Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics.

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻6). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻5). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

Using a pharmacogenomic algorithm to guide the treatment of depression.

The objective of this study was to evaluate the potential benefit of utilizing a pharmacogenomic testing report to guide the selection and dosing of psychotropic medications in an outpatient psychiatric practice. The non-randomized, open label, prospective cohort study was conducted from September 2009 to July 2010. In the first cohort, depressed patients were treated without the benefit of pharmacogenomic testing (the unguided group). A DNA sample was obtained from patients in the unguided group, but the results were not shared with either the physicians or patients until the end of the 8-week study period. In the second cohort (the guided group), testing results were provided at the beginning of the 8-week treatment period. Depression ratings were collected at baseline and after 2 weeks, 4 weeks and 8 weeks of treatment using the Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C16) and the 17-item Hamilton Rating Scale for Depression (HAM-D17). Clinician and patient satisfaction was also assessed. The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P=0.002) or HAM-D17 (P=0.04). We concluded that a rapidly available pharmacogenomic interpretive report provided clinical guidance that was associated with improved clinical outcomes for depressed patients treated in an outpatient psychiatric clinic setting.

Age- and limb-related differences in the vasoconstrictor response to limb dependency are not mediated by a sympathetic mechanism in humans.

AIMS: We tested the hypotheses that vasoconstrictor responses to limb dependency are: (i) greater in the leg than the arm, (ii) impaired with age and (iii) not sympathetically mediated. METHODS: Vascular responses to limb dependency (i.e. lowering the limb from heart level to 30 cm below heart level) were determined in 17 young and 17 older adults. Indices of blood flow were obtained in the brachial and popliteal arteries (Doppler ultrasound) as well as in the cutaneous circulation (forearm and calf using laser-Doppler flowmetry). Vasoconstriction was quantified by calculating the indices of vascular resistance as height corrected mean arterial pressure/limb blood velocity or skin flux. A second group of subjects repeated the limb dependency trials after acute systemic sympathetic blockade. RESULTS: Limb dependency increased vascular resistance index in the brachial artery (∆59 ± 8%; P<0.05) and popliteal artery (∆99 ± 10%; P<0.05 for change in heart level and brachial vs. popliteal) of young and older adults (∆60 + 9% brachial and ∆61 ± 7% popliteal arteries; P<0.05 for change in heart level and response in popliteal young vs. older adults). In contrast, cutaneous vasoconstrictor responses to limb dependency were similar in the forearm (∆218 ± 29% and ∆200 ± 29% for young and older adults, respectively) and calf (∆257 ± 32% and ∆236 ± 29%; all P<0.05 from heart level) of young and older adults. Vasoconstrictor responses to limb dependency were not affected by sympathetic blockade in young or older adults. CONCLUSION: These findings indicate that age-, limb-, and tissue-related differences may exist in the vasoconstrictor response to limb dependency in healthy humans, which are not sympathetically mediated.

SLC6A4 variation and citalopram response.

The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non-Hispanic subjects, variations in the intron 2 VNTR (point-wise P = 0.041) and the indel promoter polymorphism (point-wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p-value of 0.040 and a maximum statistic simulation p-value of 0.0031 for the S-a-12 haplotype, under a dominant model. One SNP identified through re-sequencing the SLC6A4 gene, Intron7-83-TC, showed point-wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non-Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined.

Extensive summer water pulses do not necessarily lead to canopy growth of Great Basin and northern Mojave Desert shrubs.

Plant species and functionally related species groups from arid and semi-arid habitats vary in their capacity to take up summer precipitation, acquire nitrogen quickly after summer precipitation, and subsequently respond with ecophysiological changes (e.g. water and nitrogen relations, gas exchange). For species that respond ecophysiologically, the use of summer precipitation is generally assumed to affect long-term plant growth and thus alter competitive interactions that structure plant communities and determine potential responses to climate change. We assessed ecophysiological and growth responses to large short-term irrigation pulses over one to three growing seasons for several widespread Great Basin and northern Mojave Desert shrub species: Chrysothamnus nauseosus, Sarcobatus vermiculatus, Atriplex confertifolia, and A. parryi. We compared control and watered plants in nine case studies that encompassed adults of all four species, juveniles for three of the species, and two sites for two of the species. In every comparison, plants used summer water pulses to improve plant water status or increase rates of functioning as indicated by other ecophysiological characters. Species and life history stage responses of ecophysiological parameters (leaf N, delta15N, delta13C, gas exchange, sap flow) were consistent with several previous short-term studies. However, use of summer water pulses did not affect canopy growth in eight out of nine comparisons, despite the range of species, growth stages, and site conditions. Summer water pulses affected canopy growth only for C. nauseosus adults. The general lack of growth effects for these species might be due to close proximity of groundwater at these sites, co-limitation by nutrients, or inability to respond due to phenological canalization. An understanding of the connections between short-term ecophysiological responses and growth, for different habitats and species, is critical for determining the significance of summer precipitation for desert community dynamics.

Night-time conductance in C3 and C4 species: do plants lose water at night?

Significant night-time stomatal conductance and transpiration were found for 11 out of 17 species with a range of life histories (herbaceous annual, perennial grass, shrub, tree), photosynthetic pathways (C(3), C(4)), and habitats in the western United States. Across species and habitats, higher night-time conductance and transpiration were associated with higher daytime values. The prevalence, mechanisms and ecological implications of substantial night-time water loss deserve further investigation.

Preventing tractor rollover fatalities: performance of the NIOSH autoROPS.

Approximately 132 agricultural tractor overturn fatalities occur per year. The use of rollover protective structures (ROPS), along with seat belts, is the best known method for preventing these fatalities. One impediment to ROPS use, however, is low clearance situations, such as orchards and animal confinement buildings. To address the need for ROPS that are easily adapted to low clearance situations, the Division of Safety Research, National Institute for Occupational Safety and Health (NIOSH), developed an automatically deploying, telescoping ROPS (Auto-ROPS). The NIOSH AutoROPS consists of two subsystems. The first is a retractable ROPS that is normally latched in its lowered position for day-to-day use. The second subsystem is a sensor that monitors the operating angle of the tractor. Ifa rollover condition is detected by the sensor, the retracted ROPS will deploy and lock in the full upright position before ground contact. Static load testing and field upset tests of the NIOSH AutoROPS have been conducted in accordance with SAE standard J2194. Additionally, timed trials of the AutoROPS deployment mechanism were completed. The design of the retractable ROPS and sensor, as well as the results of the different testing phases are discussed.

Performance of an automatically deployable ROPS on ASAE tests.

In the U.S., approximately 132 agricultural tractor overturn fatalities occur per year. The use of rollover protective structures (ROPS), along with seat belts, is the best-known method for preventing these fatalities. However, one impediment to ROPS use is low-clearance situations, such as orchards and animal confinement buildings. To address the need for ROPS that are easily adapted to low-clearance situations, the Division of Safety Research, National Institute for Occupational Safety and Health, developed a prototype automatically deploying, telescoping ROPS (AutoROPS). The NIOSH AutoROPS consists of two subsystems. The first is a retractable ROPS that is normally latched in its lowered position for day-to-day use. The second subsystem is a sensor that monitors the operating angle of the tractor. If an overturn condition is detected by the sensor, the retracted ROPS will deploy and lock in the full upright position before ground contact. Static load testing and field upset tests of the NIOSH AutoROPS have been conducted in accordance with SAE standard J2194. Additionally, timed trials of the AutoROPS deployment mechanism were completed. The results of these tests show that the NIOSH AutoROPS has significant potential to overcome the limitations of current ROPS designs for use in low clearance as well as unrestricted clearance operations.

Finite element modeling of ROPS in static testing and rear overturns.

Even with the technological advances of the last several decades, agricultural production remains one of the most hazardous occupations in the United States. Death due to tractor rollover is a prime contributor to this hazard. Standards for rollover protective structures (ROPS) performance and certification have been developed by groups such as the Society of Automotive Engineers (SAE) and the American Society of Agricultural Engineers (ASAE) to combat these problems. The current ROPS certification standard, SAE J2194, requires either a dynamic or static testing sequence or both. Although some ROPS manufacturers perform both the dynamic and static phases of SAE J2194 testing, it is possible for a ROPS to be certified for field operation using static testing alone. This research compared ROPS deformation response from a simulated SAE J2194 static loading sequence to ROPS deformation response as a result of a simulated rearward tractor rollover. Finite element analysis techniques for plastic deformation were used to simulate both the static and dynamic rear rollover scenarios. Stress results from the rear rollover model were compared to results from simulated static testing per SAE J2194. Maximum stress values from simulated rear rollovers exceeded maximum stress values recorded during simulated static testing for half of the elements comprising the uprights. In the worst case, the static model underpredicts dynamic model results by approximately 7%. In the best case, the static model overpredicts dynamic model results by approximately 32%. These results suggest the need for additional experimental work to characterize ROPS stress levels during staged overturns and during testing according to the SAE standard.

Using Impedance Spectroscopy to Assess the Viability of the Rapid Chloride Test for Determining Concrete Conductivity.

The suitability of using the initial current from the rapid chloride test (ASTM C 1202) to determine specimen conductivity is tested using impedance spectroscopy with a frequency spectrum of 10 Hz to 1 MHz. The specimen conductivity has an analytical relationship to specimen diffusivity and so is a useful quantity in service life prediction. Measurements made on specimens of different lengths indicate that the total charge passed during the six hour conduction test carried out according to ASTM C 1202 is not a direct measure of specimen conductivity. Further, ohmic heating during the 6 hour test makes it nearly impossible to directly measure any specimen transport property from the results. The total charge passed during the 6 hour conduction test is, therefore, not a reliable quantity for service life prediction. Results indicate that the direct current (dc) measurement of resistance using a voltage of 60 V is sufficient to overwhelm polarization effects, thereby yielding an accurate estimate of the true specimen conductivity. Impedance spectroscopy measurements also indicate that corrosion may form on the brass electrodes, adding bias to a conductivity estimate based upon a dc measurement.

The Affective Auditory Verbal Learning Test: peripheral arousal correlates.

The present study assessed the usefulness of the affective list alternatives to the Rey Auditory Verbal Learning Test (RAVL) in the induction of physiological arousal. It was anticipated that affective verbal learning would lead to arousal patterns characteristic of different emotions (Izard, 1977), with significant increases in blood pressure following negative list learning and significant decreases following positive list learning. Since diastolic blood pressure increased significantly following the learning of negatively valanced words and decreased significantly following the learning of positively valanced words, this was supported. Given the abundance of research on lateral asymmetries in emotional and verbal processing, the affective list alternatives to the RAVL may provide an objective means for evaluating individual differences in affective verbal learning as well as the induction of emotion. The Affective Auditory Verbal Learning Test (AAVL) may potentially provide a tool for assessment of cerebral dysfunction in the clinic or in the assessment of affective disorders.

Age differences in intention to left and right hemispace using a dichotic listening paradigm.

This study assessed the influence of age (younger women and elderly women living in communities) on cerebral laterality using dichotic listening. Previous research has purported to show a relative right cerebral decline with age. To date, however, research on the right hemiaging hypothesis has provided mixed findings. It is possible that these mixed findings are caused by use of simple versus complex dichotic listening tasks. As a test of this hypothesis, older women were expected to have a heightened right ear advantage (REA) for phonemic speech sounds and greater difficulty switching intention to the left ear when instructed to focus to either the left or the right ear. No age difference was found using the traditional presentation of concurrent phonemes. However, the right hemiaging hypothesis was supported on the intentional task, in which older women were less able to switch intention to the left but not to the right ear. Implications for right hemiaging are discussed.

The affective Auditory Verbal Learning Test.

The study of emotion is hindered by the lack of tests for affect perception or comprehension. One solution is to develop affective versions of well-known tests. Using an index of word norms (Toglia & Battig, 1978), positively and negatively valenced word lists were developed as alternate forms of the affectively neutral Auditory Verbal Learning Test (RAVL; Rey, 1964). Participants (N=102) received either the original RAVL list, the positively valenced list, or the negatively valenced list. Results are depicted across acquisition trials and location within the list for comparison of primacy and recency effects. Each word list yielded comparable patterns of acquisition. Participants receiving the negative list evidenced an enhanced primacy effect, while participants receiving the positive list evidenced an enhanced recency effect. The positive and negative lists may prove useful in the evaluation of individuals with affective disorders and may provide an alternative for affect induction through an active learning paradigm.

The effects of long-term, moderate intensity, intermittent exercise on aerobic capacity, body composition, blood lipids, insulin and glucose in overweight females.

OBJECTIVE: To test the hypotheses that the accumulation of 30 min of moderate intensity, intermittent exercise, 5d/week-1, for 32 weeks, will increase aerobic capacity, alter body composition and improve blood lipids, insulin and glucose. Secondly, to identify individuals who may respond to moderate intensity, intermittent exercise. SUBJECTS: Thirteen sedentary, moderately obese females, aged 43 +/- 11 (y), body mass index (BMI) 32.7 +/- 7.7 (kg/M2), body fat 40.6 +/- 8.8 (%), VO2max 24.0 +/- 4.6 (ml/kg-1/min-1). MEASUREMENTS: Aerobic capacity, body composition, blood lipids, fasting insulin and glucose, energy intake. RESULTS: Group data showed no significant changes for aerobic capacity, body composition, blood lipids, insulin or glucose. However, 7 of the 13 subjects increased aerobic capacity, lost fat weight and improved insulin. Adherence to the exercise regimen was excellent with 82.6 +/- 10.0% of the exercise completed. CONCLUSIONS: Moderate intensity, intermittent exercise for a total of 30 min, 5d/week,-1 for 32 weeks duration, was not a sufficient stimulus to significantly increase aerobic capacity, and alter weight, body composition or improve blood lipids, insulin or glucose for the entire group. However, those subjects who increased aerobic capacity and decreased fat weight were significantly older, had lower maximal aerobic capacity and greater body fat at baseline compared to the six subjects who did not increase aerobic capacity and decrease fat weight. For both groups, moderate intensity, intermittent exercise showed excellent adherence and this may be a useful model for future research studies.

Auditory affect perception in a dichotic listening paradigm as a function of verbal fluency classification.

This study evaluated cerebral asymmetry for affect perception as a function of fluency classification. After being assigned to a fluency category using scores on the FAS test (Borkowski, Benton, & Spreen, 1967), forty-five right-handed subjects with normal auditory acuity listened to the Bryden and MacCrae (1989) Dichotic Emotional Words Tape. Subjects higher in fluency exhibited significantly greater right and left ear advantages than subjects lower in fluency. Conversely, REA scores for words were significantly greater than REA scores for affect, while LEA scores for affect were significantly greater than LEA scores for words.

Medical-legal issues in radiology: prevention and control.

Concerns about legal implications affect many decisions of the average radiologist, and physicians do not always appreciate the validity of these concerns. However, such concerns often influence radiologists' decisions more than is warranted. An improved understanding of the law and its ramifications may serve to prevent adverse legal effects found in the everyday practice of radiology. Legal issues influence radiology in many ways. Two important ways the law affects the practice of radiology relate to the business affairs of radiologists and to the radiologist's duty to perform to a standard of care. Legal issues relate to the business aspects of radiology through radiologists' relationship to their group practice and the radiology group's relation to the outside world. Radiology groups use legal services for issues such as employment contracts, hospital privileges, group relations, and bylaws. They make decisions with major legal implications when they establish their standard business practices. These decisions range from business procedures that ensure a timely delivery of service to the choice and implementation of quality assurance systems to how to ensure that patients are informed of the results of a radiologic examination. Legal matters affect many business decisions radiology groups make. Antitrust law is concerned about issues such as cost sharing, price sharing, mergers, acquisitions, and practice patterns. Laws limit the right to practice radiology. Billing practices, conflicts of interest, self-referral, right to refuse care, employment practices--all have substantial legal implications. These issues are a concern of every practicing radiologist. Changes in our health care system may cause new legal obligations. An appreciation of the relationship radiologists must have with payors and patients is increasingly important in preventing medical-legal problems. These additional duties and responsibilities occur when many physicians and the public at large seem to feel they are already overburdened with legal duties and responsibilities. A lack of familiarity with the legitimate relationship of the law to everyday life may greatly affect radiologists' job satisfaction. Many acts physicians perform in the practice of radiology have legal implications not often recognized by the practicing radiologist. This monograph seeks to enhance radiologists' understanding of some common and important legal issues related to their practice of medicine. We hope that this monograph will help radiologists appreciate the legal implications of their behavior. The opinions expressed in this monograph are those of the authors and should not be inferred to represent the official views of any government agency.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding by immunoglobulin to the HPV-16-derived proteins L1 and E4 in cervical secretions of women with HPV-related cervical disease.

Although DNA of the human papillomaviruses (HPV) can be identified in epithelium of a large proportion of patients with genital squamous lesions, relatively little is known about the extent of the local host immune response to this virus. We analyzed cervical secretions from patients undergoing evaluation because of abnormal Papanicolaou smears (cervical biopsy showed nonspecific atypia, flat condyloma, or intraepithelial neoplasia), as well as controls, for immunoglobulin binding to proteins produced in vitro to HPV-16 L1, E4, and E7 open reading frames. Segments of the HPV-16 genome, including portions of the L1 (nucleotides 6153-6794), E4 (nucleotides 3399-3648), and E7 (nucleotides 686-880) open reading frames, were cloned into pATH vectors and expressed as tryptophan synthetase E fusion proteins in Escherichia coli and used as a source of study antigens. Fusion proteins containing the HPV L1, E4, and E7 polypeptides were found to be distinct by molecular weight (59,000; 45,000; and 42,000) as well as by immunological determinants recognized by heterologous immune sera. Of 8 cervical intraepithelial neoplasia lesions tested by RNA-RNA in situ hybridization, 7 were found to be positive for HPV-16-related nucleic acids, in contrast to none (0 of 4) in the condyloma group (three positive for HPV DNA other than type 16). Immunoglobulin in cervical secretions showed reactivity to HPV type 16 E4 or L1 or both, with highest binding in patients with cervical intraepithelial neoplasia (P less than 0.01 for HPV-16 L1 and E4 compared with controls). Binding was not tryptophan synthetase E dependent and was, in general, coincident for the HPV-16 E4 and L1 proteins. We conclude that study of cervical secretions, using a quantitative assay for immunoglobulin binding to HPV-16 proteins produced in vitro, may be useful to document the quality and quantity of the immune response of the host to this important human pathogen.

Locomotion in the pulmonate snail Melampus--II. Recovery after pedal ganglion excision.

1. When one pedal ganglion is removed, snails first crawl using the unoperated side of the foot, but in 4-8 weeks the operated side exhibits an anterior-to-posterior gradient of recovery. 2. A ganglion bud bridges the site of the missing ganglion and axons project from intact central ganglia into the foot. 3. Rhythmic activity in right and left pedal nerve pairs is correlated during locomotion in the regenerated snails. 4. The oscillator in the remaining pedal ganglion drives bilaterally coordinated activity. Regenerated projections from the cerebral ganglia through the bud to the remaining pedal ganglion suffice to initiate locomotion.