Non-competitive cyclic peptides for targeting enzyme-substrate complexes.

Affinity reagents are of central importance for selectively identifying proteins and investigating their interactions. We report on the development and use of cyclic peptides, identified by mRNA display-based RaPID methodology, that are selective for, and tight binders of, the human hypoxia inducible factor prolyl hydroxylases (PHDs) - enzymes crucial in hypoxia sensing. Biophysical analyses reveal the cyclic peptides to bind in a distinct site, away from the enzyme active site pocket, enabling conservation of substrate binding and catalysis. A biotinylated cyclic peptide captures not only the PHDs, but also their primary substrate hypoxia inducible factor HIF1-α. Our work highlights the potential for tight, non-active site binding cyclic peptides to act as promising affinity reagents for studying protein-protein interactions.

Quantifying midbrain serotonin transporter in depression: a preliminary study of diagnosis and naturalistic treatment outcome.

INTRODUCTION: Serotonin may play an important role in the pathology of major depressive disorder (MDD). However, the relationship between serotonin transporter (SERT) availability and the medical outcome of antidepressant treatment is uncertain. METHODS: In this naturalistic study, SERT availability (expressed as the specific uptake ratio, SUR) in the midbrain of 17 drug-free patients with MDD and 17 controls matched for age and gender was measured using SPECT with [(123)I]ADAM. The severity of MDD was measured by the Hamilton Depression Rating Scale before, and after 6 weeks of non-standardized antidepressant treatment. RESULTS: A total of 12 patients completed the study. The SUR of the patients with MDD was significantly lower than that of the healthy controls. The SUR of SERT was not found to have a linear relationship with the treatment outcome; however, supplemental analysis found a curvilinear relationship between treatment outcome and the SUR of SERT. DISCUSSION: The findings indicate that the SUR of SERT is lower in patients with MDD; however it did not predict treatment outcome in a linear fashion. Studies with larger sample sizes are required.

The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers.

PURPOSE: This study was performed to investigate the association between the mid-brain serotonin transporter (SERT) availability and intelligence quotient (IQ). METHODS: One hundred and thirteen healthy participants, including 52 male and 61 female subjects, were recruited. We used SPECT with [(123)I]ADAM images to determine the SERT availability in the mid-brain, and measured the subjects' IQ using the WAIS-R. RESULTS: We found a significant positive correlation between the mid-brain SERT availability and the IQ of the participants. Even when controlling for age and sex, the significant association still existed. CONCLUSION: This result implied that the higher the SERT binding in the mid-brain, the better the IQ in healthy participants.

Lower availability of midbrain serotonin transporter between healthy subjects with and without a family history of major depressive disorder - a preliminary two-ligand SPECT study.

PURPOSE: Serotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depressive disorder (MDD) who are in a depressed state in comparison with healthy controls. In addition, a family history of depression is a potent risk factor for developing depression, and inherited vulnerability to serotonergic and dopaminergic dysfunction is suspected in this. The aim of this study was to examine the availabilities of midbrain SERT and striatal DAT in healthy subjects with and without a first-degree family history of MDD. METHODS: Eight healthy subjects with first-degree relatives with MDD and 16 sex- and age-matched healthy controls were recruited. The availabilities of SERT and DAT were approximated using SPECT, employing [¹²³I] 2-((2-((dimethylamino) methyl) phenyl)thio)-5-iodophenylamine (ADAM) and [(99m)Tc] TRODAT-1 as the ligands, respectively. There are missing data for one participant with a first-degree family history of MDD from the ADAM study, due to a lack of the radio-ligand at the time of experiment. RESULTS: SERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects. However, DAT availability was no different between two groups. CONCLUSIONS: The results with regard to the midbrain SERT level suggest the heritability of MDD.

Cardiac autonomic function and insulin resistance for the development of hypertension: a six-year epidemiological follow-up study.

BACKGROUND AND AIMS: To explore the impact of cardiac autonomic function (CAF) and insulin resistance (IR) on incident hypertension. METHODS AND RESULTS: In 1996, 1638 subjects finished baseline examination, which included anthropometry, blood pressures, CAF, blood biochemistry, plasma insulin, urine examination and electrocardiogram. CAF included standard deviation of normal-to-normal intervals or RR intervals (SDNN), low- and high-frequency power spectrum (LF and HF), and LF/HF ratio at supine for 5 min, the RR interval changes during lying-to-standing maneuver, and the ratio between the longest RR interval during expiration and the shortest RR interval during inspiration (E/I ratio). We used homeostasis model assessment to define beta cell function (HOMA-B) and insulin resistance (HOMA-IR). In total, 992 non-hypertensive participants completed the follow-up assessment in 2003 and 959 participants were included for the final analysis. Incident hypertension was determined by blood pressure status at follow-up. In unadjusted model, both square root of HOMA-IR (OR:3.37, 95%CI: 2.10-6.64) and HOMA-B (OR:0.996, 95%CI: 0.992-0.999) were related to incident hypertension. In multivariate model, square root of HOMA-IR (OR:1.97, 95%CI: 1.05-3.70), but not HOMA-B, was associated with incident hypertension. After further adjustment for baseline CAF, the positive relationship between the square root of HOMA-IR and incident hypertension disappeared. In contrast, LF/HF ratio (OR:1.18, 95%CI: 1.01-1.37), HF power (OR:0.98, 95%CI: 0.96-0.999), and E/I ratio (OR:0.71, 95%CI: 0.54-0.95) were each independently associated with incident hypertension after further adjustment for HOMA measures. CONCLUSION: Sympathovagal imbalance with an apparently decreased parasympathetic tone is an important predictor of incident hypertension independent of IR.

Common-path phase-shift interferometry surface plasmon resonance imaging system.

Surface plasmon resonance (SPR) and common-path phase-shift interferometry (PSI) techniques are integrated in a biosensing imaging system for measuring the two-dimensional spatial phase variation caused by biomolecular interactions on a sensing chip without the need for additional labeling. The common-path PSI technique has the advantage of long-term stability, even when it is subjected to external disturbances. Hence the system meets the requirements of the real-time kinetic studies involved in biomolecular interaction analysis. The proposed SPR-PSI imaging system demonstrates a detection limit of a 2 x 10(-7) refractive-index change, a long-term phase stability of 2.5 x 10(-4) pi rms for 4 h, and a spatial phase resolution of 10(-3) pi with a lateral resolution of 100 microm.

Prenatal bupropion exposure enhances the cocaine reward and stress susceptibility in adult mice.

Although a growing body of evidence supports the notion that certain antidepressant treatments in pregnancy produce earlier delivery and minor behavioral teratogenesis in infants, the long-term effects of such treatments in adulthood remain ill-defined. Recently, postnatal exposure to psychotropic drugs was found to affect the emotional development and susceptibility to abused drugs. Thus, this study aimed to examine whether prenatal exposure of four frequently-used antidepressants, bupropion, fluvoxamine, citalopram, and trazodone, altered the responsiveness to stress and cocaine in the adulthood. Dams received daily injection of bupropion (25 or 12.5 mg/kg), citalopram (5 mg/kg), fluvoxamine (10 mg/kg), trazodone (20 mg/kg) or saline throughout their third trimester of gestation, and several birth outcome indices were then examined. Locomotor activity, naive anxiety levels, and the sensitivity to the cocaine reinforcing effects were observed in pups at their day 56-60 post partum. We found that trazodone treatment produced a high mortality rate in pups after weaning. Mice, prenatally treated with bupropion at 25 mg/kg, exhibited lower rearing numbers and ambulatory activity as compared to the saline-treated mice. More importantly, such treatment enhanced the mouse sensitivity to the reinforcing effects of cocaine. Taken together, these results suggest that use of bupropion in the late pregnancy may run a risk of enhancing the offspring's susceptibility to stress and cocaine reward in adulthood.

Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population-based sample of postpartum Taiwanese women.

Depression and anxiety disorders often coexist clinically and both are known to have a genetic basis, but the mode of inheritance is too complicated to be determined so far. Serotonin is the biogenic amine neurotransmitter most commonly associated with depression and anxiety. Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied. In this study, we examined whether polymorphism of the TPH1 gene is related to the etiology of major depression, anxiety and comorbid depression and anxiety. Five single nucleoside polymorphisms of the TPH1 gene were studied in a population-based sample of postpartum Taiwanese women consisting of 120 subjects with depression or/and anxiety and 86 matched normal controls. A significant difference (P = 0.0107) in genotype frequency for the T27224C polymorphism was found between the comorbid and normal groups, and risk analysis showed that the C allele conferred a strong protective effect (odds ratio = 0.27; 95% confident interval = 0.11-0.7). Three-allele haplotypes involving T27224C polymorphism were constructed and haplotype associations between particular haplotype combinations and various diseases identified. However, the associations were weak and the overall haplotype frequency profiles in all groups were similar. The results suggest that depression, anxiety, and comorbid depression and anxiety disorders may have related etiologies. In addition, this study suggests that the TPH1 gene might play a role in the pathogenesis of these closely related disorders.

An experimental design for quantification of cardiovascular responses to music stimuli in humans.

There have been several researches on the relationship between music and human physiological or psychological responses. However, there are cardiovascular index factors that have not been explored quantitatively due to the qualitative nature of acoustic stimuli. This study proposes and demonstrates an experimental design for quantification of cardiovascular responses to music stimuli in humans. The system comprises two components: a unit for generating and monitoring quantitative acoustic stimuli and a portable autonomic nervous system (ANS) analysis unit for quantitative recording and analysis of the cardiovascular responses. The experimental results indicate that the proposed system can exactly achieve the goal of full control and measurement for the music stimuli, and also effectively support many quantitative indices of cardiovascular response in humans. In addition, the analysis results are discussed and predicted in the future clinical research.

Cycloheximide enhances maintenance of methamphetamine-induced conditioned place preference.

Accrued evidence demonstrated the necessity of protein synthesis at acquisition, consolidation and expression stages in conditioning/learning tasks, while the underlying mechanisms of the maintenance of memory remained less explored. This study was designed to characterize the maintenance of methamphetamine-induced conditioned place preference, a drug-induced learning and memory. In addition, cycloheximide, a protein synthesis inhibitor, was used to examine the involvement of protein synthesis in the maintenance of such place preference memory. We found that the maintenance of the rapidly-established methamphetamine (2 mg/kg, i.p.) -induced conditioned place preference could be long-lasting and even over fifty days under the present protocol of extinction. Moreover, it was of interest to note the undulating expression of this conditioned place preference throughout the extinction protocol. Most importantly, as the methamphetamine-induced conditioned place preference was acquired and expressed by mice, the saline-pretreated control mice underwent numbers of intermittent extinction across a long-term retention test period, while cycloheximide-pretreated mice exhibited unaltered methamphetamine-induced conditioned place preference throughout the same retention test period. Taken together, we conclude that [1] methamphetamine-induced conditioned place preference could last for a long period of time, and such place preference memory is reluctant to extinguish even animals' repeated exposure to the previous conditioned environment at a drug-free status, and [2] blockade of protein synthesis may enhance the maintenance of the methamphetamine-induced conditioned place preference.

Respiratory effect on the pulse spectrum.

During the last decade, progressive achievements in haemodynamics have shown that radial artery pulse pressure can be used to estimate the vascular properties of the internal organs. Clinical experiments have shown that slow and regular respiration has a large effect on the heart rate variability (HRV). This phenomenon is called respiratory sinus arrhythmia (RSA). It is known that respiration-related oscillations in venous return cause oscillations in stroke volume and blood pressure. It also can be inferred from cardiac output that systemic blood pressure has a similar respiration-related cycle. Moreover we found that the fluctuations of harmonics of arterial pulse are consistent with the fluctuation of HRV. This means that the whole cardiovascular system (CVS) makes rapid adaptation during respiration, and the harmonic proportions of arterial pulse were modified during different breath rates. This result shows that the regular respiration also has a large effect upon Windkessel properties of CVS.

Asperger's disorder: a case report of repeated stealing and the collecting behaviours of an adolescent patient.

OBJECTIVE: To discuss special behavioural problems shown by a patient with Asperger's disorder from adolescence onward. METHOD: The case and treatment of a 21-year-old male patient is described. RESULTS: A 21-year-old male developed obstinate stealing behaviours when he was 17 years old. He was regarded as a schizophrenic at first, and was suspected of kleptomania later. Asperger's disorder was diagnosed after we reconsidered the relationship between the schizoid psychopathy in childhood and the stealing behaviours which occurred in adolescence. CONCLUSION: A wide variety of bizarre behaviours and so-called borderline behaviours occur in late adolescence and adult life of patients with Asperger's disorder. But classic schizophrenia is very rare. Psychiatrists unacquainted with the clinical diagnosis/context may find it difficult to evaluate 'concrete', 'childish', or 'bizarre' symptoms in patients with Asperger's disorder, and thus are prone to misdiagnose them as having schizophrenia disorders or other similar disorders.

Methamphetamine-induced conditioned place preference is facilitated by estradiol pretreatment in female mice.

Ovarian hormones were well documented to modulate the dopamine release in the central dopaminergic systems. The dopamine-releasing effects in the nucleus accumbens, a major target of the mesolimbicortical dopaminergic system, were closely associated with the reinforcing effects of two psychomotor stimulants, cocaine and methamphetamine. This study aimed to examine the sex differences in the cocaine- and methamphetamine-reinforcing behavior, conditioned place preference. In addition, the modulating effects of estradiol and progesterone on methamphetamine-induced conditioned place preference were investigated in both sexes of adult gonadectomized mice. There was no sex difference in the sensitivity to the cocaine (5 mg/kg)-induced conditioned place preference. However, female mice exhibited a more potent methamphetamine (1 mg/kg)-induced conditioned place preference than did male mice. Moreover, pretreatment with estradiol for two consecutive days before the beginning of the conditioning and throughout the four daily conditionings (0.47 microg/day for totally six days) effectively facilitated methamphetamine-induced conditioned place preference in gonadectomized female mice, but not in gonadectomized male mice. Progesterone, under a similar treatment regimen (0.47 microg/day for six consecutive days), did not alter the methamphetamine-induced conditioned place preference in either sex of gonadectomized mice. Taken together, we conclude that the facilitating effects of estradiol on methamphetamine-induced conditioned place preference could be sex-dependent with an eminent sensitivity associated with the adult female mice.

Psychiatric morbidity and post-traumatic symptoms among survivors in the early stage following the 1999 earthquake in Taiwan.

This study reports the clinical psychiatric presentations and post-traumatic symptoms among 525 survivors at Yu-Chyr District in Nantou County who sought psychiatric service in the first month following the devastating earthquake that struck the central area of Taiwan. All subjects received psychiatric interviews and assessments using the 12-item Chinese Health Questionnaire (CHQ-12) and a checklist for post-traumatic symptoms. The most common psychiatric symptoms reported were insomnia, palpitations, nervousness, and dizziness with headache. Eleven percent of the subjects reported having thought of death or having suicidal ideation. The mean score on the CHQ-12 was 6.43 (S.D.=2.89). The rate of probable psychiatric morbidity as defined by a CHQ-12 score > or =3 was 89.9%. Post-traumatic symptoms were very prevalent, particularly symptoms of re-experiencing the earthquake and hyper-arousal. Factors significantly associated with high psychiatric morbidity were being female, serious destruction of property and house, and personality characteristics of nervousness and obsessiveness. Findings of this study suggest that early psychiatric intervention, including pharmacological treatment for acute stress disorder, is indicated during the early stages following a disastrous earthquake.

Community study of depression in old age in Taiwan: prevalence, life events and socio-demographic correlates.

BACKGROUND: Published studies of prevalence of depression in old age in Taiwan have yielded equivocal results. AIMS: To study the prevalence of depressive disorders among community-dwelling elderly; further, to assess socio-demographic correlates and life events in relation to depression. METHOD: A randomised sample of 1500 subjects aged 65 and over was selected from three communities. Research psychiatrists conducted all assessments using the Geriatric Mental State Schedule. The diagnosis of depression was made with the GMS-AGECAT (Automated Geriatric Examination for Computerised Assisted Taxonomy); data on life events were collected with the Taiwanese version of the Life Events and Difficulties Schedule. RESULTS: One-month prevalence of psychiatric disorders was 37.7%, with 15.3% depressive neurosis and 5.9% major depression. A high risk of depressive disorders was found among widows with a low educational level living in the urban community, and among those with physical illnesses. CONCLUSIONS: Contrary to most previous reports, we found that the prevalence of depressive disorders among the elderly in the community in Taiwan is high and comparable to rates reported in some studies of UK samples.

Help-seeking behaviors in relatives of schizophrenics in Taiwan.

Despite its merits, the Western-style psychiatric community rehabilitation model is not well accepted by caregivers in Taiwan. We examined factors affecting the utilization of community rehabilitation programs in Taiwan. Our stepwise logistic regression revealed that psychoeducation regarding the biological cause of schizophrenia emerged as the major factor for increasing utilization treatment modality. Eighty-nine pairs of schizophrenic patients (who had been recommended for rehabilitation) and their relatives were divided into two groups, the rehabilitation group and the nonrehabilitation group. Both groups were surveyed on help-seeking behavior scales and mental function measurements. The results showed no significant differences in patients' psychopathology, though the rehabilitation group had higher employment rates. As for caregivers, the rehabilitation group scored significantly better on some cognitive appraisals, whereas the nonrehabilitation group was more inclined to institutionalize the patients for life. No significant differences were noticed on rejection attitude, subjective care burden, or expressed emotion measures. Improving caregiver's knowledge about the disease, providing activities that lend emotional, physical, and financial support and thereby reduce the burden and increase the satisfaction of caregivers may be useful. Besides making the Western-style psychiatric community rehabilitation model more effective and accessible for patients and caregivers in Taiwan, cultural adaptation is also needed.

MRI morphometric analysis and neuropsychological function in patients with neurofibromatosis.

Volumes of cerebral gray and white matter were measured in 22 children with neurofibromatosis type 1 (NF1) and in 20 controls. Judgment of Line Orientation (JLO) and the Developmental Test of Visual-Motor Integration (DTVMI) were administered to 16 of the NF1 patients. General linear models analysis of covariance revealed significantly larger brain volumes in NF1 children than in controls, particularly in white matter, and particularly in girls. JLO and DTVMI performance were positively related to right-hemisphere gray-matter volume. The results implicate a failure of growth control in NF1, leading to aberrant neurodevelopment. Our findings also suggest a basis for refined understanding of learning disabilities, which are a prominent feature of NF1.