is rapidly emerging which suggests that uncoupling protein 2 (UCP2), by virtue of its ubiquitous expression, may be important for determining basal metabolic rate. To assess the functional modulation of UCP2 gene expression in relation to body weight control, we examined the effects of hyperthyroid state induced by chronic treatment with triiodothyronine (T3) on UCP2 mRNA expression in male rats. Daily subcutaneous injection of T3 (37 pmol/100 g body weight) for 7 days increased UCP2 mRNA expression in brown adipose tissue (BAT), white adipose tissue (WAT) and the soleus muscle 1.6-, 1.6- and 1.7-fold compared to the controls, respectively, and increased UCP1 mRNA expression in BAT 1.2-fold. In contrast, the same treatment with T3 decreased both ob mRNA expression in WAT and plasma leptin level 0.5-fold for each. The present results suggest that T3 may directly increase UCP2 expression independently of leptin action.

Objective: The purpose of this study was to examine whether the brainstem evoked responses of geriatric depressed patients with vascular disease show greater changes in wave V latency after increased stimulation than do responses of geriatric depressed patients without vascular disease and elderly comparison subjects with and without vascular disease., Method: Geriatric patients with unipolar depression (N = 53) were recruited from a university psychiatric hospital. Elderly comparison subjects (N = 23) were recruited through advertisements. All subjects were assessed for depressive symptoms, cognitive performance, overall medical burden, vascular disease, and disability. Brainstem evoked response was elicited at stimulation rates of 11.4 and 80.0 clicks/sec., Results: The interaction between depression and vascular disease had a significant effect on change in wave V latency. This effect was synergistic, more than an additive effect. Post hoc comparisons showed that the depressed patients with vascular disease had greater changes in wave V latency that did the depressed patients without vascular disease, comparison subjects with vascular disease, and comparison subjects without vascular disease. Linear discriminant function analysis showed that 82% of the subjects with abnormal changes in wave V latency (sensitivity: 75%, specificity: 81%) could be identified on the basis of ratings for depression and vascular disease., Conclusions: Demyelination afflicting the pons and mesencephalon may explain the greater change in wave V latency for the brainstem evoked response in depressed patients with vascular disease. Further studies combining brainstem evoked response with brain imaging may determine whether depression develops only after vascular disease leads to demyelination.

Signal detection theory measures of thermal responsivity were examined to determine whether differences in reported pain experienced during self-injurious behavior in female patients with borderline personality disorder (BPD) are explained by neurosensory factors and/or attitudinal factors (response bias). Female patients with BPD who do not experience pain during self-injury (BPD-NP group) were found to discriminate more poorly between noxious thermal stimuli of similar intensity, low P(A), than female patients with BPD who experience pain during self-injury (BPD-P group), female patients with BPD who do not have a history of self-injury (BPD-C group), and age-matched normal women. The BPD-NP group also had a higher response criterion, B (more stoical) than the BPD-C group. These findings suggest that 'analgesia' during self-injury in patients with BPD is related to both neurosensory and attitudinal/psychological abnormalities.

Objective: The authors' goal was to examine the clinical presentation of a group of depressed elderly patients with clinically defined risk factors for vascular depression compared with a group of elderly depressed patients without such risk factors., Method: Cognitive deficits, disability, and depressive symptoms were examined in 33 consecutively recruited elderly patients defined as having vascular depression and 32 patients defined as having nonvascular depression according to their scores on the Cumulative Illness Rating Scale-Geriatrics., Results: The patients with vascular depression had greater overall cognitive impairment and disability than those with nonvascular depression. Fluency and naming were more impaired in patients with vascular depression, and they had more retardation and less agitation as well as less guilt feelings and greater lack of insight., Conclusions: The symptoms of vascular depression are consistent with lesions that may damage striato-pallido-thalamo-cortical pathways and other areas. The concept of vascular depression can provide the impetus for investigations of prevention and treatment of cerebrovascular disease and for studies of the course of vascular depression and selection of antidepressants.

The authors assessed the limits of reliable history-taking in depressed elderly patients (N = 20) with some cognitive impairment. Each subject and an informant was interviewed with structured instruments by two trained raters. An expert panel formed consensus judgments after reviewing information reported by the patients, the informants, and each of the clinical raters. Intraclass correlation between the two raters was 0.99 for the duration of depressive episodes and 0.88 for age at onset. The raters agreed on the duration of major depressive episodes in 85% of cases and on age at onset in 80% of cases. The duration of previous depressive episodes and age at depression onset cannot always be determined reliably even when informants and structured interviews are used. Greater difficulties may be encountered in patients with minor depression or chronic intermittent depression and early-onset depression. Clinicians should obtain history from as many reliable sources as possible and critically evaluate this information while considering the entire clinical picture. The aggregate kappa statistic can provide a clinically meaningful way of assessing interrater reliability of psychopathological constructs for which several definitions are used.

An enzyme, 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase), is present in various organisms and plays an important role in the control of spontaneous mutagenesis. The enzyme hydrolyzes 8-oxo-dGTP, an oxidized form of dGTP, to 8-oxo-dGMP, thereby preventing the occurrence of A:T to C:G transversion, caused by misincorporation. We isolated the mouse genomic sequence encoding the enzyme and elucidated its structure. The gene, named MTH1 for mutT homologue 1, is composed of at least five exons and spans approximately 9 kilobase pairs. A genomic region containing the pseudogene was also isolated. The promoter region for the gene is GC-rich, contains many AP-1 and AP-2 recognition sequences, and lacks a typical TATA box. Primer extension and S1 mapping analyses revealed the existence of multiple transcription initiation sites, among which a major site was defined as +1. The putative promoter region was placed upstream of the chloramphenicol acetyltransferase reporter gene, and control of expression of the gene was examined by introducing the construct into mouse NIH 3T3 cells. Deletion analysis indicated that a sequence from -321 to +9 carries the basic promoter activity while an adjacent region, spanning from +352 to +525 stimulates the frequency of transcription.

Distortions in interpersonal perceptions among patients with borderline personality disorder (BPD) were explored to investigate the validity of object relations theories. Depressed patients with BPD were compared to patients with major depressive disorder (MD) without BPD. Subjects were 77 male and female inpatients (BPD = 55, MD = 22). The mean ages were 30.5 for BPD subjects and 36.3 for MD subjects. Perceptions of patients, relatives, and interviewers were compared on the following measures: Structural Analysis of Social Behavior, Perceived Criticism Scale, and Camberwell Family Interview. Findings are consistent with object relations theory. BPD patients saw themselves as hostile, labile, and unstable. MD patients avoid acknowledging and responding to relatives criticallity.

Objective: The authors' purpose was to identify the relationship of disability to clinical measures that are part of a comprehensive psychiatric examination of depressed elderly patients., Method: The disability of 75 elderly inpatients and outpatients with major depression whose cognitive function ranged from normality to mild dementia was assessed with the Philadelphia Multilevel Assessment Instrument. Age at onset of depression, chronicity of depression, severity of depression, cognitive impairment, medical burden, social support and living environment were assessed with standardized instruments., Results: Impairment in instrumental activities of daily living was significantly associated with advanced age, severity of depression, and medical burden. The relationship of depressive symptoms to impairment in instrumental activities of daily living was not influenced by age or medical burden. Anxiety and depressive ideation as well as retardation and weight loss were significantly associated with impairment in instrumental activities of daily living. Interviewer-rated global disability was associated with advanced age at onset of depression, medical burden, and overall cognitive impairment. Specifically, a disturbance in initiation and perseveration was significantly related to global disability., Conclusions: Impairment in instrumental activities of daily living appears to be a relatively independent dimension of health status that is related to depressive symptoms, particularly anxiety and depressive ideation as well as retardation and weight loss. Global disability may be associated with impairment in initiation and perseveration and with late onset of depression. These findings provide a basis for studies investigating whether psychotherapy aimed at depressive ideation and rehabilitation efforts focused on instrumental activities of daily living can improve the outcome of geriatric depression.

Fifteen women with borderline personality disorder who do not experience pain during self-injury were found to discriminate more poorly between imaginary painful and mildly painful situations, to reinterpret painful sensations (a pain-coping strategy related to dissociation), and to have higher scores on the Dissociative Experiences Scale than 24 similar female patients who experience pain during self-injury and 22 age-matched normal women. "Analgesia' during self-injury in borderline patients may be related to a cognitive impairment in the ability to distinguish between painful and mildly painful situations, as well as to dissociative mechanisms.

Although contractile interstitial cells (CIC) in the alveolar septum have been suggested to be involved in hypoxic pulmonary vasoconstriction (HPV), direct demonstration of cellular contraction under hypoxia has been lacking. To achieve this, we purified CIC from collagenase-dissociated bovine lung cells and examined the response of these cells to hypoxia. Prostaglandin (PG) F synthase served as a marker of CIC, and the isolated PGF synthase-positive cells were shown to preserve the ultrastructural features characteristic of CIC, most notably bundles of microfilaments. Isolated CIC seeded onto collagen gel disks became embedded and formed a lattice network with collagen fibrils. Exposure of these CIC-bearing gels to hypoxia (PO2 = 20-40 Torr) evoked a reversible reduction in gel volume, as assessed by measuring the surface area of the gel disks photographically. Thus CIC were shown to contract under hypoxia, providing the supportive evidence for the involvement of CIC in HPV.

The authors studied elderly patients with major depression (MDD) who recovered after nortriptyline treatment to determine the relationship of affective symptoms at completion of continuation treatment to eventual MDD recurrence. Independent objective measures of depressive and anxiety symptoms were obtained before and after nortriptyline tapering. Univariate log-rank analysis demonstrated a trend for total post-discontinuation anxiety scores to predict time-to-recurrence in 12 subjects with complete data sets. Items assessing excessive worry and psychic tension (subjective anxiety) were significant predictors. No relationship was found between continuation-phase anxiety or depressive symptoms either immediately preceding or after discontinuation and course., (Copyright © 1996 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Clinical characteristics of depression, age at illness onset, medical burden, disability, cognitive impairment, lack of social support, and poor living conditions may influence the course of depression. This study investigates the timetable of recovery and the role of the above factors in predicting recovery in elderly patients with major depression., Methods: Recovery was studied in 63 elderly (age >63 years) and 23 younger patients with depression who were followed up for an average of 18.2 months (SD, 13.1 months) under naturalistic treatment conditions. Diagnosis was assigned according to Research Diagnostic Criteria after administration of the Schedule for Affective Disorders and Schizophrenia. The Longitudinal Follow-up Interval Examination was used to identify recovery., Results: The recovery rate of depressed elderly patients was similar to that of younger depressed patients. In the elderly patients, age, antidepressant treatment, age at onset, and chronicity of episode were significantly associated with time to recovery since entry. Among these parameters, late age at onset was the strongest predictor of slow recovery. In younger patients, long time to recovery was predicted by weak social support, younger age, cognitive impairment, and low intensity of antidepressant treatment. In the elderly, the intensity of antidepressant treatment began to decline within 16 weeks from entry and approximately 10 weeks prior to recovery., Conclusions: These findings challenge the view that geriatric depression has a worse outcome than depression in younger adults. However, depressed patients with onset of first episode in late life may be at higher risk for chronicity. Antidepressant treatment prescribed by clinicians may decline prior to recovery despite evidence that high treatment intensity is effective in preventing relapse.

Objective: To determine the prevalence and types of dementia in centenarians and to examine whether the ApoE epsilon 4 allele has significant impact on the development of Alzheimer's disease (AD) in the population., Design: Cross-sectional study and a 6-month prospective study., Setting: Yamanashi Prefecture, Japan., Participants: Forty-seven centenarians participated in the study to determine the prevalence and types of dementia. Thirty-three of the 47 participated in the study of ApoE genotyping. As controls, 224 demented older adults participated in the genetic study. Their age at onset was < 90 years., Outcomes: Prevalence of dementia based on DSM-III-R; types of dementia based on NINCDS-ADRDA and ICD-10; distribution on ApoE alleles in the centenarians and in the controls; and the 6-month mortality rate of the subjects., Main Results: Of 47 centenarians, 70.2% had dementia, and AD accounted for the majority (75.8%) of the dementia cases. The distribution of ApoE alleles in all the subjects and the AD subjects was epsilon 2: 4.6% vs. 0%; epsilon 3: 90.1% vs. 94.1%; epsilon 4: 4.6% vs. 5.9%. The frequency of the epsilon 4 allele in the AD patients showed a tendency to decrease with increasing age, ranging from 38% for those with an age at onset of < 60 years to 22% for those with an age at onset of ranging from 80 to 89 years. The 6-month mortality rate was 27% (9/33) for the demented centenarians, whereas none of the 14 nondemented centenarians died., Conclusion: This almost-complete survey, conducted in a prefecture of Japan, revealed a high prevalence of dementia in centenarians. The ApoE epsilon 4 allele does not have an impact on the development of AD in centenarians.

To determine the annual incidence of fall-related injuries among community-dwelling elderly people with dementia and to identify the factors predicting those likely to sustain such injuries, we conducted a cohort study with a one-year follow-up. As predicting factors, we paid particular attention to behavioural problems and difficulties in helping with activities of daily living based on the Assessment of Basic Care for the Demented (ABCD) scale. Thirty-five of 86 final study subjects and nine of 98 final control subjects sustained fall-related injuries. Significant factors associated with fall-related injuries to demented elderly subjects were ABCD score (adjusted odds ratio 0.73, 95% confidence interval 0.60-0.89), history of falls in the past year (3.65, 1.34-9.95), and Barthel index score (1.04, 1.00-1.08). This highlights the predictive value of better physical function but more difficult care status in relation to ADL for fall-related injuries.

Comorbidity of sensorineural hearing deficits and both depressive states and dementia in late life provided the rationale for this investigation. Cognitively intact geriatric major depressives (n = 43) were assessed for depressive symptoms, cognitive performance, and delusions while symptomatic, and following treatment, when audiometry was performed. Late-onset depressed patients (LOD) had more hearing deficits compared to early-onset depressives (EOD). Age at onset of depression was found to have a significant effect on Pure-Tone Thresholds for 0.5-4.0 kHz and on Word Recognition in Noise in the better ear (0.001 < p < 0.031; ANCOVA). Criteria for neural deficit were met more frequently in LODs compared to EODs, although this was attributable to the older age of LOD. Additional investigations can contribute to our understanding of the relationship between forms of hearing loss and both the course of geriatric depression and its relationship to dementia.

8-Oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism, and when it is incorporated into DNA causes mutation. Organisms possess 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. We isolated cDNA for mouse 8-oxo-dGTPase, using as a probe human MTH1 (Escherichia coli mutT homolog) cDNA. The nucleotide sequence of the cDNA revealed that the mouse MTH1 protein (molecular weight of 17,896) comprises 156 amino acid residues. When the cDNA for mouse 8-oxo-dGTPase was expressed in E. coli mutT- mutant cells devoid of their own 8-oxo-dGTPase activity, an 18-kDa protein, which is cross-reactive with an anti-human MTH1 antibody, was formed. In such cells, the level of spontaneous mutation frequency that was elevated reverted to normal. High levels of 8-oxo-dGTPase activity were found in liver, thymus, and large intestine, whereas all other organs examined contained smaller amounts of the enzyme. In embryonic stem cells, an exceedingly high level of the enzyme was present.

The enzyme, 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase), is present in various organisms and plays an important role in control of spontaneous mutagenesis. This enzyme degrades 8-oxoguanine-containing deoxyribonucleoside triphosphate, a potentially mutagenic substrate for DNA synthesis, to the corresponding monophosphate. To obtain appropriate probes for expression of the gene in various tissues and also to construct appropriate experimental models for carcinogenesis, we cloned cDNA for rat 8-oxo-dGTPase and elucidated its structure. The nucleotide sequence of the cDNA revealed that the rat 8-oxo-dGTPase protein is composed of 156 amino acid residues. The molecular weight of rat 8-oxo-dGTPase, calculated from the predicted amino acid sequence, was 18,006, and the 8-oxo-dGTPase protein of this size was detected when the cDNA was expressed in 8-oxo-dGTPase-deficient Escherichia coli mutT- cells. The predicted amino acid sequence of the rat 8-oxo-dGTPase has a close homology with those of human and bacterial counterparts. Using the cDNA as a probe, part of the rat gene for 8-oxo-dGTPase was isolated and was found to consist of at least three exons and spanned about 10 kb. A genomic region containing the pseudogene was also isolated.

Objective: The study examined several aspects of inpatient psychiatric treatment to determine if differences existed between treatment of African-American and white patients., Methods: Using a structured chart review, data were collected on 76 African-American and 88 white patients consecutively admitted to an acute inpatient setting with a principal axis I diagnosis of a major mood or psychotic disorder. Racial differences in treatment were examined using analysis of variance and logistic regression to assess the effects of diagnosis and socioeconomic status., Results: Nonpsychotic African-American patients had shorter lengths of stay than white patients with similar disorders. White patients were more likely to be on one-to-one observational status. Clinicians were more likely to order urine drug screens for African-American patients with high socioeconomic status than for comparable white patients. African-American patients with schizophrenic disorders received higher neuroleptic dosages than white patients with similar diagnoses., Conclusions: Most racial differences cited in earlier studies of psychotic patients were not found or were not statistically significant once socio-economic status and diagnosis were accounted for. However, racial differences related to the detection, phenomenology, treatment, and course of psychotic disorders and the diagnosis and management of alcohol and drug use disorders and personality disorders were found.

Objective: This paper reports comprehensive data on psychiatric symptoms and disorders and medical problems of first- and second-degree biological relatives of prepubertal children who have contemplated or attempted suicide., Method: Standard family study and family history interview techniques were used to obtain information about psychopathology and medical illness in 488 first- and 1,062 second-degree relatives of 25 child psychiatric inpatients who reported suicide attempts, 28 child psychiatric inpatients who contemplated suicide, 16 nonsuicidal child inpatients, and 54 normal children., Results: Suicidal behavior in children was associated with suicidal behavior in their families, although no first-degree relatives committed suicide. More first-degree relatives of child suicide attempters, compared to first-degree relatives of normal children, had antisocial personality disorder, assaultive behavior, and substance abuse. Mood disorders in first-degree relatives were not associated with child suicidal behavior. No significant associations were identified for psychopathology of second-degree relatives and child suicidal behavior., Conclusions: The results suggest the importance of evaluating familial psychopathology during assessments of suicidal children. Self-directed and externally directed violence, antisocial personality disorder, and substance abuse of relatives of suicidal children should be studied to elucidate the etiology of youth suicidal behavior.

The relationship of antisocial traits to treatment response in 35 female inpatients with borderline personality disorder was studied. Antisocial traits were measured with the Personality Assessment Inventory. Treatment response was measured by weekly ratings on the Symptom Checklist-90-Revised over 25 weeks of hospitalization. Treatment course was found to be significantly associated with the level of antisocial behavior reported at admission.

Objective: This study examined cardiac and respiratory activity in panic disorder patients and healthy comparison subjects during sleep, when the effects of anxious cognition and expectancy set are minimized., Method: Heart rate, respiratory rate, end-tidal PCO2, and oxygen saturation were recorded for 11 panic disorder patients and 12 comparison subjects before and during sleep and before and after infusions of sodium lactate and a saline control., Results: Panic disorder patients had higher oxygen saturations than comparison subjects before sleep onset and during sleep stages 0 and 2 before any infusions. The two groups did not differ on other respiratory variables and heart rate. Panic disorder patients responded to lactate infusions during stage 3-4 sleep with greater increases in heart rate and oxygen saturation, and possibly in respiratory rate and end-tidal PCO2, than comparison subjects. The saline control infusion had little effect., Conclusions: These findings suggest that panic disorder patients have greater cardiac and respiratory reactivity than healthy comparison subjects during sleep, when the influence of cognitive factors is minimal or absent.

Five healthy adult women aged 20 to 28 had 12-15 polysomnographic recordings, as well as daily basal body temperature and multiple LH, FSH, estrogen and progesterone measurements taken during a single menstrual cycle. Sleep stages were scored both visually and with a spindle and delta-wave, real-time, automatic analysing system. A cubic growth-curve model showed that the frequency of sleep spindles changed markedly over the menstrual cycle: spindle frequency was lowest about 18 days before onset of menses and highest 3 days before onset of menses. Slow waves did not change. The percentages of Stage 1 and REM sleep showed small changes during the menstrual cycle, and other parameters of visually scored sleep showed no tendency to change. Spindle frequency may reflect the effects of sex hormones on the reticular thalamic nucleus and may be a quantitative marker of premenstrual sleep disturbances.

Objectives: This paper describes risk for first recurrent suicidal episodes in follow-up of suicidal child psychiatric inpatients. It identifies relations between suicide attempts in follow-up and psychosocial and psychopharmacological treatments., Methods: First suicidal episodes involving either suicidal ideation or a suicide attempt in a 6 to 8 year follow-up period were rated for 69 child psychiatric inpatients and 64 children selected from the community. Psychiatric treatments were determined from reports from multiple sources., Results: Forty-five percent of 133 subjects reported a suicidal episode during follow-up. Children who reported suicidal ideation or a suicide attempt were greater than twice as likely to report a suicidal episode in follow-up than were children from the community. Children treated with antidepressants in follow-up were more likely to attempt suicide than were those not treated with antidepressants., Conclusions: Close follow-up of suicidal children is warranted to identity risk and to intervene to prevent suicidal episodes. Lack of efficacy of naturalistic treatments implies that controlled treatment studies are needed to determine effective intervention for suicidal children.

8-Oxoguanine (8-oxo-7, 8-dihydroguanine) is produced in DNA, as well as in nucleotide pools of cells, by active oxygen species normally formed during cellular metabolic processes. 8-Oxoguanine nucleotide can pair with cytosine and adenine nucleotides at almost equal efficiencies, and transversion mutation ensues. Human cells contain enzyme activity, which hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, and this enzyme is responsible for preventing misincorporation of 8-oxoguanine into DNA. We purified this particular human enzyme to physical homogeneity and determined a partial amino acid sequence. We then cloned the cDNA for human 8-oxo-dGTPase and examined its nucleotide sequence. The human protein comprises 156 amino acid residues and has some sequence homology with the Escherichia coli MutT protein, which has a distinct 8-oxo-dGTPase activity. When the human cDNA was expressed in E. coli mutT- mutant cells, there was a significant amount of 8-oxo-dGTPase activity. In such cells, the frequency of spontaneous mutation was greatly reduced. We propose that the human 8-oxo-dGTPase protects genetic information from the untoward effects of endogenous oxygen radicals.