bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial S-layer preservation and rare arsenic–antimony–sulphide bioimmobilization in siliceous sediments from Champagne Pool hot spring, Waiotapu, New Zealand
Authors: Phoenix Vernon R. , Renaut Robin W. , Jones Brian , Ferris F. Grant
Published: April 2005

Siliceous sinter, loose sediments, and suspended flocs in Champagne Pool, an anoxic hot (75 °C) spring at Waiotapu, New Zealand, are composed of opaline silica and metal-rich sulphides that contain many well-preserved, mineralized microbes. Detailed analysis by transmission electron microscopy and energy dispersive spectrometry has shown that bacterial cell wall and capsular material is preserved by the immobilization of high levels of As, Sb and S in the organic matrix. Calculation of the probable metal species in the spring water suggests that arsenic and antimony are present in solution as negative and neutrally charged sulphide or hydroxide complexes (such as HAs
2
S
4
−
, H
3
AsO
3
and HSb
2
S
4
−
). The early adsorption of these complexes onto reactive groups on the bacterial surface may be paramount in the excellent preservation of cell morphology. As biomineralization progresses, biomineral composition commonly becomes dominated by the precipitation of a supersaturated Al-rich amorphous silica phase. Biomineralization commonly preserves S-layers, an ordered mosaic of proteins on the outer surface of the cell wall. These are the finest ultrastructure details thus far found in microbes preserved by hydrothermal mineralization, and can be used as an aid to identify microfossils. The S-layers preserved here probably belong to
Clostridium thermohydrosulfuricum
or
Desulfotomaculum nigrifacans
.
Ages and cooling history of the Early Cretaceous Caleu pluton: testimony of a switch from a rifted to a compressional continental margin in central Chile
Authors: Parada Miguel A. , Féraud Gilbert , Fuentes Francisco , Aguirre Luis , Morata Diego , Larrondo Paula
Published: April 2005

The Caleu pluton, in the Coastal Range of central Chile, represents the last magmatic event related to the Early Cretaceous rifting along the western margin of South America. The pluton was emplaced into a
c
. 10 km thick pile of mainly basalts and basaltic andesites deposited in an Early Cretaceous subsiding basin, and affected by very low-grade metamorphism. The cooling history of the pluton is documented on the basis of U–Pb,
40
Ar/
39
Ar step-heating and fission-track dating. The U–Pb date suggests an age of emplacement in the interval 94.2–97.3 Ma. Rapid subsolidus cooling between 550–500 °C and 250 °C is documented by
40
Ar/
39
Ar plateau ages on amphibole, biotite and plagioclase between 94.9 ± 1.8 and 93.2 ± 1.1 Ma. Slower subsolidus cooling to
c
. 100 °C is identified at the 94–90 Ma interval by the fission-track thermal model. The geochronological data show that the emplacement of the pluton is coeval with the very low-grade metamorphism of the host rocks. Therefore, this metamorphism is probably not the result simply of burial, but also of a regional thermal gradient related to the plutonism. Exhumation of the pluton started coevally with its emplacement and continued to about 90 Ma, being associated with the closure of the Early Cretaceous rifting. The Caleu plutonism represents an asthenospheric-derived event during maximum extension, and marks a turning point between extensional- and compressional-related magmatism.
Interleukin-1 inhibits the induction of insulin-like growth factor-I by growth hormone in CWSV-1 hepatocytes
Authors: Shumate Margaret L. , Yumet Gladys , Ahmed Tamer A. , Cooney Robert N.
Published: April 2005

Sepsis results in hepatic “growth hormone (GH) resistance” with reductions in plasma IGF-I despite a two- to fourfold increase in circulating GH. In this study, we examine the effects of IL-1 on GH receptor (GHR) expression, GH signaling (via the JAK/STAT and MAPK pathways), and the induction of gene expression [IGF-I mRNA and serine protease inhibitor (Spi) 2.1] by GH in CWSV-1 hepatocytes. Incubation of cells with IL-1β (10 ng/ml, 24 h) had no effect on the relative abundance of GHR or signaling proteins JAK2, STAT5b, and ERK1/2 in cell lysates. Baseline phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 was minimal. After GH stimulation, tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 increased 2- to 10-fold. However, neither the time course nor the magnitude of GHR, JAK2, and ERK1/2 phosphorylation by GH were significantly altered by IL-1. The GH-induced translocation of STAT5b to the nucleus was not prevented by IL-1. Although phosphorylated STAT5 in nuclear extracts from GH + IL-1 cells was decreased by 24% (vs. controls) 15 min after GH stimulation, this did not result in reduced STAT5-DNA binding activity. Pretreatment with IL-1 did not significantly decrease IGF-I mRNA stability. We conclude that IL-1 only minimally affects the time course of JAK2/STAT5 and MAPK signaling by GH. Therefore, an inhibitory effect of IL-1 on IGF-I and Spi 2.1 mRNA synthesis by GH represents the most likely mechanism for IL-1-mediated GH resistance.
Contribution of Na+-K+ pump and KIR currents to extracellular pH-dependent changes of contractility in rat superior mesenteric artery
Authors: Kim Moon Young , Liang Guo Hua , Kim Ji Aee , Park Seong Hoon , Hah Jong Sik , Suh Suk Hyo
Published: April 2005

We compared the branches and trunk of rat superior mesenteric artery (SMA) with respect to extracellular pH (pHo)-dependent changes in vascular contractility. Decreases in pHo from 7.8 to 6.4 significantly reduced apparent affinity (pD2) to norepinephrine (NE) and maximal contraction by NE, which were more prominent in larger-diameter arteries. On the other hand, decreases in pHo significantly reduced Ba2+-sensitive K+-induced relaxation (which was evoked by elevation of extracellular K+ concentration from 6 to 12 mM) in the first branch and inhibited inwardly rectifying K+ (KIR) currents in cultured smooth muscle cells (SMCs) of SMA. RT-PCR revealed transcripts for Kir2.1 in the SMCs. Real-time PCR analysis revealed 6.1-, 3.3-, and 2.2-fold increases in the Kir2.1 mRNA-to-β-actin mRNA ratios of SMCs of the third, second, and first branches, respectively, vs. the corresponding relative levels of trunk SMCs. The magnitudes of K+-induced relaxation were significantly greater in smaller-diameter arteries, and there was a strong correlation between the transcript levels of Kir2.1 and K+-induced relaxation. A decrease in pHo reduced ouabain-sensitive K+-induced relaxation and ouabain-induced contraction. A decrease in pHo from 7.4 to 6.4 depolarized membrane potential of the cultured SMCs. From these results, we conclude that an increase in pHo activates KIR currents and the Na+-K+ pump, which then reduces vascular contractility. Inasmuch as KIR channel densities are significantly greater in smaller-diameter arteries, the reduction in vascular contractility on increasing pHo is more pronounced in smaller-diameter arteries.
Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure
Authors: Liu Fen-Fen , Stone James R. , Schuldt Adam J. T. , Okoshi Katashi , Okoshi Marina P. , Nakayama Masaharu , Ho Kalon K. L. , Manning Warren J. , Marchionni Mark A. , Lorell Beverly H. , Morgan James P. , Yan Xinhua
Published: April 2005

Neuregulins and their erbB receptors are essential for cardiac development and postulated to be cardioprotective in the presence of injury in the postnatal heart. We tested the hypothesis that the development of doxorubicin-induced cardiotoxicity in vivo is more severe in mice with heterozygous knockout of the neuregulin-1 gene (NRG-1+/−) compared with wild-type mice (WT). Three-month old NRG-1+/− and WT mice were injected with a single dose of doxorubicin (20 mg/kg ip). Survival was analyzed by the Kaplan-Meier approach. Left ventricular (LV) function and signaling pathways were analyzed 4 days after treatment. Fifteen days after treatment, survival was significantly lower in doxorubicin-treated NRG-1+/− mice (NRG-1+/−-Dox) compared with doxorubicin-treated WT mice (WT-Dox) (15% vs. 33%, P < 0.01). LV mass was significantly lower in NRG-1+/−-Dox but not in WT-Dox compared with nontreated animals. LV systolic pressure and LV midwall fractional shortening were significantly lower in NRG-1+/−-Dox compared with WT-Dox mice. LV protein levels of NRG-1, erbB2, and erbB4 receptors were similar in WT-Dox and NRG-1+/−-Dox mice. However, levels of phosphorylated erbB2, Akt, and ERK-1/2 were significantly decreased in NRG-1+/−-Dox compared with WT-Dox mice. A significant decrease in phosphorylated P70S6K levels was also observed in NRG-1+/−-Dox compared with nontreated NRG-1+/− mice. These results demonstrate that heterozygous knockout of the neuregulin-1 gene worsens survival and LV function in the presence of doxorubicin-induced cardiac injury in vivo. This is associated with the depression of activation of the erbB2 receptor as well as Akt, p70S6K, and ERK-1/2 pathways.
Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?
Authors: Rummel Christoph , Barth Stephan W. , Voss Thilo , Korte Stefan , Gerstberger Rüdiger , Hübschle Thomas , Roth Joachim
Published: April 2005

In guinea pigs, dose-dependent febrile responses were induced by injection of a high (100 μg/kg) or a low (10 μg/kg) dose of bacterial lipopolysaccharide (LPS) into artificial subcutaneously implanted Teflon chambers. Both LPS doses further induced a pronounced formation of prostaglandin E2 (PGE2) at the site of localized subcutaneous inflammation. Administration of diclofenac, a nonselective cyclooxygenase (COX) inhibitor, at different doses (5, 50, 500, or 5,000 μg/kg) attenuated or abrogated LPS-induced fever and inhibited LPS-induced local PGE2 formation (5 or 500 μg/kg diclofenac). Even the lowest dose of diclofenac (5 μg/kg) attenuated fever in response to 10 μg/kg LPS, but only when administered directly into the subcutaneous chamber, and not into the site contralateral to the chamber. This observation indicated that a localized formation of PGE2 at the site of inflammation mediated a portion of the febrile response, which was induced by injection of 10 μg/kg LPS into the subcutaneous chamber. Further support for this hypothesis derived from the observation that we failed to detect elevated amounts of COX-2 mRNA in the brain of guinea pigs injected subcutaneously with 10 μg/kg LPS, whereas subcutaneous injections of 100 μg/kg LPS, as well as systemic injections of LPS (intra-arterial or intraperitoneal routes), readily caused expression of the COX-2 gene in the guinea pig brain, as demonstrated by in situ hybridization. Therefore, fever in response to subcutaneous injection of 10 μg/kg LPS may, in part, have been evoked by a neural, rather than a humoral, pathway from the local site of inflammation to the brain.
Molecular cloning and expression of leptin in gray and harbor seal blubber, bone marrow, and lung and its potential role in marine mammal respiratory physiology
Authors: Hammond John A. , Bennett Kimberley A. , Walton Michael J. , Hall Ailsa J.
Published: April 2005

Leptin is a multifunctional hormone, produced predominantly in adipocytes. It regulates energy balance through its impact on appetite and fat metabolism, and its concentration indicates the size of body fat reserves. Leptin also plays a vital role in stretch-induced surfactant production during alveolar development in the fetus. The structure, expression pattern, and role of leptin have not previously been explored in marine mammals. Phocid seals undergo cyclical changes in body composition as a result of prolonged fasting and intensive foraging bouts and experience rapid, dramatic, and repeated changes in lung volume during diving. Here, we report the tissue-specific expression pattern of leptin in these animals. This is the first demonstration of leptin expression in the lung tissue of a mature mammal, in addition to its expression in the blubber and bone marrow, in common with other animals. We propose a role for leptin in seal pulmonary surfactant production, in addition to its likely role in long-term energy balance. We identify substitutions in the phocine leptin sequence in regions normally highly conserved between widely distinct vertebrate groups, and, using a purified seal leptin antiserum, we confirm the presence of the leptin protein in gray seal lung and serum fractions. Finally, we report the substantial inadequacies of using heterologous antibodies to measure leptin in unextracted gray seal serum.
Ingestion of a high-glycemic index meal increases muscle glycogen storage at rest but augments its utilization during subsequent exercise
Authors: Wee Shiou-Liang , Williams Clyde , Tsintzas Kostas , Boobis Leslie
Published: April 2005

The aim of this study was to compare the effect of preexercise breakfast containing high- and low-glycemic index (GI) carbohydrate (CHO) (2.5g CHO/kg body mass) on muscle glycogen metabolism. On two occasions, 14 days apart, seven trained men ran at 71% maximal oxygen uptake for 30 min on a treadmill. Three hours before exercise, in a randomized order, subjects consumed either isoenergetic high- (HGI) or low-GI (LGI) CHO breakfasts that provided (per 70 kg body mass) 3.43 MJ energy, 175 g CHO, 21 g protein, and 4 g fat. The incremental areas under the 3-h plasma glucose and serum insulin response curves after the HGI meal were 3.9- ( P < 0.05) and 1.4-fold greater ( P < 0.001), respectively, than those after the LGI meal. During the 3-h postprandial period, muscle glycogen concentration increased by 15% ( P < 0.05) after the HGI meal but remained unchanged after the LGI meal. Muscle glycogen utilization during exercise was greater in the HGI (129.1 ± 16.1 mmol/kg dry mass) compared with the LGI (87.9 ± 15.1 mmol/kg dry mass; P < 0.01) trial. Although the LGI meal contributed less CHO to muscle glycogen synthesis in the 3-h postprandial period compared with the HGI meal, a sparing of muscle glycogen utilization during subsequent exercise was observed in the LGI trial, most likely as a result of better maintained fat oxidation.
The Child and Its Family: The Social Network Model
Authors: Lewis Michael
Published: April 2005

The classical attachment theory holds to the notion of a monotropic model. Such a model leads to a view of the mother as first and most important figure in an infant’s life. A polytropic view of attachment moves us toward a model of simultaneous and multiple attachment figures. In particular, it is argued that peer attachment is a separate but related system. A review of children’s peer relationships, including siblings, leads to the consideration of a social network model in which a variety of different people satisfy a variety of different needs of the child.
Social Relations in Childhood and Adolescence: The Convoy Model Perspective
Authors: Levitt Mary J.
Published: April 2005

Research on the development of social relations has been largely fragmented along role-specific lines and dominated conceptually by attachment theory. The Convoy Model is presented as an alternative to traditional approaches that fail to capture the complexity of social relationships across time and context. Research based on the model converges with that of other investigators to indicate that children benefit from the presence of multiple relations that play diverse roles in their lives, although the importance of specific relations may vary across individuals. A broader conceptualization of social relations is needed to address the place of attachment figures within a larger network of developmentally significant relations.
Mother-Infant Attachment, Peer Relationships, and the Development of Social Networks in Rhesus Monkeys
Authors: Suomi Stephen J.
Published: April 2005

The social networks that rhesus monkeys develop in nature are centered around multiple generations of matrilineal kin embedded in larger social groupings that have some degree of distinctiveness and permanence. Within each family, infants initially grow up in the care of their mothers and the close presence of relatives, and they subsequently expand their social network to include peers and others in the larger community and beyond while continuing to retain strong family ties throughout adolescence (for males) and for the rest of their lives (for females). Rhesus monkey families differ in relative status within their community-like troops, and these differences can have long-term consequences for individuals within each family. Yet there is also evidence that changes in within-family relationships, particularly those between mothers and offspring, can eventually lead to changes in the basic nature of the troop itself. It seems appropriate to characterize the social relationships that emerge between rhesus monkey mothers and their offspring in attachment-like terms, especially given Bowlby’s reliance on observations of rhesus monkey mother-infant interactions to provide the biological basis of the attachment theory he was formulating in the late 1950s and 1960s. Contrastingly, it may be overly simplistic to describe the various other social relationships that rhesus monkeys routinely develop within their expanding social networks exclusively from an attachment perspective. Instead, these other social relationships clearly differ from their relationship with their mother with respect to the specific behaviors that characterize each type of relationship, the physical and social contexts in which the relationships are expressed, and the manner in which each relationship changes throughout development. Moreover, the different relationships each monkey develops as it matures appear to complement one another as it becomes integrated into its overall social network.
Physical Activity and Postural Control in the Elderly: Coupling between Visual Information and Body Sway
Authors: Prioli Ana Caroline , Freitas Júnior Paulo B. , Barela José Angelo
Published: April 2005

Background: Aging is characterized by a decline in the postural control performance, which is based on a coherent and stable coupling between sensory information and motor action. Therefore, changes in postural control in elderlies can be related to changes in this coupling. In addition, it has been observed that physical activity seems to improve postural control performance in elderlies. These improvements can be due to changes in the coupling between sensory information and motor action related to postural control. Objective: The purpose of this study was to verify the coupling between visual information and body sway in active and sedentary elderlies. Methods: Sixteen sedentary elderlies (SE), 16 active elderlies (AE) and 16 young adults (YA) were asked to stand upright inside a moving room in two experimental conditions: (1) discrete movement and (2) continuous movement of the room. Results: In the continuous condition, the results showed that the coupling between the movement of the room and body sway was stronger and more stable for SE and AE compared to YA. In the discrete condition, SE showed larger body displacement compared to AE and YA. Conclusions:SE have more difficulty to discriminate and to integrate sensory information than AE and YA indicating that physical activity may improve sensory integration.
Treadmill Training Effects in Different Age Groups following Middle Cerebral Artery Occlusion in Rats
Authors: Wang Ray-Yau , Yu Shang-Ming , Yang Yea-Ru
Published: April 2005

Background: Despite the increased understanding of treadmill training on stroke patients, its effects on different age groups are not clearly known. The present study presents such effects through a model of cerebral ischemia on young and old groups of rats. Objectives: To investigate the effect of treadmill training on young and old rats after cerebral ischemia caused by middle cerebral artery occlusion (MCAO). Methods: Forty old (22–24 months of age) and 32 young (3–4 months of age) rats underwent the MCAO procedure for 60 min. Rats that survived the procedure were randomly assigned to a 1- or a 2-week treadmill training group, or a time-matched control group (n = 6–8 for each group). The infarct volume was compared between the treadmill training and the control groups for both the young and old rats at 1 or 2 weeks. Results: After treadmill training for 1 week, the mean infarct volume was 7.26 ± 0.49 and 9.51 ± 0.84% for the young and old rats, respectively. The 1-week treadmill training effect was significant in the young rats (p = 0.0207) but not in the old rats (p = 0.0840). The mean infarct volume was 6.84 ± 0.51 and 7.63 ± 0.52% for the young and old rats, respectively, after the 2-week treadmill training. Both the young and old rat groups demonstrated a significant reduction in the infarct volume compared with that of the control group (p = 0.021 for the young group and p = 0.039 for the old group) after 2 weeks of treadmill training. Conclusion: The present findings clearly demonstrate the different training effects of locomotor activity in reducing ischemic infarction in young and old rats. The delayed reduction in ischemic infarction in old rats was notable and may be attributable to the slow response of angiogenic and neurogenic mechanisms in the old rats.
Hierachy of Needs of Geriatric Patients
Authors: Majercsik E.
Published: April 2005

Background: The aim of the study is to contribute to the improvement of the quality of care of geriatric patients. In order to be able to improve the geriatric care we have to know clearly the needs of the elderly patients. Objective: The hierarchy of needs of geriatric patients in clinical circumstances had to be assessed by a psychometric technique based on a motivational approach. Methods: The process was based on the method of paired comparisons, and a duly composed questionnaire was administered to the geriatric patients who were proven to have consistent thinking and surpassed a pre-established threshold in the Mini Mental State Examination. The evaluation of the responds leads to a numerical derivation (on an interval scale) of the hierarchy of needs. Results: The received hierarchy of needs proved to oppose the general hypothesis of Maslow’s motivation theory. Conclusion: This may induce a necessary shift in the approach to the care of the elderly, and accentuate the self-actualization and esteem needs beside the overtly emphasized physiological care.
Non-Invasive (Transcutaneous) Monitoring of PCO2 (TcPCO2) in Older Adults
Authors: Janssens Jean-Paul , Laszlo André , Uldry Christophe , Titelion Véronique , Picaud Claudette , Michel Jean-Pierre
Published: April 2005

Background: Transcutaneous measurements of arterial blood gases (ABG) may decrease the need for repeated arterial puncture in older patients treated for acute cardiac or pulmonary disorders. However, age-related changes in skin perfusion, metabolism, or thickness may alter the validity of the technique. Objective: To analyse the agreement between transcutaneous and arterial measurement of PaO2 and PaCO2 in older adults. Design: Prospective descriptive study performed in the intermediate-care unit of a geriatric university hospital and a pulmonary rehabilitation centre. Methods: 40 patients, aged 82.5 ± 8 years (66–97), hemodynamically stable, without vasopressor treatment, underwent simultaneous measurement of arterial blood gases (ABG) and transcutaneous CO2 (TcPCO2) and O2 (TcPO2) with a Radiometer TINA TCM3® capnograph, and a probe T° set at 43°C. Results: Correlation between PaCO2 and TcPCO2 was high (r2 = 0.86) with a low bias (–0.1 mm Hg) and limits of agreement quite compatible with clinical use: (8.3; –8.5 mm Hg). The probe was well tolerated without any cutaneous lesion even after prolonged recordings (up to 8 h). Conversely, although TcPO2 and PaO2 were significantly correlated, the variability around the regression line precludes the use of transcutaneous measurements for monitoring PaO2 in a clinical setting. Conclusion: In older subjects, TcPCO2 (but not TcPO2) measurements are reliable when repeated assessment of ABG is warranted.
Nutritional Supplementation of Very Old People at Hospital Discharge Increases Muscle Strength: A Randomised Controlled Trial
Authors: Price Rosemary , Daly Fergus , Pennington Christopher R. , McMurdo Marion E.T.
Published: April 2005

Background: Undernutrition is common in older people admitted to hospital, but little is known about how nutritional state changes after discharge. Objective: This randomised controlled trial was designed to examine the effect of oral nutritional supplementation of undernourished very old people prepared to take supplements after hospital discharge following acute illness. Methods: Participants aged ≧75 years with a BMI ≤24 kg/m2 and triceps skin fold thickness or mid-arm muscle circumference below the 10th centile and/or weight loss ≧5% during an acute hospital stay were allocated at random to either oral nutritional supplementation for 8 weeks from hospital discharge or to usual care. Primary outcome was change in weight, secondary outcomes were handgrip strength and anthropometry. Results: Of 198 patients eligible to participate, 136 patients (mean age 85 years) were randomised and 76/136 (56%) completed the study. Twenty percent (13/66) of the intervention group withdrew after only 2 weeks, citing intolerance of the supplements. Using intention-to-treat analysis, body weight increased by a mean of 1.6 and 2.2% in the control and intervention groups, respectively, but this between-group difference was not significant (p = 0.188). However, handgrip strength increased more (p = 0.055) in the intervention group (13.9%) than in the control group (7.2%). Conclusions: Oral nutritional supplementation was associated with a greater increase in handgrip strength than in non-supplemented controls and this observation merits further study.
Cross-Domain Variability of Cognitive Performance in Very Old Nursing Home Residents and Community Dwellers: Relationship to Functional Status
Authors: Rapp Michael A. , Schnaider-Beeri Michael , Sano Mary , Silverman Jeremy M. , Haroutunian Vahram
Published: April 2005

Background: Recent evidence suggests that cross-domain variability in cognition may be related to subsequent cognitive decline beyond mean performance levels in cognitive tasks. Objectives: To examine age-related changes in cross-domain variability across cognitive task performance in very old nursing home residents in contrast to community-dwelling older adults. To explore the relationship between cross-domain variability in cognition and functional disability in very old age. Methods: 204 very old (82.00 ± 8.51 years) residents from the Jewish Home and Hospital, Bronx, N.Y., and 376 community-dwelling older adults of similar age (86.75 ± 5.84 years) were tested on a cognitive battery. Cross-domain variability scores were computed across the cognitive tasks. Functional disability measures were derived from the CDR (Clinical Dementia Rating) Scale. Results: Whereas oldest old community-dwelling adults showed a decrease in variability across domains with age, variability increased with age in nursing home residents, irrespective of the level of cognitive performance. Cross-domain variability was associated with functional disability beyond the effects of age, gender, education, dementia status, residential status, and level of cognitive performance. Conclusion: Findings suggest that cross-domain variability in cognition is related to functional decline with age. Cross-domain variability in cognition may be a prominent predictor for the development of functional decline in very old adults.
Rethinking Models of Psychotropic Drug Action
Authors: Moncrieff Joanna , Cohen David
Published: April 2005

Theoretical assumptions about how psychotropic drugs ‘work’ are rarely discussed explicitly. In a ‘disease-centred model,’ drugs are believed to work by acting on a disease process. In contrast, in a ‘drug-centred model,’ the characteristic physiological, behavioural and subjective effects of drugs are used to define drug action. The therapeutic value of a drug stems from the usefulness of these effects in clinical situations. The disease-centred model appears dominant but has weaknesses: (1) it cannot logically justify the use of drugs since major pathophysiological hypotheses were derived from selectively observed actions of drugs; (2) comparisons between drugs believed to have specific effects in certain conditions and drugs thought to have non-specific effects fail to support it; (3) outcome measures for various disorders include items responsive to non-specific drug effects; (4) studies with healthy volunteers describe characteristic drug-induced states independently of a psychiatric diagnosis; (5) animal tests show effects with agents not usually thought of as specific treatments for the conditions modelled by tests. This article offers suggestions to develop a drug-centred model and discusses its potential impact on clinical practice.
Internet-Guided Self-Help with or without Exposure Therapy for Phobic and Panic Disorders
Authors: Schneider Andreas J. , Mataix-Cols David , Marks Isaac M. , Bachofen Martin
Published: April 2005

Background: As many sufferers from phobic and panic (phobia/panic) disorders cannot get to suitable therapists, routine aspects of therapy were delegated to internet-accessed computer-aided self-help with or without exposure instructions. Methods: Phobia/panic referrals were randomised to computer-aided self-help via the internet at home in a 2:1 ratio either by self-exposure cognitive behaviour therapy (CBT) [FearFighter (FF), n = 45] or by minimal CBT without exposure [Managing Anxiety (MA), n = 23]. All had brief backup phone advice from a clinician concerning their computer guidance. Results: On self-ratings and blinded assessor ratings, patients improved equally with each form of self-help over 10 treatment weeks but significantly more on 5 out of 10 measures by week 14 (1-month follow-up) when the self-help included self-exposure instructions than when it did not. In accord with this, standardised effect sizes (Cohen’s d) indicated superiority of FF over MA on 5 measures by week 14. Satisfaction with treatment in all patients pooled correlated positively with improvement after treatment and at 1-month follow-up. Conclusions: At the end of treatment, computer-aided CBT self-help at home via the internet plus brief live helpline support was effective with or without exposure instructions, and at 1-month follow-up it was more effective on some measures if exposure instructions had been included. Analysis is needed of how non-exposure CBT produced its shorter-term effect.
Tridimensional Personality Questionnaire Factors in Major Depressive Disorder: Relationship to Anxiety Disorder Comorbidity and Age of Onset
Authors: Öngür Dost , Farabaugh Amy , Iosifescu Dan V. , Perlis Roy , Fava Maurizio
Published: April 2005

Objective: We used the Tridimensional Personality Questionnaire (TPQ) to study the relationship between temperamental traits and comorbid anxiety disorders as well as age of onset of major depressive disorder (MDD) in 263 patients with MDD. Methods: Patients recruited for a large clinical study on MDD underwent a Structured Clinical Interview for DSM-III-R assessment and were administered the self-rated TPQ [mean age = 39.5 ± 10.5 years, women = 138 (53%), initial 17-item Hamilton Rating Scale for Depression (HAM-D-17) score = 19.6 ± 3.4]. The TPQ was scored for three previously identified factors – harm avoidance (HA), novelty seeking (NS), and reward dependence (RD). Multiple linear regression methods were used to evaluate the relationship between TPQ factors and each comorbid anxiety disorder as well as between early- vs. late-onset MDD, after controlling for age, gender and initial HAM-D-17 score (when these were related to the dependent variable in simple regressions). Results: Social anxiety disorder in MDD was strongly associated with higher scores on HA and lower scores on NS and RD (t = 5.4, p < 0.0001; t = 2.6, p = 0.009; t = 2.2, p = 0.028, respectively). A diagnosis of generalized anxiety disorder in MDD was significantly related to higher HA scores (t = 2.8, p = 0.006). The presence of comorbid obsessive-compulsive disorder was associated with lower NS scores (t = 2.3, p = 0.023) as was that of comorbid panic disorder (t = 2.0, p = 0.051). Finally, the presence of simple phobias was associated with lower scores on RD (t = 2.4, p = 0.016). HA scores were higher in patients with early onset of MDD (adjusted p = 0.05). Early versus late onset of MDD was not significantly related to NS or RD scores. Limitations: Since our sample consisted of moderately depressed outpatients, our ability to generalize our findings to other populations is limited. Conclusions: Features of temperament are related to patterns of anxiety disorder comorbidity and age of onset among patients with MDD. Higher levels of HA and lower levels of RD and NS were associated with an increased risk of anxiety disorder comorbidity in our sample. HA may also be related to early onset of depression.
Stressful Life Events, Depression and Demoralization as Risk Factors for Acute Coronary Heart Disease
Authors: Rafanelli Chiara , Roncuzzi Renzo , Milaneschi Yuri , Tomba Elena , Colistro Maria Cristina , Pancaldi Leonardo Goffredo , Di Pasquale Giuseppe
Published: April 2005

Background: While the effect of psychological stress and depression on the course of heart disease is commonly recognized, the relationship between recent life events, major depression, depressive symptomatology and the onset of acute coronary heart disease (CHD) has been less considered. The aim of this study was to investigate the presence of stressful life events, major and minor depression, recurrent depression and demoralization in the year preceding the occurrence of a first acute myocardial infarction (AMI) and/or a first episode of instable angina and to compare stressful life events, also related with mood disorders, in patients and healthy controls. Methods: 97 consecutive patients with a first episode of CHD (91 with AMI and 6 with instable angina) and 97 healthy subjects matched for sociodemographic variables were included. All patients were interviewed with Paykel’s Interview for Recent Life Events, a semistructured interview for determining the psychiatric diagnosis of mood disorders (DSM-IV), a semistructured interview for demoralization (DCPR). Patients were assessed while on remission from the acute phase. The time period considered was the year preceding the first episode of CHD and the year before the interview for controls. Results: Patients with acute CHD reported significantly more life events than control subjects (p < 0.001). All categories of events (except entrance events) were significantly more frequent. 30% of patients were identified as suffering from a major depressive disorder; 9% of patients were suffering from minor depression, 20% from demoralization. Even though there was an overlap between major depression and demoralization (12%), 17% of patients with major depression were not classified as demoralized and 7% of patients with demoralization did not satisfy the criteria for major depression. Independently of mood disorders, patients had a higher (p < 0.001) mean number of life events than controls. With regard to life events, the same significant difference (p < 0.001) compared to controls applied to patients with and without mood disorders. Conclusions: Our findings emphasize, by means of reliable methodology, the relationship between life events and AMI. These data, together with those regarding traditional cardiac risk factors, may have clinical and prognostic implications to be verified in longitudinal studies.
Comparison of Intravenous Iron Sucrose to Oral Iron in the Treatment of Anemic Patients with Chronic Kidney Disease Not on Dialysis
Authors: Charytan Chaim , Qunibi Wajeh , Bailie George R.
Published: April 2005

Background: Few studies compare oral to intravenous (IV) iron for managing anemia in patients with chronic kidney disease (CKD) not on dialysis. Methods: We enrolled 96 CKD anemic patients on erythropoietin in a randomized, open-label, multicenter, controlled study. Patients received 29 days of oral FeSO4 (325 mg t.i.d.) or intravenous (IV) iron sucrose (5 doses of 200 mg weekly). Assessments were made up to 14 days after the last dose. Primary endpoints were changes in hemoglobin and ferritin, and clinical success was evaluated from the percent of patients with combined endpoints of rises in hemoglobin/ferritin, hemoglobin/ferritin/TSAT, and hemoglobin/TSAT. Results: There was no significant difference in hemoglobin values between IV and oral therapy. IV iron patients had greater increases in mean serum ferritin (288 ng/ml, p < 0.0001) compared to oral iron patients (–5.1 ng/ml, p = NS). IV iron patients with baseline ferritin <100 ng/ml had a greater increase in hemoglobin (1.4 g/dl) compared to oral iron patients (0.9 g/dl) (p < 0.05). More IV iron patients (54.2%) attained hemoglobin values >11.0 g/dl compared to oral iron patients (31.3%, p = 0.028), and met hemoglobin/ferritin (62.5%), hemoglobin/TSAT (47.9%), hemoglobin/ferritin/TSAT (43.8%), and ferritin/TSAT criteria (54.2%) than oral iron patients (0, 22.9, 0, and 0%, respectively). There were no serious side effects. Conclusions: These CKD patients had increases in both hemoglobin and ferritin following IV iron therapy, whereas those treated with oral iron had increases in hemoglobin without increases in iron stores. Iron sucrose, given weekly as 200 mg IV push over 5 min is an effective and safe anemia treatment in this population.
Gene Expression of Perforin by Peripheral Blood Lymphocytes as a Marker of Acute Rejection
Authors: Shin Gyu-Tae , Kim Seung-Jung , Lee Tae-Seung , Oh Chang-Kwon , Kim Heungsoo
Published: April 2005

Background: Previous findings have demonstrated that the expression of cytotoxic effector molecules is increased in acute rejection of renal allografts. In the present study, we serially examined the gene expression of perforin, granzyme B and Fas ligand (FasL) in peripheral blood lymphocytes (PBLs) of renal allograft recipients to assess the potential of their expression as a marker of acute rejection. Methods: PBLs were isolated from blood samples taken on days 2, 4, 6, 8, 10 and 12 after transplantation. Competitive PCR was performed to evaluate the abundance of mRNA of perforin, granzyme B and FasL. The mean value + 2 SD of each molecule in the control group was set as a discriminatory level for that particular molecule. Results: When all measured samples were compared, perforin expression was significantly higher in patients with acute rejection than in the control group (1.84 ± 3.01 vs. 0.71 ± 0.48, p = 0.01). The percentage of perforin expression exceeding the discriminatory level was also significantly higher in patients with acute rejection (p = 0.0003). Five patients in the rejection group (5/7, 71.4%) showed perforin expression exceeding the discriminatory level, while only 1 patient in the control group did so (1/8, 12.5%) (p = 0.02). Perforin expressions of days 0 and 1 of rejection crisis were the highest over the study period. No consistent pattern of granzyme B and FasL expression was identified in relation to rejection crisis. Conclusion: Gene expression of perforin by PBLs was upregulated in accordance with acute rejection, thus offering the possibility that it may be utilized as a marker of acute rejection.
Lymphocyte Apoptosis: Role of Uremia and Permeability of Dialysis Membrane
Authors: Soriano Sagrario , Martín-Malo Alejandro , Carracedo Julia , Ramírez Rafael , Rodríguez Mariano , Aljama Pedro
Published: April 2005

Background: Uremia is associated to host defense mechanism disorders. Lymphocyte apoptosis, which may cause alteration of the immune system, is increased in uremic patients. The aim of the present study was to determine if, in addition to uremia, dialysis membranes with different biocompatibility and permeability have an effect on lymphocyte apoptosis. Methods: Cell apoptosis and Fas expression were assessed using flow cytometry in four groups of patients: (1) uremic non-dialyzed (Non-D) patients; (2) hemodialysis (HD) patients on hemophan; (3) low-flux polysulfone, and (4) high-flux polysulfone membrane. Ten healthy volunteers were used ascontrols. Results: At baseline, lymphocytes from patients on hemophan showed an increase in apoptosis (18.4 ± 6.9%) as compared with Non-D (7.2 ± 2.8%; p < 0.001), low-flux (6.4 ± 2.4%; p < 0.001), high-flux (2.6 ± 1.2%; p < 0.001) and controls (2.0 ± 1.0%; p < 0.001). Fas expression was similar in lymphocytes from Non-D and hemophan dialyzed patients (40.5 ± 5% vs. 40.4 ± 6%), and in both groups it was greater than low-flux (30%±7%; p < 0.001), high-flux (11 ± 4%; p < 0.001) and controls (12.6 ± 3%; p < 0.001). When lymphocytes were cultured for 48 h, apoptosis was similar in Non-D and hemophan (27.0 ± 4.3% vs. 27.1 ± 6.9%); apoptosis of lymphocyte from patients on low-flux (14.1 ± 3.5%) was greater than on high-flux polysulfone membrane (7.0 ± 2.0%; p < 0.001). Conclusion: These findings suggest that in dialysis patients lymphocyte apoptosis is influenced not only by the biocompatibility but also by the permeability of the dialysis membrane.
Mycophenolate Mofetil for Remission Induction in Severe Lupus Nephritis
Authors: Cross Jane , Dwomoa Adu , Andrews Peter , Burns Aine , Gordon Caroline , Main John , Mathieson Peter , O’Donoghue Donal , Jayne David
Published: April 2005

Background: Mycophenolate mofetil (MMF) is a potential alternative immunosuppressive to cyclophosphamide or azathioprine for the treatment of lupus nephritis. It has a superior toxicity profile to cyclophosphamide and is more effective than azathioprine when used in combination with cyclosporin for renal transplantation. Methods: This open label study assessed the safety and efficacy of an induction regimen of MMF and prednisolone in 24 patients, with active WHO Class III, IV or V lupus nephritis, without previous exposure to cyclophosphamide or MMF. Patients received MMF 2 g/day and a tapering dose of oral prednisolone and were followed for 12 months. Renal response was defined using the validated BILAG (British Isles Lupus Assessment Group) Index. Results: 20 patients achieved complete renal remission, 2 partial renal remission and 2 had renal disease refractory to MMF. Five patients were withdrawn, 2 for progressive renal disease, 2 for extra-renal flares and 1 following a severe infection. No patient was withdrawn for drug intolerance. There were 18 adverse events of which 10 were infections. Clinical improvement was mirrored by normalisation of complement levels and marked falls in circulating anti-double-stranded DNA antibodies. Follow-up for a mean period of 35 months documented only one episode of renal relapse which subsequently remitted with re-introduction of MMF. One patient died after 18 months’ follow-up with uterine malignancy. Conclusions: MMF with prednisolone was effective for remission induction in severe lupus nephritis and was well tolerated.
A2A Adenosine Receptor Agonist and PDE4 Inhibition Delays Inflammation but Fails to Reduce Injury in Experimental Obstructive Nephropathy
Authors: Lange-Sperandio Bärbel , Forbes Michael S. , Thornhill Barbara , Okusa Mark D. , Linden Joel , Chevalier Robert L.
Published: April 2005

Background: Renal interstitial inflammation is a consequence of unilateral ureteral obstruction (UUO). Following ischemia/reperfusion, adenosine reduces renal inflammation and injury, effects which are potentiated by type 4 phosphodiesterase inhibitors. We therefore studied the effects of A2A adenosine receptor agonist (ATL146e), and PDE4 inhibitor (rolipram) in mice subjected to UUO. Methods: Mice were subjected to UUO or sham operation, and received either vehicle or ATL146e + rolipram by osmotic minipump for 1 or 7 days. At 1, 3, 7, or 14 days after operation, renal macrophage infiltration, apoptosis, proliferation, tubular atrophy, and interstitial fibrosis were quantitated, and expressions of IL-6 and TGF-β mRNA were determined. Results: ATL146e + rolipram reduced macrophage infiltration by 40% after 3 days UUO (p < 0.05). Tubular apoptosis, tubular atrophy, and interstitial fibrosis were increased by 7 or 14 days UUO, but were unaffected by ATL146e + rolipram. However, cellular proliferation was increased by ATL146e + rolipram in the obstructed kidney. ATL146e + rolipram had no effect on the renal expression of IL-6 and TGF-β mRNA. Conclusions: A2A receptor activation and PDE4 inhibition transiently reduce renal macrophage infiltration, but do not ameliorate the renal response to UUO. We speculate that the persistent stimulus for inflammation triggered by UUO cannot be reversed by agents that suppress inflammatory cell activation alone.
Suppressive Mechanisms of Sairei-to on Mesangial Matrix Expansion in Rat Mesangioproliferative Glomerulonephritis
Authors: Ono Takahiko , Liu Ning , Makino Toshiaki , Nogaki Fumiaki , Muso Eri , Honda Gisho , Kita Toru
Published: April 2005

Background: Sairei-to (TJ-114) is a Japanese herbal medicine of standardized quality, originating from traditional Chinese medicine. In the present in vivo study, we investigated the suppressive effects of TJ-114 and related drugs, Shosaiko-to (TJ-9), and Saiboku-to (TJ-96), on mesangioproliferative glomerulonephritis (MsPGN) in rats. TJ-9 is a basal prescription of TJ-96 and TJ-114. We evaluated the efficacy of these drugs on proteinuria, extracellular matrix (ECM) accumulation, and superoxide dismutase (SOD)-activity. Methods: MsPGN in Wistar rats was induced by intravenous injection of rabbit anti-rat thymocyte serum (ATS). TJ-114, TJ-9, TJ-96 (500 mg/kg/day), or prednisolone (PSL, 2 mg/kg/day) was orally administered to the rats as drinking water from the day of ATS injection (day 0) to day 8, when rats were sacrificed and the kidney specimens were collected. Macrophage infiltration was evaluated by immunostaining for ED-1. ECM was measured by trichrome-staining, and fibronectin immunostaining. Northern blotting was performed to clarify the mRNA expression of cytokines and fibronectin. SOD-activity in the homogenate of renal cortex was also evaluated. Results: The amount of urinary protein was significantly decreased only in the TJ-114-treated group compared with the disease control group (p < 0.05). The number of ED-1-positive cells was significantly decreased in all the treatment groups (p < 0.05, respectively). Decreases in the trichrome-stained area were observed moderately in the TJ-114-treated group (66% of control, p < 0.001) and mildly in the PSL-treated group (76% of control, p < 0.001). The staining area of fibronectin in the glomerulus was significantly decreased in all the treated groups except PSL, and was especially suppressed in the TJ-114-treated group (45% of control, p < 0.001). Transforming growth factor (TGF) and connective tissue growth factor (CTGF) expression significantly decreased in the TJ-114-treated group to the control level (p < 0.05). TGF-β, CTGF, and fibronectin mRNA were upregulated in the disease control group, and TJ-114 suppressed these mRNA expressions in glomeruli. The SOD-activity of renal cortex-homogenate was significantly augmented in all the treated groups except PSL, markedly in the TJ-96- and TJ-114-treated groups. Conclusion: These results suggest that TJ-114 ameliorates ECM accumulation in experimental rat MsPGN, partly suppressing TGF-β and CTGF expression through the recovery of SOD-activity.