bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal hyperinsulinemia predisposes rat fetuses for hyperinsulinemia, and adult-onset obesity and maternal mild food restriction reverses this phenotype
Authors: Srinivasan Malathi , Aalinkeel Ravikumar , Song Fei , Mitrani Paul , Pandya Jignesh D. , Strutt Brenda , Hill David J. , Patel Mulchand S.
Published: September 2005

We have previously shown that artificial rearing of newborn female rat pups on a high-carbohydrate (HC) milk formula resulted in chronic hyperinsulinemia and adult-onset obesity (HC phenotype) and that the maternal HC phenotype was transmitted to their progeny (2-HC rats) because of fetal development in the HC female rat. The aims of this study were to investigate 1) the fetal adaptations that predisposed the progeny for the expression of the HC phenotype in adulthood and 2) whether the transfer of the HC phenotype to the progeny could be reversed by maternal food restriction. Fetal parameters such as plasma insulin and glucose levels, mRNA level of preproinsulin gene, pancreatic insulin content, and islet insulin secretory response in vitro were determined. On gestational day 21, 2-HC fetuses were hyperinsulinemic, had increased insulin content and mRNA level of the preproinsulin gene in their pancreata and demonstrated an altered glucose-stimulated insulin secretory response by isolated islets. Modification of the intrauterine environment in HC female rats was achieved by pair feeding them to the amount of diet consumed by age-matched control rats from the time of their weaning. This mild dietary restriction reversed their HC phenotype and also prevented the development of the HC phenotype in their progeny. These findings show that malprogramming of the progeny of the hyperinsulinemic-obese HC female for the expression of the HC phenotype is initiated in utero and that normalization of the maternal environment in HC female rats by mild food restriction resulted in the normal phenotype in their progeny.
Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway
Authors: Lee Vivian Y. , Schroedl Clara , Brunelle Joslyn K. , Buccellato Leonard J. , Akinci Ozkan I. , Kaneto Hideaki , Snyder Colleen , Eisenbart James , Budinger G. R. Scott , Chandel Navdeep S.
Published: September 2005

Exposure to bleomycin in rodents induces lung injury and fibrosis. Alveolar epithelial cell death has been hypothesized as an initiating mechanism underlying bleomycin-induced lung injury and fibrosis. In the present study we evaluated the contribution of mitochondrial and receptor-meditated death pathways in bleomycin-induced death of mouse alveolar epithelial cells (MLE-12 cells) and primary rat alveolar type II cells. Control MLE-12 cells and primary rat alveolar type II cells died after 48 h of exposure to bleomycin. Both MLE-12 cells and rat alveolar type II cells overexpressing Bcl-XLdid not undergo cell death in response to bleomycin. Dominant negative Fas-associating protein with a death domain failed to prevent bleomycin-induced cell death in MLE-12 cells. Caspase-8 inhibitor CrmA did not prevent bleomycin-induced cell death in primary rat alveolar type II cells. Furthermore, fibroblast cells deficient in Bax and Bak, but not Bid, were resistant to bleomycin-induced cell death. To determine whether the stress kinase JNK was an upstream regulator of Bax activation, MLE-12 cells were exposed to bleomycin in the presence of an adenovirus encoding a dominant negative JNK. Bleomycin-induced Bax activation was prevented by the expression of a dominant negative JNK in MLE-12 cells. Dominant negative JNK prevented cell death in MLE-12 cells and in primary rat alveolar type II cells exposed to bleomycin. These data indicate that bleomycin induces cell death through a JNK-dependent mitochondrial death pathway in alveolar epithelial cells.
3′-Untranslated region of the type 2 bradykinin receptor is a potent regulator of gene expression
Authors: Zamorano Rocio , Suchindran Sunil , Gainer James V.
Published: September 2005

Regulation of the constitutively expressed type 2 bradykinin (B2) receptor, which mediates the principal actions of bradykinin, occurs at multiple levels. The goal of the current study was to determine whether the human B2 3′-untranslated region (UTR) has effects on gene expression, with particular focus on the variable number of tandem repeats (B2-VNTR) polymorphic portion of the 3′-UTR and its flanking AU-rich elements (AREs). When inserted downstream of the luciferase coding region of the pGL3-Promoter vector, the B2-VNTR reduced reporter gene activity by 85% compared with pGL3-Promoter alone (promoter control; P < 0.001), an effect that was not appreciably affected by mutation of the flanking AREs. The negative regulatory effects of the B2-VNTR region were position and orientation dependent and strongly positively correlated with the number of tandem repeats in the B2-VNTR region ( r = 0.85, P < 0.001). With respect to mechanism, quantitative RT-PCR revealed that the B2-VNTR mRNA level was 32% of that of promoter control ( P = 0.008), whereas the number of polyadenylated transcripts was 4% ( P = 0.02). In contrast, the mRNA half-life of the B2-VNTR was increased (B2-VNTR: 14.9 vs. promoter control: 12.2 h, P = 0.009). Transient transfection of human kidney-derived tsA201 cells with the B2-VNTR construct increased transcription of the native B2 receptor mRNA by 43% ( P < 0.05), supporting an endogenous B2 receptor-regulatory capacity of the B2-VNTR. In conclusion, these results identify novel pretranslational effects of the B2-VNTR region to act as a potent negative regulator of heterologous gene expression and support the notion that the bradykinin B2 3′-UTR may impact endogenous receptor regulation.
Downregulation of AQP2 expression in the kidney of polydipsic STR/N mice
Authors: Tsumura Keiko , Li Xuefei , Murdiastuti Kwartarini , Parvin Most. Nahid , Akamatsu Tetsuya , Yao Chenjuan , Kanamori Norio , Inenaga Kiyotoshi , Yamashita Hiroshi , Hosoi Kazuo
Published: September 2005

Aquaporin-2 (AQP2) is responsible for the concentration of urine in the kidney collecting tubule under the regulation of vasopressin. The mRNA level of this water channel in polydipsic STR/N mice was extremely reduced compared with that in normal ICR mice. In male mice, reduction of the AQP2 mRNA level was not evident at 3 wk of age, at which time water intake was not increased. At 10 wk of age, however, the AQP2 mRNA level was reduced to 10% of that in control mice, whereas water intake was increased by 36%. At 44 wk, the water intake became five times that of the control ICR mice, and the AQP2 mRNA level in these polydipsic mice was only ∼5% of control. Similar changes were observed in the AQP2 protein level, suggesting that the mRNA level of AQP2 reflects the protein level of AQP2. These inverse changes in the AQP2 mRNA level and water intake were also evident in female mice. The data imply that polydipsia in STR/N mice may have affected AQP2 mRNA transcription in the kidney, resulting in reduced AQP2 expression, which would contribute to a reduction in overretention of water.
Asynchrony Between Position and Motion Signals in the Saccadic System
Authors: Schreiber Céline , Missal Marcus , Lefèvre Philippe
Published: September 2005

The influence of position and motion signals on saccades was studied in two dimensions (2D) using a double step-ramp paradigm. We showed the presence of a predictive component in 2D catch-up saccade programming that is based on motion signals and influences both saccade amplitude and orientation. Interestingly, a significant proportion of catch-up saccades was characterized by a large curvature or a sudden change of direction in midflight for large values of retinal slip. For these saccades, a quantitative analysis showed that their trajectory could be explained by an asynchrony between position and motion signals in saccade programming. When the saccade trajectory was not straight, position error was always available first and influenced the initial orientation of the saccade, whereas retinal slip determined the final orientation. This new paradigm could be used in electrophysiological experiments, where it should prove to be very useful to study position and motion pathways separately in catch-up saccades.
Idiographic Formulations, Symbols, Narratives, Context and Meaning
Authors: Phillips James
Published: September 2005

To locate the place of idiographic, narrative formulations in a psychiatric nosology and to address the problems stemming from the absence of such formulations in ICD-10 and DSM-IV, the author begins with a review of the stated goals of DSM-IV: that it should serve clinical, research, educational and information-management purposes. He argues that there is a conflict between the clinical and research goals of both manuals and that, with their emphasis on categorical diagnoses, criteria sets and statistical reliability, they serve the purposes of the biomedically oriented researcher better than those of the clinician. The latter is focused on the individual patient and tends in his diagnostic assessment toward a narrative fleshing out of the particulars of the patient’s life and personality. Clinicians do not work with tight criteria sets but rather with a prototypal or ideal-type approach, and they emphasize individual histories, psychodynamic formulations and other kinds of idiographic accounts. If a psychiatric nosology is to serve as a clinically useful instrument, it will have to allow for such formulations. The author then offers a description and definition of idiographic, narrative formulations, along with remarks on the conceptual background to this approach. He concludes by highlighting the work of the workgroup of the World Psychiatric Association in developing a section of their International Guidelines for Diagnostic Assessment entitled ‘Idiographic (personalised) Diagnostic Formulation’.
Categories, Dimensions and Prototypes: Critical Issues for Psychiatric Classification
Authors: Jablensky Assen
Published: September 2005

Being descendants of the Kraepelinian nosology, DSM-IV and ICD-10 rely largely on the internal cohesion of the clinical picture and the pattern of course and outcome as validating criteria of the definitions of mental disorders. The majority of the research diagnostic criteria are provisional and should be extensively tested against empirical evidence. The crucial issue is whether psychiatric disorders, as currently defined in DSM-IV and ICD-10, are clearly separated from one another and from normality. Options for future revisions of the classifications include categorical typologies, dimensional models and empirically derived prototypes. The advantages and disadvantages of each option are outlined, highlighting the need for new research focusing on these critical issues.
Mutually Exclusive versus Co-Occurring Diagnostic Categories: The Challenge of Diagnostic Comorbidity
Authors: First Michael B.
Published: September 2005

Diagnostic comorbidity is the rule rather than the exception in both DSM-IV and ICD-10. Three types of comorbidity include true comorbidity (clinically distinct entities), artifactual comorbidity (a byproduct of the DSM/ICD strategy to split categorical diagnoses) and spurious comorbidity. DSM has established ‘mutually exclusive’ relationships between disorders to reduce such spurious comorbidity. Four types of mutually exclusive relationships are identified: (1) between disorders that are on different levels of the Kraepelinian-defined hierarchy (e.g., schizophrenia and major depressive disorder); (2) between categories with identical features that are split according to age or duration (schizophrenia and schizophreniform disorder); (3) between categories in which the defining features of one disorder are contained in the definition of more broadly-defined disorder (Asperger’s disorder and autistic disorder), and (4) between categories in which the defining features of one disorder are an associated feature of another disorder (e.g., dysthymic disorder and schizophrenia). Although less comorbidity may be desirable to reduce diagnostic complexity, in the absence of knowledge about underlying pathophysiology, the trend in successive editions of the DSM has been to reduce diagnostic hierarchies and increase comorbidity (e.g., elimination of exclusion between panic disorder and major depression in DSM-III-R because of evidence of independence). It is important to understand that comorbidity in psychiatry does not imply the presence of multiple diseases or dysfunctions but rather reflects our current inability to apply Occam’s razor (i.e., a single diagnosis to account for all symptoms).
Genetics, Neuroscience and Psychiatric Classification
Authors: Robert Jason Scott , Plantikow Thane
Published: September 2005

Some psychiatrists anticipate a revolution in psychiatric nosology, on the basis of emerging data from genetics and genomics. There are, however, good empirical and conceptual reasons to resist any such revolution. Basing an understanding of psychiatric entities on one of multiple biological (not to mention sociocultural and psychological) considerations is a specious method of approaching the project of psychiatric taxonomy. A classification system that lacks sufficient consensus on the phenomenology of those classified cannot be adequately buttressed by exclusively genetic accounts. This paper advocates a more diversely informed nosology that, in turn, fosters attention to broader diagnostic considerations. We explore more plausible ways in which genetics and genomics, in conjunction with neuroscience and other biological disciplines, can help to shape diagnostic classification in psychiatry. There are, of course, differing views on the degree of prominence that genetics should take in psychiatric diagnosis and classification. We outline these accounts in illustration of this continuum. Drawing on Wimsatt’s work on robustness analysis, we dismiss optimistic scenarios about the potential nosological advantages of psychiatric genetics and genomics, and offer a novel defense of realism about psychiatric entities. We also briefly sketch an integrative methodology for psychiatric research and classification.
Psychotherapy and Classification: Psychological, Psychodynamic, and Cognitive Aspects
Authors: Mundt Christoph , Backenstrass Matthias
Published: September 2005

Psychotherapists’ needs for diagnoses and classification in terms of the psychosocial model of a disorder are different from those of the medical model of psychiatric disorders as predominantly used in the DSM and ICD manuals. The challenges emerging from these different diagnostic needs and traditions of diagnosing are formulated as three dichotomies: grouping according to a medical versus psychosocial perspective; using objective versus hermeneutic methodology with the claim of producing factual knowledge versus constructivistic self-interpretation; defining a lasting categorical diagnostic state for the present time versus a versatile monitoring process with attention to the most salient dysfunction at a given time. Disorder-specific psychotherapy cannot overcome these dichotomies. It needs to combine them, and by doing so to reconcile them. It would be desirable that future diagnostic manuals meet psychotherapists’ diagnostic needs.
Nitric Oxide Stimulates a Large-Conductance Ca2+-Activated K+ Channel in Human Skin Fibroblasts through Protein Kinase G Pathway
Authors: Lim I. , Yun J. , Kim S. , Lee C. , Seo S. , Kim T. , Bang H.
Published: September 2005

In order to investigate the large-conductance Ca2+-activated K+ (BKCa) channel and determine the effects of nitric oxide (NO) on the channel in human skin fibroblasts, we performed electrophysiological patch clamp recordings on 5th-passage cells of human genital skin cultures. The whole-cell outward K+ current was increased with depolarization, and proved to be sensitive to NS1619 (a selective BKCa channel activator) and iberiotoxin (a specific BKCa channel inhibitor). The single-channel currents showed 226 pS of mean conductance in symmetrical K+. Sodium nitroprusside (SNP; an NO donor) significantly increased the K+ current amplitude in the whole-cell mode, and open probability of the channel (NPo) in the cell-attached mode, but not in the inside-out mode. S-nitroso-N-acetylpenicillamine (an NO donor) and 8-Br-cGMP (a membrane-permeant cGMP analogue) also increased the BKCa channel activity. The stimulatory effect of SNP on BKCa channels was inhibited by pretreatment with 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (a soluble guanylyl cyclase inhibitor), or KT5823 [a specific protein kinase G (PKG) inhibitor]. Cytoplasmic PKG also increased the channel activity in inside-out patches. In conclusion, the present data indicate that BKCa channels constitute a significant fraction of K+ current in human skin fibroblasts, and that NO increases NPo of BKCa channels, which are mediated via the cGMP/PKG pathway, without direct effects on the channel.
Endothelial Function in the Forearm Circulation of Patients with the Metabolic Syndrome – Effect of Different Lipid-Lowering Regimens
Authors: Bulut D. , Hanefeld C. , Bulut-Streich N. , Graf C. , Mügge A. , Spiecker M.
Published: September 2005

We compared the effect of statin therapy (either alone or combined with ezetimibe) on the inhibition of cholesterol resorption and endothelial function by measuring forearm blood flow in male patients with the metabolic syndrome. Compared to 40 mg atorvastatin alone, combination therapy with 10 mg ezetimibe and 10 mg atorvastatin for 8 weeks resulted in significantly decreased total serum cholesterol and triglycerides levels (n = 14). Endothelium-dependent, acetylcholine-mediated vasodilation was significantly better with combination therapy (p < 0.05). In contrast, endothelium-independent forearm blood flow response to sodium nitroprusside was comparable in both groups. Our data suggest a more effective restoration of endothelial function with the statin/ezetimibe combination compared to statin monotherapy in patients with the metabolic syndrome.
Graded Doses of Recombinant Interleukin-1β Induce Generalized Osteopenia in Rats without Altering Skeletal Growth and Joint Integrity
Authors: del Pozo E. , Popp A.W.E. , MacKenzie A. , Perrelet R. , Lamberts S.W.J. , Lippuner K.
Published: September 2005

Background: Whereas a primary role of interleukin-1β (IL-1β) in local bone remodelling and articular inflammation has been well established, the effect of prolonged systemic administration of this cytokine on total skeletal Ca, somatic growth and joint tissue has not yet been investigated. Methods: Five groups of 14 rats each, aged 7–8 weeks, had miniosmotic pumps (Alzet 200 µl) implanted and primed to release 100, 200, 500, 1,000 and 2,000 ng/kg/24 h of human recombinant IL-1β (rIL-1β) daily for 14 days. On days 0 and 14 total skeletal mineral content (BMC) was assessed by means of X-ray absorptiometry and vertebral and tibial growth was measured by computer-assisted radiometry. On the same days, blood was drawn and analyzed for rat growth hormone (rGH), insulin-like growth factor (IGF-1), and osteocalcin. Also 24-hour urine was collected for d-pyridinoline (dpd) determinations. Hind- and forepaw diameter as a parameter of joint inflammation was assessed using a micrometric calliper. Subsequently the animals were sacrificed and one tibia dissected for measurement of trabecular volume by computerized histomorphometry. Results: BMC decreased in a dose-dependent manner reaching significance at 1,000 and 2,000 ng/kg (p < 0.03 and 0.04) in close correlation with tibial trabecular volumes (r = 0.84; p < 0.02). Normal vertebral and tibial growth was recorded at all dosages. There was no evidence of joint involvement. Blood rGH and IGF-1 remained normal as did osteocalcin, the latter reflecting lack of osteoblast activation. In contrast dpd increased in a dose-dependent manner indicating enhanced bone matrix turnover. Conclusion: It is concluded that graded infusions of supraphysiological doses of rIL-1β capable of inducing osteopenia did not affect skeletal growth in the absence of articular reaction. This is in contrast with the experience recorded in experimental arthritis in which growth retardation, in addition to osteopenia, may be caused by factors other than circulating IL-1β.
Differential Gender Differences in Ischemic and Nephrotoxic Acute Renal Failure
Authors: Wei Qingqing , Wang Mong-Heng , Dong Zheng
Published: September 2005

Background/Aims:Recent work has shown that female animals are more resistant to ischemic acute renal failure (ARF) than male animals. The mechanism underlying the gender difference is unclear. Moreover, whether the gender difference holds true for ARF induced by other insults is unknown. This study sought to determine the gender differences in ischemic and nephrotoxic ARF. Methods: Gender differences were tested in two experimental models of ARF. For ischemic ARF, bilateral clamping of renal pedicles was conducted in C57BL/6 and129/Sv mice followed by reperfusion. For nephrotoxic ARF, cisplatin was administered to the animals. Renal function, tissue damage, animal survival, and renal cell apoptosis were examined. Results: Ischemic ARF was significantly ameliorated in female mice, as shown by lower serum creatinine and blood urea nitrogen (BUN). Female mice also showed better renal histology, less apoptosis and caspase activation, and a much better survival rate than male mice following ischemic insult. On the contrary, female mice were more sensitive to cisplatin-induced ARF. In these animals, BUN increased at day 1 following cisplatin injection, while in males BUN increases were not shown until day 3. Higher levels of serum creatinine were also recorded in female mice. Renal histology showed severer necrotic tubular damage in females, although apoptosis and caspase activation appeared similar in both genders. Consistently, male mice survived better than females in the nephrotoxic model. Conclusion: While female mice were resistant to ischemic ARF, they appeared more sensitive to cisplatin-induced ARF. Investigation of the gender differences at the cellular and molecular levels might provide a new area for mechanistic study of ARF.
Altered AT
1
Receptor Regulation of ETB Receptors in Renal Proximal Tubule Cells of Spontaneously Hypertensive Rats
Authors: Zeng Chunyu , Hopfer Ulrich , Asico Laureano D. , Eisner Gilbert M. , Felder Robin A. , Jose Pedro A.
Published: September 2005

The renin-angiotensin and endothelin systems regulate blood pressure, in part, by affecting renal tubular sodium transport. In rodents, ETB receptors decrease proximal tubular reabsorption, whereas AT
1
receptors produce the opposite effect. We hypothesize that ETB and AT
1
receptors interact at the receptor level, and that the interaction is altered in spontaneously hypertensive rats (SHRs). In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto (WKY) rats, angiotensin II, via AT
1
receptors, increased ETB receptor protein in a time- and concentration-dependent manner. In contrast, in SHR RPT cells, angiotensin II (10
−8
M/24 hours) had no effect on ETB receptor protein. AT
1
/ETB receptors colocalized and co-immunoprecipitated in both rat strains but long-term angiotensin II (10
−8
M/24 hours) treatment increased AT
1
/ETB co-immunoprecipitation in WKY but not in SHR cells. Short-term angiotensin II (10
−8
M/15 minutes) treatment decreased ETB receptor phosphorylation in both WKY and SHR cells, and increased ETB receptors in RPT cell surface membranes of RPT cells in WKY but not SHRs. Basal cell surface membrane ETB receptor expression was also higher in WKY than in SHRs. We conclude that AT
1
receptors regulate ETB receptors by receptor interaction and modulation of receptor expression. The altered AT
1
receptor regulation of ETB receptors in SHRs may play a role in the pathogenesis of hypertension.
Vitamin D Intake and Risk of Incident Hypertension
Authors: Forman John P. , Bischoff-Ferrari Heike A. , Willett Walter C. , Stampfer Meir J. , Curhan Gary C.
Published: September 2005

Emerging evidence suggests an inverse relation between vitamin D and blood pressure. We examined the independent association between intake of vitamin D and the risk of incident hypertension among participants of 3 large and independent prospective cohorts: Nurses Health Study I (NHS I; n=77 436), NHS II (n=93 803), and Health Professionals’ Follow-up Study (HPFS; n=38 074). Relative risks and 95% confidence intervals for incident hypertension were computed according to quintiles of vitamin D intake using Cox proportional hazards regression and adjusted for relevant covariates. Each cohort was followed for ≥8 years. Vitamin D intake was not associated with the risk of developing hypertension. The multivariable relative risk estimates for the highest compared with lowest quintile of intake were 0.98 (0.93 to 1.04) in NHS I, 1.13 (0.99 to 1.29) in NHS II, and 1.03 (0.93 to 1.15) in HPFS. When we compared participants who consumed ≥1600 to <400 IU per day and those who consumed ≥1000 to <200 IU per day, no association was found. We conclude that higher intake of vitamin D is not associated with a lower risk of incident hypertension.
Regression of Medial Elastocalcinosis in Rat Aorta
Authors: Essalihi Rachida , Dao Huy Hao , Gilbert Liz-Ann , Bouvet Céline , Semerjian Yves , McKee Marc D. , Moreau Pierre
Published: September 2005

Background—

We sought to determine whether carbonic anhydrase (CA), which plays an important role in bone resorption, contributes to vascular mineral loss induced by an endothelin receptor antagonist.

Methods and Results—

Wistar rats were compared with rats receiving warfarin and vitamin K
1
(WVK) for 8 weeks alone or in association with the endothelin receptor antagonist darusentan (30 mg/kg per day), the CA inhibitor acetazolamide (100 mg/kg per day), or both for the last 4 weeks. Rats were also treated with WVK for 5 or 6 weeks, and darusentan was added for the last week or last 2 weeks of treatment, respectively. Treatment with WVK produced medial elastocalcinosis in the aorta and carotid arteries. Immunohistochemistry revealed that CA II was already abundant in the adventitia and in calcified areas of aortic sections from WVK-treated rats. Darusentan did not significantly modify its abundance or distribution. In contrast, CA IV immunostaining, which was weak in WVK-treated rats, became apparent after 1 week of darusentan treatment and declined toward basal levels thereafter. These findings were confirmed by a parallel increase in CA IV protein abundance and activity in the aorta. The mineral loss induced by darusentan was blunted by acetazolamide treatment, confirming the functional relevance of the biochemical findings. Moreover, CA IV immunostaining was enhanced much later in the carotids, where darusentan did not cause regression of elastocalcinosis.

Conclusions—

Vascular mineral loss induced by the blockade of endothelin receptors seems dependent on the activation of membrane-bound CA IV, suggesting that mineral loss may proceed via local changes in pH similar to that seen in bone resorption.
Molecular Profiling of Heart Endothelial Cells
Authors: Zhang Lianglin , Hoffman Jason A. , Ruoslahti Erkki
Published: September 2005

Background—

Endothelial cells that line the vascular lumen can express cell-surface proteins that are specific to the endothelium of a particular tissue. In this study, we probed the heart vasculature for heart-specific endothelial markers by phage display.

Methods and Results—

We used a novel combination of in vivo phage selection and a bacterial 2-hybridization scheme against a heart cDNA library, which allows simultaneous identification of peptides that specifically bind to the target endothelium, as well as the endothelial molecules (receptors) recognized by the peptides. We found 5 heart-targeting peptides and their receptors. We confirmed and quantified the selective expression of 4 of the proteins in heart endothelial cells by independent methods. The heart specificity of phages was as high as 300-fold greater than that of nonrecombinant control phages. The proteins selectively expressed by the heart endothelium were in most cases also expressed by cardiomyocytes and, at lower levels, in some other tissues.

Conclusions—

These findings provide new markers for the endothelium of heart vessels and reveal a commonality between parenchymal and endothelial gene expression in the heart. The heart-homing peptides provide a means of targeting diagnostic and therapeutic agents to the heart, and their receptors are potential drug discovery targets.
Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease
Authors: Tanaka Masashi , Sydow Karsten , Gunawan Feny , Jacobi Johannes , Tsao Phil S. , Robbins Robert C. , Cooke John P.
Published: September 2005

Background—Graft coronary artery disease (GCAD) is the leading cause of death after the first year of heart transplantation. The reduced bioavailability of endothelium-derived nitric oxide (NO) may play a role in endothelial vasodilator dysfunction and the structural changes that are characteristic of GCAD. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor. We hypothesized that lowering ADMA concentrations by dimethylarginine dimethylaminohydrolase (DDAH) overexpression in the recipient might suppress GCAD and long-term immune responses in murine cardiac allografts.

Methods and Results—In one series, donor hearts of C-H-2bm12KhEg (H-2bm12) wild-type (WT) mice were heterotopically transplanted into C57BL/6 (H-2b) transgenic mice overexpressing human DDAH-I or WT littermates and procured after 4 hours of reperfusion (WT and DDAH-I recipients, n=6 each). In a second series, donor hearts were transplanted into DDAH-I–transgenic or WT mice and procured 30 days after transplantation (n=7 each). In DDAH-I recipients, plasma ADMA concentrations were lower, in association with reduced myocardial generation of superoxide anion (WT versus DDAH-I, 465.7±79.8 versus 173.4±32.3 μmol · L−1· mg−1· h−1;P=0.02), inflammatory cytokines, adhesion molecules, and chemokines. GCAD was markedly reduced in cardiac allografts of DDAH-I–transgenic recipients as assessed by luminal narrowing (WT versus DDAH, 79±2% versus 33±7%;P<0.01), intima-media ratio (WT versus DDAH, 1.1±0.1 versus 0.5±0.1;P<0.01), and the percentage of diseased vessels (WT versus DDAH, 100±0% versus 62±10%;P<0.01).

Conclusions—Overexpression of DDAH-I attenuated oxidative stress, inflammatory cytokines, and GCAD in murine cardiac allografts. The effect of DDAH overexpression may be mediated by its reduction of plasma and tissue ADMA concentrations.
Unmasking of Brugada Syndrome by Lithium
Authors: Darbar Dawood , Yang Tao , Churchwell Keith , Wilde Arthur A.M. , Roden Dan M.
Published: September 2005

Background—

The characteristic ECG pattern of ST-segment elevation in V
1
and V
2
in the Brugada syndrome is dynamic; it is often intermittently present in affected individuals and can be unmasked by sodium channel blockers, including antiarrhythmic drugs and tricyclic antidepressants. We report here 2 patients who developed the Brugada ECG pattern after administration of lithium, a commonly used drug not previously reported to block cardiac sodium channels.

Methods and Results—

Lithium induced transient ST-segment elevation (type 1 Brugada pattern) in right precordial leads at therapeutic concentrations in 2 patients with bipolar disorder. Lithium withdrawal in the patients resulted in reversion to type 2 or 3 Brugada patterns or resolution of ST-T abnormalities. In Chinese hamster ovary cells transfected with
SCN5A
, which encodes the cardiac sodium channel, lithium chloride caused concentration-dependent block of peak
I
Na
at levels well below the therapeutic range (IC
50
of 6.8±0.4 μmol/L).

Conclusions—

The widely used drug lithium is a potent blocker of cardiac sodium channels and may unmask patients with the Brugada syndrome.
Humanistic Psychology in Japan
Authors: Muramoto Shoji , Hoffman Edward
Published: September 2005

This article provides an overview of humanistic psychology in Japan. Its growth is traced from its prehistory up through the establishment of its own organization in 1982. Recent developments and current challenges are also highlighted. A dominant concern for Japanese humanistic psychologists has been to synthesize traditional Eastern spiritualities and modern Western rationalism.
A Critique of Posttraumatic Stress Disorder and the DSM
Authors: Burstow Bonnie
Published: September 2005

Posttraumatic stress disorder (PTSD) is one of the few DSM categories that was created and became widely accepted as a result of people other than psychiatrists wanting it. Even progressive practitioners tend to assume that it is essentially well constructed and benign. This article shows otherwise. The article fundamentally problematizes PTSD. It demonstrates that the category PTSD is confused, reductionist, contradictory, and arbitrary and that it pathologizes purposeful and valuable coping strategies commonly used by people who are traumatized. It demonstrates, in addition, that the category does not even serve the purpose for which progressive therapists have engaged with the diagnosis and that it cannot simply be “corrected.”
Marriage and Family Counseling: Ethics in Context
Authors: Southern Stephen , Smith Robert L. , Oliver Marvarene
Published: September 2005

Codes of ethics typically provide rules and guidelines for best practices in marriage and family counseling. An emerging model for ethical decision making emphasizes the ethics of virtues and aspirations. Exploring fundamental models of helping, as well as contemporary issues in community systems, affords context for examining the professional development of marriage and family counseling. Dialectical reasoning, professional discourse, and case study present means by which 21st-century marriage and family counselors can resolve ethical dilemmas.
A Therapeutic Interviewing Strategy for Effective Counseling Practice: Application to Health and Medical Issues in Individual and Couples Therapy
Authors: Sperry Len
Published: September 2005

Training to become an effective provider of health-focused counseling with individuals and couples can be a daunting challenge given the complexity that medical and other health issues adds to the counseling process. To facilitate the process of learning to do such health-focused counseling, a relatively straightforward interview strategy, derived from cognitive behavior analysis system of psychotherapy, is described. The strategy is then illustrated with a couple experiencing relational discord, which is exacerbated by one spouse’s chronic illness (i.e., systemic lupus erythematosus, commonly referred to as lupus).
Three Constructive Interventions for Divorced, Divorcing, or Never-Married Parents
Authors: Sommers-Flanagan John , Barr Laura
Published: September 2005

Divorce in the United States affects millions of children and families. Many of these children and families seek individual/family counseling or educational services offered by counselors and, therefore, counselors need to be well-equipped to work with nontraditional families. The purpose of this article is to share three counseling techniques for use with parents undergoing separation and/or divorce. These techniques are primarily constructive and educational. They include a reframing technique for mandated clients, a reframing technique to help parents recognize the difference between their coparenting wishes and goals, and an educational problem-solving strategy for parents who struggle with their children’s postseparation/divorce behaviors. Anecdotes and case examples are used to articulate how these techniques can be used in clinical practice.
Will Genetic Testing for Complex Diseases Increase Motivation to Quit Smoking? Anticipated Reactions in a Survey of Smokers
Authors: Sanderson Saskia C. , Wardle Jane
Published: September 2005

The aim of this study was to improve understanding of smokers’ potential reactions to genetic testing for smoking-related diseases. One thousand twenty-four respondents completed a postal survey; 186were smokers. Questions addressed anticipated psychological and behavioral reactions to genetic test results using hypothetical scenarios. Of smokers, 65% anticipated being motivated to quit smoking upon receiving a positive genetic test result; 39% anticipated being demotivated by a negative result. More smokers anticipated being depressed in response to receiving a positive result for cancer than for heart disease (40% vs. 24%). Anticipated motivation was associated with higher desire to quit and lower nicotine addiction, anticipated depression with poorer understanding of genetic testing, and anticipated demotivation with lower education. Smokers who have a high desire to quit may use genetic testing as a motivational tool. Understanding of genetics may be important in determining how individuals respond to genetic tests for complex diseases.
Marketing Genetic Tests: Empowerment or Snake Oil?
Authors: Bowen Deborah J. , Battuello Kathryn M. , Raats Monique
Published: September 2005

Genetic tests are currently being offered to the general public with little oversight and regulation as to which tests are allowed to be sold clinically and little control over the marketing and promotion of sales and use. This article provides discussion and data to indicate that the general public holds high opinions of genetic testing and that current media outlets for public education on genetic testing are not adequate to increase accurate knowledge of genetics. The authors argue that more regulation is needed to control and correct this problem in the United States.
Research and Practice Opportunities at the Intersection of Health Education, Health Behavior, and Genomics
Authors: Wang Catharine , Bowen Deborah J. , Kardia Sharon L. R.
Published: September 2005

Researchers and practitioners in health behavior and health education (HBHE) can play a pivotal leadership role in the integration of genomic advances to improve the public’s health. The purpose of this article is to outline research and practice opportunities at the intersection of genomics and HBHE. We begin this article by briefly summarizing the existing evidence in the literature pertaining to the public’s use of genetic services, the effectiveness of genetic counseling, and the impact of genetic testing. Following this, we outline and expand on several areas that we believe are ripe for further exploration, understanding, and public health application:(a) public understanding of genetic information, (b) interventions for health behavior change, and (c) public health assurance and advocacy. This analysis has identified the need to consider potential application efforts in genomics and HBHE from an ecological perspective, with an emphasis on multiple levels of intervention and analysis.
Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL
Authors: Carew Jennifer S. , Nawrocki Steffan T. , Krupnik Yelena V. , Dunner Kenneth , McConkey David J. , Keating Michael J. , Huang Peng
Published: September 2005

Previous studies showed that chronic lymphocytic leukemia (CLL) cells exhibit certain mitochondrial abnormalities including mtDNA mutations, increased superoxide generation, and aberrant mitochondrial biogenesis, which are associated with impaired apoptosis and reduced sensitivity to fludarabine. Here we report that CLL cells and multiple myeloma cells are highly sensitive to brefeldin A, an inhibitor of endoplasmic reticulum (ER) to Golgi protein transport currently being developed as a novel anticancer agent in a prodrug formulation. Of importance, brefeldin A effectively induced apoptosis in fludarabine-refractory CLL cells. Disruption of protein trafficking by brefeldin A caused the sequestration of the prosurvival factors APRIL and VEGF in the ER, leading to abnormal ER swelling and a decrease in VEGF secretion. Such ER stress and blockage of secretory protein traffic eventually resulted in Golgi collapse, activation of caspases, and cell death. Notably, the cellular sensitivity to this compound appeared to be independent of p53 status. Taken together, these findings suggest that malignant B cells may be highly dependent on ER-Golgi protein transport and that targeting this process may be a promising therapeutic strategy for B-cell malignancies, especially for those that respond poorly to conventional treatments.
Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis
Authors: Fransson Mattias , Adner Mikael , Erjefält Jonas , Jansson Lennart , Uddman Rolf , Cardell Lars-Olaf
Published: September 2005

Background

Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen.

Methods

27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins.

Results

mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season.

Conclusion

The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation.
Rhinosinusitis derived Staphylococcal enterotoxin B possibly associates with pathogenesis of ulcerative colitis
Authors: Yang Ping-Chang , Liu Tao , Wang Bin-Quan , Zhang Tao-Yuan , An Zi-Yuan , Zheng Peng-Yuan , Tian Dao-Fa
Published: September 2005

Background

During clinical practice, we noticed that some patients with both ulcerative colitis (UC) and chronic rhinosinusitis (CRS) showed amelioration of UC after treatment of CRS. This study was designed to identify a possible association between CRS and UC.

Methods

Thirty-two patients with both CRS and UC received treatment with functional endoscopic sinus surgery (FESS) for CRS. Clinical symptom scores for CRS and UC, as well as serum levels of anti-Staphylococcal enterotoxin B (SEB) were evaluated at week 0 and week 12. Sinus wash fluid SEB content was measured with enzyme-linked immunosorbent assay (ELISA). The surgically removed tissues were cultured to identify growth ofStaphylococcus. aureus(S. aureus). Immunohistochemistry was employed to identify anti-SEB positive cells in the colonic mucosa. Colonic biopsies were obtained and incubated with SEB. Mast cell activation in the colonic mucosa in response to incubation with SEB was observed with electron microscopy and immunoassay.

Results

The clinical symptom scores of CRS and UC severe scores (UCSS) were significantly reduced in the UC-CRS patients after FESS. The number of culturedS. aureuscolonies from the surgically removed sinus mucosa significantly correlated with the decrease in UCSS. High levels of SEB were detected in the sinus wash fluids of the patients with UC-CRS. Histamine and tryptase release was significantly higher in the culture supernate in the patients with UC-CRS than the patients with UC-only and normal controls. Anti-SEB positive cells were located in the colonic mucosa.

Conclusion

The pathogenesis of UC in some patients may be associated with their pre-existing CRS by a mechanism of swallowing sinusitis-derived SEB. We speculate that SEB initiates inappropriate immune reactions and inflammation in the colonic mucosa that further progresses to UC.
Persistence of Natural Killer (NK) cell lymphocytosis with hyposplenism without development of leukaemia
Authors: Khan Sujoy , Myers K
Published: September 2005

Background

Natural killer (NK) cell lymphocytosis usually has an indolent course and can progress into massive lymphocytosis with development of cytopenias and neoplastic diseases. NK-cells usually express one or more "NK-associated" antigens (CD16, CD56, CD57). Reactive expansions are seen in autoimmune diseases, viral infections, solid tumours and non-Hodgkin's lymphoma.

Case presentation

We report a lady with a benign clinical course over 10 years and persistent CD8+/CD3-/CD57+/CD16+ LGL proliferation with presence of Howell-Jolly bodies (functional hyposplenism), an association not previously described.

Conclusion

We discuss the possible causes of clonal expansion and conclude that this may be part of the spectrum of immune dysregulation associated with NK-cell lymphocytosis.
Classification of the extracellular fields produced by activated neural structures
Authors: Richerson Samantha , Ingram Mark , Perry Danielle , Stecker Mark M
Published: September 2005

Background

Classifying the types of extracellular potentials recorded when neural structures are activated is an important component in understanding nerve pathophysiology. Varying definitions and approaches to understanding the factors that influence the potentials recorded during neural activity have made this issue complex.

Methods

In this article, many of the factors which influence the distribution of electric potential produced by a traveling action potential are discussed from a theoretical standpoint with illustrative simulations.

Results

For an axon of arbitrary shape, it is shown that a quadrupolar potential is generated by action potentials traveling along a straight axon. However, a dipole moment is generated at any point where an axon bends or its diameter changes. Next, it is shown how asymmetric disturbances in the conductivity of the medium surrounding an axon produce dipolar potentials, even during propagation along a straight axon. Next, by studying the electric fields generated by a dipole source in an insulating cylinder, it is shown that in finite volume conductors, the extracellular potentials can be very different from those in infinite volume conductors. Finally, the effects of impulses propagating along axons with inhomogeneous cable properties are analyzed.

Conclusion

Because of the well-defined factors affecting extracellular potentials, the vague terms far-field and near-field potentials should be abandoned in favor of more accurate descriptions of the potentials.