bluuebunny/crossref_metadata_2025 huggingface dataset:
Traditional and patient-centred outcomes with three classes of asthma medication
Authors: Jenkins C. R. , Thien F. C. K. , Wheatley J. R. , Reddel H. K.
Published: July 2005

Lung function is commonly used as the primary endpoint in asthma clinical trials, but it may not reflect changes which are important to patients. The present study compared changes in, and relationships between, traditional and patient-centred end-points during treatment with three classes of asthma medication.

Subjects with mild-to-moderate asthma were randomised to double-blind, double-dummy crossover treatment with eformoterol 12 µgb.i.d.or montelukast 10 mgq.d., then single-blind treatment with fluticasone 250 µgb.i.d./placebo capsules, with 6-week treatment periods and 1-week washouts. Individual “traditional” end-points (symptoms, reliever use, forced expiratory volume in one second per cent predicted, morning peak expiratory flow, airway hyperresponsiveness) and “patient-centred” end-points (asthma control questionnaire, quality of life, patient global assessments) were assessed. Principal component analysis and linear modelling were used to explore overall rank orders for treatment, and relationships between outcomes.

A total of 58 subjects were randomised. The rank order of benefit from eformoterol and fluticasone differed for three factors derived from principal component analysis (eformoterol>fluticasone for symptom/reliever use factor, fluticasone>eformoterol for lung function factor, eformoterol = fluticasone for patient-centred factor). Montelukast was ranked third for all three factors. A significant relationship between patient-based variables and lung function was found only for montelukast treatment.

In asthma treatment, traditional end-points do not fully capture patient-centred benefits, and the relationship between end-points differs with medication class.
Ukrain – a new cancer cure? A systematic review of randomised clinical trials
Authors: Ernst E , Schmidt K
Published: July 2005

Background

Ukrain is an anticancer drug based on the extract of the plantChelidonium majusL. Numerous pre-clinical and clinical investigations seem to suggest that Ukrain is pharmacologically active and clinically effective. We wanted therefore to critically evaluate the clinical trial data in the form of a systematic review.

Methods

Seven electronic databases were searched for all relevant randomised clinical trials. Data were extracted and validated by both authors, tabulated and summarised narratively. The methodological quality was assessed with the Jadad score.

Results

Seven trials met our inclusion criteria. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was poor. In addition, the interpretation of several trials was impeded by other problems.

Conclusion

The data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, numerous caveats prevent a positive conclusion, and independent rigorous studies are urgently needed.
Association of CETP TaqI and APOE polymorphisms with type II diabetes mellitus in North Indians: a case control study
Authors: Dixit Manjusha , Bhattacharya Sandeep , Mittal Balraj
Published: July 2005

Background

Genetic variants of proteins involved in lipid metabolism may play an important role in determining the susceptibility for complications associated with type II diabetes mellitus (T2DM). Goal of the present study was to determine the association of cholesteryl ester transfer proteinTaqI B, D442G, andAPOE HhaI polymorphisms with T2DM and its complications.

Methods

Study subjects were 136 patients and 264 healthy controls. All polymorphisms were detected using PCR-RFLP and statistical analysis done with χ2test and ANOVA.

Results

AlthoughCETP TaqI B polymorphism was not associated with the T2DM, yet B1B2 genotype was significantly (p = 0.028) associated with high risk of hypertension in diabetic patients (OR = 3.068, 95% CI 1.183–7.958). In North Indians D442G variation inCETPgene was found to be absent. Frequency ofAPOE HhaIpolymorphism was also not different between patients and controls. In diabetic patients having neuropathy and retinopathy significantly different levels of total-cholesterol [(p = 0.001) and (p = 0.029) respectively] and LDL-cholesterol [(p = 0.001) and (p = 0.001) respectively] were observed when compared to patients with T2DM only. However, lipid levels did not show any correlation with theCETP TaqI B andAPOE HhaI genetic polymorphisms.

Conclusion

CETP TaqI B andAPOE HhaI polymorphism may not be associated with type II diabetes mellitus in North Indian population, howeverCETP TaqI B polymorphism may be associated with hypertension along with T2DM.
Genomic analysis of metabolic pathway gene expression in mice
Authors: Ghazalpour Anatole , Doss Sudheer , Sheth Sonal S , Ingram-Drake Leslie A , Schadt Eric E , Lusis Aldons J , Drake Thomas A
Published: July 2005

Background

A segregating population of (C57BL/6J × DBA/2J)F2 intercross mice was studied for obesity-related traits and for global gene expression in liver. Quantitative trait locus analyses were applied to the subcutaneous fat-mass trait and all gene-expression data. These data were then used to identify gene sets that are differentially perturbed in lean and obese mice.

Results

We integrated global gene-expression data with phenotypic and genetic segregation analyses to evaluate metabolic pathways associated with obesity. Using two approaches we identified 13 metabolic pathways whose genes are coordinately regulated in association with obesity. Four genomic regions on chromosomes 3, 6, 16, and 19 were found to control the coordinated expression of these pathways. Using criteria that included trait correlation, differential gene expression, and linkage to genomic regions, we identified novel genes potentially associated with the identified pathways.

Conclusion

This study demonstrates that genetic and gene-expression data can be integrated to identify pathways associated with clinical traits and their underlying genetic determinants.
The doctor-manager relationship
Authors: Garelick Antony , Fagin Leonard
Published: July 2005

The different cultures of doctors and managers and the impact of these on their working relationships are described. A historical resumé tracks organisational change, the evolving nature of the relationship and the stresses it engenders. The phenomenon of scapegoating and an approach to managing risk is explored. Vignettes describing familiar problems, with suggested strategies for analysing them and resolving difficulties, are presented.
Stimulant use still going strong
Authors: Seivewright Nicholas , McMahon Charles , Egleston Paul
Published: July 2005

Amphetamines, cocaine and methylenedioxymethamphetamine (MDMA, ‘ecstasy’) have been prominent on the UK drugs scene over the past decade. Much cocaine is now in the form of ‘crack’, which produces particularly acute versions of well-known complications including paranoid psychosis, mood disorders and cardiovascular problems. Ecstasy has additional hallucinogenic properties, and the slightly different range of psychiatric effects can be long-lasting. Assessment for stimulant misuse should include drug screening more than is currently common in general settings. Management comprises psychosocial (particularly behavioural counselling) and pharmacological approaches. A wide range of dopaminergic and other medications have been studied in cocaine misuse, and specialised substitute prescribing may be appropriate for heavy amphetamine injecting. There has been recent focus on problems of dual diagnosis, with particular strategies required to address stimulant misuse by people with severe mental illnesses.
Another triumph of hope over experience?
Authors: Mortimer Ann M.
Published: July 2005

Schizophrenia continues to challenge services: recent advances in antipsychotic drug treatment and psychosocial interventions are hindered by non-adherence, disengagement and substance misuse. Furthermore, new side-effect concerns attach to atypical drugs, and psychosocial interventions may be underresourced or of unproven benefit. It is important to address all issues with which patients, families and carers need assistance, and to take a well-informed, creative approach to pharmacological treatment, using medication according to individual patient need rather than mechanistic adherence to guidelines. Psychiatrists should be realistic in their expectations of patient outcome, accepting outcomes that fall short of recovery and imply long-term supportive care, and insisting that this care be available to their patients. Psychiatrists should support early diagnosis and intervention as being possibly the only means to alleviate the burden of long-term schizophrenia for patients, families and services.
Benchmarking in mental health: an introduction for psychiatrists
Authors: Bayney Richard
Published: July 2005

Benchmarking has been advocated by the Department of Health as a tool of clinical governance. The essence of benchmarking is learning from the best practice of others. Its ability to compare services and outcomes of care can facilitate change, ensuring quality control and continuous service improvement. The concept is in its infancy in the National Health Service despite its exceptionally rapid growth in business organisations over the past 25 years. Many of the characteristics that make the process so valuable in business are equally relevant in healthcare. This article reviews the history of benchmarking and describes its application in mental health services for improving patient care. It includes an analysis of the centrality of the benchmarking doctrine to the core principles of clinical governance and reflects on the assets health services possess to facilitate benchmarking. It concentrates on the principles of setting up a team and uses a case example to highlight the organisational and clinical effect that a benchmarking project could have.
Birth weight and psychological distress at age 45–51 years
Authors: Wiles Nicola J. , Peters Tim J. , Leon David A. , Lewis Glyn
Published: July 2005

Background

It is unclear whether the effect of low birth weight on common affective disorders in later life is director mediated through childhood factors.

Aims

To determine whether birth weight has a direct effect on psychological distress in adulthood not mediated by childhood IQ or behavioural problems.

Method

Participants (n=5572) of the Aberdeen Children of the 1950s study had data on birth weight for gestational age and adult psychological distress. Logistic regression was used to examine the association between these factors, with adjustment for confounders and potential childhood mediators.

Results

Children born full term but weighing less than 5.5 lb had increased odds of psychological distress in later life after adjustment for potential confounders (OR=1.49, 95% CI 1.01–2.20). Further adjustment for childhood IQ and behaviour did not attenuate the association. A 1 s.d. decrease in birth weight for gestational age was associated with a 4% increased odds of psychological distress in adulthood (OR=1.04, 95% CI 0.97–1.12).

Conclusions

Low birth weight for gestational age, particularly atterm, was associated with adult psychological distress. This was not mediated by childhood factors, suggesting a direct effect of early life factors on adult mental health. A neurodevelopmental pathway may therefore be implicated.
The role of proteomics in investigating psychiatric disorders
Authors: Pennington K. , Cotter D. , Dunn M. J.
Published: July 2005

Proteomics is the study of protein expression and function on a genome-wide scale and its application in psychiatric research is relatively new. As protein expression is the mediator of genetic vulnerabilities, it is critical that this area is explored further to increase our understanding of psychiatric disease and reveal potential new treatments.
Socio-economic inequalities in suicide: A European comparative study
Authors: Lorant Vincent , Kunst Anton E. , Huisman Martijn , Costa Giuseppe , Mackenbach Johan
Published: July 2005

Background

Social factors have been shown to be predictors of suicide. It is not known whether these factors vary between countries.

Aims

To present a first European overview of socio-economic inequalities in suicide mortality among men and women.

Method

We used a prospective follow-up of censuses matched with vital statistics in ten European populations. Directly standardised rates of suicide were computed for each country.

Results

In men, a low level of educational attainment was a risk factor for suicide in eight out often countries. Suicide inequalities were smaller and less consistent in women. In most countries, the greater the socio-economic disadvantage, the higher is the risk of suicide. The population of Turin evidenced no socio-economic inequalities.

Conclusions

Socio-economic inequalities in suicide are a generalised phenomenon in western Europe, but the pattern and magnitude of these inequalities vary between countries. These inequalities call for improved access to psychiatric care for lower socio-economic groups.
Modafinil modulates anterior cingulate function in chronic schizophrenia
Authors: Spence Sean A. , Green Russell D. , Wilkinson Iain D. , Hunter Mike D.
Published: July 2005

Background

Schizophrenia is associated with widespread cognitive deficits that have an impact on social function. Modafinil promotes wakefulness and is reported to enhance cognition.

Aims

To study the acute effects of modafinil administration upon brain activity and cognitive performance in people with chronic schizophrenia.

Method

In a randomised double-blind placebo-controlled crossover design, 19 patients received either modafinil (100 mg) or placebo prior to undertaking a working memory task with functional magnetic resonance imaging.

Results

Seventeen patients completed the study and another underwent acute relapse 4 days post-drug. Modafinil administration was associated with significantly greater activation in the anterior cingulate cortex during the working memory task. The anterior cingulate cortex signal correlated with cognitive performance, although only a subset of patients exhibited ‘enhancement’.

Conclusions

Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation.
Outcomes of crises before and after introduction of a crisis resolution team
Authors: Johnson Sonia , Nolan Fiona , Hoult John , White Ian R. , Bebbington Paul , Sandor Andrew , McKenzie Nigel , Patel Sejal N. , Pilling Stephen
Published: July 2005

Background

Crisis resolution teams (CRTs) are being introduced throughout England, but their evidence base is limited.

Aims

To compare outcomes of crises before and after introduction of a CRT.

Method

A new methodology was developed for identification and operational definition of crises. A quasi-experimental design was used to compare cohorts presenting just before and just after a CRT was established.

Results

Following introduction of the CRT, the admission rate in the 6 weeks after a crisis fell from 71% to 49% (OR 0.38, 95% CI 0.21–0.70). A difference of 5.6 points (95% CI 2.0–8.3) on mean Client Satisfaction Questionnaire (CSQ–8) score favoured the CRT. These findings remained significant after adjustment for baseline differences. No clear difference emerged in involuntary hospitalisations, symptoms, social functioning or quality of life.

Conclusions

CRTs may prevent some admissions and patients prefer them, although other outcomes appear unchanged in the short term.
Towards managing the whole system of care and improving continuity of care
Authors: Kennedy Peter , Pugh Robert , Millar Erville
Published: July 2005

As mental health services become more complex with additional teams, the risk of discontinuity of care for patients with complex needs may rise. Clinicians may have more difficulty in analysing the whole service picture. Hence they will be less able to contribute to the smooth running of the whole system. This paper describes how a north London trust is addressing this important challenge in straightforward and practical ways.
Triage in mental health – a new model for acute in-patient psychiatry
Authors: Inglis Gary , Baggaley Martin
Published: July 2005

Aims and Method

In-patient psychiatric care needs urgent improvement and development. A new model of psychiatric care (triage) has been used for 6 months across an adult psychiatric service covering a London borough.

Results

Preliminary results show that the new model has reduced bed occupancy, leading to more-efficient throughput, with positive feedback from patients and staff. Important factors contributing to these positive changes include a whole-systems approach, senior medical input 6 days a week, creative use of information technology and a highly skilled multidisciplinary team.

Clinical Implications

The introduction of the new model has resulted in a more-efficient use of beds. Further evaluation will enable us to assess the impact on other parts of the service. As with all innovations, the improvements must be sustained once the initial enthusiasm has passed.
Range Model of Judgments
Authors: Cowley Elizabeth , Rossiter John R.
Published: July 2005

Judgments of unfamiliar objects are likely to take the psychological form of a range rather than a precise point estimate as is commonly assumed in consumer research. A range model of attitude judgments is formulated to investigate attitude shifts after exposure to a persuasive message. In Study 1, the message was not only shown to affect consumers’ point‐estimate judgments but also their range judgments about the attribute targeted by the information. A message consistent with the consumer's pretrial attitude caused the range to narrow, and a message that was inconsistent with the consumer's pretrial attitude caused the range to widen asymmetrically in the direction of the message. In Study 2, judgment ranges were shown to have psychological validity in that a model based on whether the believed and desired judgment ranges overlap predicted purchase intention better than the conventional model that is based on differences in point estimates.
The Interactive Effects of Mood and Involvement on Brand Extension Evaluations
Authors: Barone Michael J.
Published: July 2005

This article examines the interactive effects of mood and involvement on evaluations of product extensions that vary in their similarity to the core brand. Results from an initial experiment show that, under conditions of high involvement, participants’ mood influenced their evaluations of extensions that were moderately similar to the core brand, but did not affect evaluations of either very similar or dissimilar extensions. Under low‐involvement conditions, however, the influence of positive mood was independent of core brand‐extension similarity. A second experiment demonstrates that mood's effect on extension evaluations may further depend on the measurement procedures used to elicit product appraisals. Collectively, these studies highlight important contingencies regarding mood's influence on extension evaluations and, as such, improve our understanding of consumers’ appraisals of brand extensions.
The Role of Conscious Awareness in Consumer Behavior
Authors: Chartrand Tanya L.
Published: July 2005

Consumer behavior can be influenced by mental processes that occur outside of conscious awareness. It is argued that in each domain of automaticity, researchers should specify the aspects of which consumers are presumably unaware. Three types of awareness are identified. These include awareness of (a) the environmental features that trigger an automatic process, (b) the automatic process itself, and (c) the outcome of that automatic process. Individuals may be unaware of one or more of these stages, thereby making the process nonconscious. With additional clarity regarding which aspects are nonconscious in which domains and the specific role that awareness plays, we can begin building a more comprehensive model of nonconscious processes in consumer behavior.
In Defense of Consciousness: The Role of Conscious and Unconscious Inputs in Consumer Choice
Authors: Simonson Itamar
Published: July 2005

Although the argument that unconscious inputs are often key determinants of consumer decision making is compelling, it may be overstated, particularly with respect to choice. A comparison of the effect of conscious inputs (e.g., the attributes of options in the choice set) and unconscious inputs (e.g., a seemingly irrelevant observation or task) indicates that the former have a significant advantage. In particular, the impact of conscious inputs is supported by choice task norms and is less susceptible to being lost in the “noise” that is characteristic of most natural consumer environments (e.g., stores). Indeed, although consumers often have limited insight into influences and processes producing their choices, the assumption that consumers base their choices on conscious, willful evaluation of task‐relevant inputs has been quite successful in explaining a wide range of phenomena. It is expected that future research will put greater emphasis on the interactions between conscious and unconscious influences on decision making.
G Protein-Coupled Receptor Kinase 2 Mediates Endothelin-1-Induced Insulin Resistance via the Inhibition of Both Gαq/11 and Insulin Receptor Substrate-1 Pathways in 3T3-L1 Adipocytes
Authors: Usui Isao , Imamura Takeshi , Babendure Jennie L. , Satoh Hiroaki , Lu Juu-Chin , Hupfeld Christopher J. , Olefsky Jerrold M.
Published: July 2005

G protein-coupled receptor kinases (GRKs) regulate seven-transmembrane receptors (7TMRs) by phosphorylating agonist-activated 7TMRs. Recently, we have reported that GRK2 can function as a negative regulator of insulin action by interfering with G protein-q/11 α-subunit (Gαq/11) signaling, causing decreased glucose transporter 4 (GLUT4) translocation. We have also reported that chronic endothelin-1 (ET-1) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and Gαq/11, and decreased insulin-stimulated glucose transport in 3T3-L1 adipocytes. In the current study, we have investigated the role of GRK2 in chronic ET-1-induced insulin resistance. Insulin-induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h, and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA. We further found that GRK2 mediates the inhibitory effects of ET-1 by two distinct mechanisms. Firstly, adenovirus-mediated overexpression of either wild-type (WT)- or kinase-deficient (KD)-GRK2 inhibited Gαq/11 signaling, including tyrosine phosphorylation of Gαq/11 and cdc42-associated phosphatidylinositol 3-kinase activity. Secondly, ET-1 treatment caused Ser/Thr phosphorylation of IRS-1 and IRS-1 protein degradation. Overexpression of KD-GRK2, but not WT-GRK2, inhibited ET-1-induced serine 612 phosphorylation of IRS-1 and restored activation of this pathway. Taken together, these results suggest that GRK2 mediates ET-1-induced insulin resistance by 1) inhibition of Gαq/11 activation, and this effect is independent of GRK2 kinase activity, and 2) GRK2 kinase activity-mediated IRS-1 serine phosphorylation and degradation.
Regulation of Protein Kinase B Tyrosine Phosphorylation by Thyroid-Specific Oncogenic RET/PTC Kinases
Authors: Jung Hye Sook , Kim Dong Wook , Jo Young Suk , Chung Hyo Kyun , Song Jung Hun , Park Jong Sun , Park Ki Cheol , Park Su Hyeon , Hwang Jung Hwan , Jo Ki-Won , Shong Minho
Published: July 2005

Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.
The N-Terminal Juxtamembrane Segment of the V1a Vasopressin Receptor Provides Two Independent Epitopes Required for High-Affinity Agonist Binding and Signaling
Authors: Hawtin Stuart R. , Wesley Victoria J. , Simms John , Argent Cymone C. H. , Latif Khalid , Wheatley Mark
Published: July 2005

It is fundamentally important to define how agonist-receptor interaction differs from antagonist-receptor interaction. The V1a vasopressin receptor (V1aR) is a member of the neurohypophysial hormone subfamily of G protein-coupled receptors. Using alanine-scanning mutagenesis of the N-terminal juxtamembrane segment of the V1aR, we now establish that Glu54 (1.35) is critical for arginine vasopressin binding. The mutant [E54A]V1aR exhibited decreased arginine vasopressin affinity (1700-fold) and disrupted signaling, but antagonist binding was unaffected. Mutation of Glu54 had an almost identical pharmacological effect as mutation of Arg46, raising the possibility that agonist binding required a mutual interaction between Glu54 and Arg46. The role of these two charged residues was investigated by 1) substituting Glu54; 2) inserting additional Glu/Arg in transmembrane helix (TM) 1; 3) repositioning the Glu/Arg in TM1; and 4) characterizing the reciprocal mutant [R46E/E54R]V1aR. We conclude that 1) the positive/negative charges need to be precisely positioned in this N terminus/TM1 segment; and 2) Glu54 and Arg46 function independently, providing two discrete epitopes required for high-affinity agonist binding and signaling. This study explains why Glu and Arg, part of an -R(X3)L/V(X3)E(X3)L- motif, are conserved at these loci throughout this G protein-coupled receptor subfamily and provides molecular insight into key differences between agonist and antagonist binding requirements.
Self-Associative Properties of Quinoline Derivatives in Solution
Authors: Latypov Shamil , Fakhfakh Mohammed A , Jullian Jean-Christophe , Franck Xavier , Hocquemiller Reynald , Figadère Bruno
Published: July 2005

Experimental data from proton NMR studies combined with ab initio calculations (energy and GIAO chemical shifts) indicated that quinoline(s), in solution, exist in equilibrium as a series of stacks (dimers or n-mers) that are slightly different in mutual orientation. The self-association constant depends dramatically on the concentration of the substrate: at low concentration, recognition occurs and dimerization, with association constants that are approximately 200 times larger than for higher n-mers at higher concentration, was observed.
Anion Recognition by 1,3-Benzenedisulfonamide Derivatives Bearing Phenolic Hydroxy Groups in MeCN-d3
Authors: Kondo Shin-ichi , Suzuki Takashi , Toyama Takuya , Yano Yumihiko
Published: July 2005

The halide anion recognition by 1,3-benzenedisulfonamides derived from 2-aminophenols was studied by 1H NMR titrations in MeCN-d3. The results demonstrated that the receptors achieved high recognition ability with chloride anion.
Rotational Isomerism Involving an Acetylenic Carbon VII. Restricted Rotation about Acetylenic Axis in a Diphenylethyne Derivative with Sterically Crowded m-Terphenyl Moieties
Authors: Toyota Shinji , Yanagihara Takashi , Yoshida Yukihiro , Goichi Michio
Published: July 2005

Bis(2,4,4″,6-tetramethyl-1,1′:3′,1″-terphenyl-2′-yl)ethyne was prepared by the Hart reaction and the Stille coupling as a sterically crowded diphenylethyne derivative. The barrier to rotation about the acetylenic axis was determined by the dynamic NMR method to be 51 kJ mol−1. The restricted rotation is attributed to the steric hindrance of the two mesityl groups in the m-terphenyl moieties.
A Mapping Study of Caspase-3 Activation Following Acute Spinal Cord Contusion in Rats
Authors: McEwen Melanie L. , Springer Joe E.
Published: July 2005

Spinal cord injury (SCI) initiates a cascade of biochemical changes that results in necrotic and apoptotic cell death. There is evidence that caspase-3 activation and apoptotic cell death occur within hours after SCI. However, the time course and cellular localization of activated caspase-3 has not been examined. Such information is essential because caspase-3–independent apoptotic pathways do exist. In this experiment, we describe the distribution of and cell types containing activated caspase-3 at 4 hr, 1 day, 2 days, 4 days, and 8 days following SCI in rats. Numerous caspase-3–positive cells were observed at 4 hr and 1 day postinjury and colocalized most often with CC1, a marker for oligodendroglia. Both markers disappeared near the injury epicenter over the next several days. Activated caspase-3 was again present in the injured spinal cord on postoperative day 8, which coincided with a reemergence of CC1-positive cells. Many of these CC1-positive cells again colocalized activated caspase-3. NeuN-positive neurons of the dorsal horn were occasionally immunopositive for activated caspase-3 at early time points. OX42-positive microglia/macrophages rarely contained activated caspase-3. The results indicate a biphasic pattern of caspase-3 activation during the first 8 days postinjury, suggesting that at least two mechanisms activate caspase-3 following SCI. This time-course study provides a framework for investigating and understanding the different signaling events contributing to this biphasic pattern of caspase-3 activation.
Expression Analysis of PMP22/Gas3 in Premalignant and Malignant Pancreatic Lesions
Authors: Li Junsheng , Kleeff Jörg , Esposito Irene , Kayed Hany , Felix Klaus , Giese Thomas , Büchler Markus W. , Friess Helmut
Published: July 2005

PMP22 is a structural protein of Schwann cells, but it also influences cell proliferation. In the present study, quantitative RT-PCR (QRT-PCR) and immunohistochemistry were used to determine PMP22 mRNA levels and to localize PMP22 in the normal pancreas ( n=20), chronic pancreatitis (CP) ( n=22), pancreatic ductal adenocarcinoma (PDAC) ( n=31), intraductal papillary mucinous neoplasms (IPMN) ( n=9), mucinous cystic tumors (MCN) ( n=4), and in a panel of PanIN lesions ( n=29). PMP22 mRNA levels were significantly higher in CP (3-fold) and PDAC (2.5-fold), compared to normal pancreatic tissues. PMP22 expression was restricted to nerves in the normal pancreas, while in CP and PDAC PMP22 was also expressed in PanIN lesions and in a small percentage of pancreatic cancer cells. PMP22 was weak to absent in the tumor cells of IPMNs and MCNs. PMP22 mRNA was present at different levels in cultured pancreatic cancer cells and up-regulated by transforming growth factor (TGF)-β1 in 2 of 8 of these cell lines. In conclusion, PMP22 expression is present in both CP and PDAC tissues. Its expression in PanIN lesions and some pancreatic cancer cells in vitro and in vivo suggests a role of PMP22 in the neoplastic transformation process from the normal pancreas to pre-malignant lesions to pancreatic cancer.
Myogenic Potential of Muscle Side and Main Population Cells after Intravenous Injection into Sub-lethally Irradiated mdx Mice
Authors: Muskiewicz Kristina R. , Frank Natasha Y. , Flint Alan F. , Gussoni Emanuela
Published: July 2005

Muscle side population (SP) cells have demonstrated hematopoietic and myogenic activities in vivo upon intravenous (IV) injection into lethally irradiated mdx mice. In contrast, muscle main population (MP) cells were unable to rescue the bone marrow of lethally irradiated mice and, consequently, their in vivo myogenic potential could not be assessed using this method. In the current study, muscle SP or MP cells derived from syngeneic wild-type male mice were delivered to sub-lethally irradiated mdx female mice by single or serial IV injections. Recipient mice were euthanized 12 weeks after transplantation at which time the quadriceps and diaphragm muscles were analyzed for the presence of donor-derived cells. Mice injected with 104 muscle SP cells or with 106 MP cells appeared to have similar numbers of dystrophin-positive myofibers containing fused donor nuclei. Analysis of the remaining tissue via real-time quantitative PCR indicated that mice injected with muscle SP cells had a higher percentage of donor-derived Y-DNA in the quadriceps than mice injected with MP cells, suggesting that muscle SP cells may be enriched for progenitors able to engraft dystrophic skeletal muscles from the circulation. Although the overall engraftment did not reach therapeutically significant levels, these results indicate that further optimization of cell delivery techniques may lead to improved efficacy of cell-mediated therapy using muscle SP cells.
Differential Intracellular Distributions of Inositol Trisphosphate and Ryanodine Receptors Within and Among Hematopoietic Cells
Authors: Clark Andrea J. , Petty Howard R.
Published: July 2005

To better understand the mechanism(s) of leukocyte Ca2+ signaling, we have studied the intracellular locations of two Ca2+-mobilizing receptors, the inositol 1,4,5-trisphosphate receptor and ryanodine receptor, by immunofluorescence microscopy. Our results show that localization differs not only between receptor classes within a cell, but among leukocyte types as well. We also illustrate the importance of preserving labile cellular filaments in maintaining cell integrity by fixation with the Safiejko-Mroczka and Bell protocol, because conventional fixation methods distort receptor patterns. We suggest that the observed differences influence intracellular Ca2+ signaling.
Endocrine and Exocrine Secretion of Leptin by the Gastric Mucosa
Authors: Cammisotto Philippe G. , Renaud Christian , Gingras Diane , Delvin Edgard , Levy Emile , Bendayan Moïse
Published: July 2005

Leptin is a hormone that plays important roles in nutritional status and in obesity. By means of immunocytochemistry, two populations of leptin-secreting cells were found in the lower half of the gastric mucosa. One consists of numerous large cells located around the gastric pits, the Chief epithelial cells, whereas the second refers to much smaller cells, strongly stained, few in number, and scattered between the gastric pits, the endocrine cells. By double immunostaining, leptin and pepsinogen were colocalized in the Chief cells, whereas the endocrine cells were positive only for leptin. Immunoelectron microscopy showed that leptin is present along the rough endoplasmic reticulum–Golgi-granules secretory pathways of the Chief and endocrine cells. On the other hand, leptin-receptor (long and short forms) immunolabelings, although absent in the gastric epithelial cell plasma membranes, were present in enterocytes at the level of their apical and basolateral membranes. Duodenal, jejunal, and ileal enterocytes displayed similar labelings for the leptin receptor. Thus, exocrine and endocrine secretions of leptin together with the presence of leptin receptors on enterocyte plasma membranes constitute a gastroenteric axis that coordinates the role played by leptin in the digestive tract.
Expression of PDE11A in Normal and Malignant Human Tissues
Authors: D'Andrea Michael R. , Qiu Yuhong , Haynes-Johnson Donna , Bhattacharjee Sheela , Kraft Patricia , Lundeen Scott
Published: July 2005

Cyclic nucleotide phosphodiesterase 11A (PDE11A) is the newest member in the PDE family. Although the tissue distribution of PDE11A mRNA has been shown, its protein expression pattern has not been well studied. The goal of this report is to investigate the distribution of PDE11A proteins in a wide range of normal and malignant human tissues. We utilized a polyclonal antibody that recognized all four PDE11A isoforms. Its specificity was demonstrated by Western blot analysis on a recombinant human PDE11A protein and native PDE11A proteins in various human tissues. Immunohistochemistry showed that PDE11A is widely expressed. Various degrees of immunoreactivity were observed in the epithelial cells, endothelial cells, and smooth muscle cells of all tissues examined. The highest expression was in the epithelial, endothelial, and smooth muscle cells of the prostate, Leydig, and spermatogenic cells of the testis, the tubule epithelial cells in the kidney, the epithelial and endothelial cells in the adrenal, the epithelial cells and macrophages in the colon, and the epidermis in the skin. Furthermore, PDE11A expression was also detected in several human carcinomas. Our results suggest that PDE11A might be involved in multiple physiological processes in various organs via its ability to modulate intracellular cAMP and cGMP levels.
Experimentally-induced hyperthyroidism is associated with activation of the rat hypothalamic–pituitary–adrenal axis
Authors: Johnson Elizabeth O , Kamilaris Themis C , Calogero Aldo E , Gold Philip W , Chrousos George P
Published: July 2005

Objective: Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary–adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic–pituitary–adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex.

Methods: The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 μg of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1α stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined.

Results: Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1α administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism.

Conclusions: The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.
An individualized GH dose regimen for long-term GH treatment in Japanese patients with adult GH deficiency
Authors: Chihara Kazuo , Koledova Ekaterina , Shimatsu Akira , Kato Yuzuru , Kohno Hitoshi , Tanaka Toshiaki , Teramoto Akira , Bates Peter C , Attanasio Andrea F
Published: July 2005

Objectives: To investigate the effects of growth hormone (GH) treatment, using a dose-adjustment regimen based on serum insulin-like growth factor (IGF)-I concentrations, in adult Japanese hypopituitary patients with GH deficiency.

Study design: Japanese patients who had initially been administered GH (n = 31) or placebo (n = 28) in a 24-week double-blind study received individualized GH treatment in an open-label study for 48 weeks. Body composition from dual-energy X-ray absorptiometry (DXA) and serum IGF-I, IGF-binding protein 3 (IGFBP-3) and lipid levels were determined centrally.

Results: Significant increases in lean body mass (4.5%) and decreases in fat mass (−10.5%) were observed in the group that received individualized GH doses in the present open-label study following placebo in the double-blind study. This was comparable with the changes observed in these parameters (4.7 and −9.2%, respectively) with fixed-dose GH treatment in the double-blind study; this latter group maintained these improvements throughout the open-label study. Individualized dose adjustment allowed for more moderate dose increases than the fixed-dose titration method. Individualized dosing also resulted in a lower mean dose for adult-onset compared with childhood-onset GH-deficient patients (0.032±0.019 versus 0.061±0.023 mg/kg per week for patients treated with GH for 48 weeks in the open-label study following placebo in the double-blind study). Dosing patterns in the two groups were paralleled by the changes in IGF-I and IGFBP-3. The incidence of oedema and cases with high IGF-I level were less frequent under the IGF-I controlled regimen compared with those during the fixed-dose titration method.

Conclusion: Individualized GH administration based on IGF-I levels was safe and effective. This regimen demonstrated differences in dose requirements between adult- and childhood-onset patients. An individualized dose regimen is recommended in adult Japanese GH-deficient patients.
Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years after thyroidectomy
Authors: Görges R , Maniecki M , Jentzen W , Sheu Sie n-Yi , Mann K , Bockisch A , Janssen O E
Published: July 2005

Objective and design: Cross-sectional studies have reported an increased prevalence of circulating thyroglobulin autoantibodies (TgAbs) in patients with differentiated thyroid carcinoma (DTC). With the advent of more sensitive assays, a longitudinal study monitoring the development of TgAb levels after ablative therapy was warranted.

Methods: One hundred and twelve consecutive patients with follicular cell-derived thyroid cancer were followed for 3 years. All patients had been thyroidectomized and received, on average, two radioiodine therapies. Residual tissue was quantified scintigraphically by 131I 24-h uptake. TgAb and thyroglobulin (Tg) serum levels were determined with a sensitive direct radioligand assay and an IRMA respectively.

Results: The prevalence of TgAbs at the initial examination was 29% (median 130 U/ml). During follow-up, TgAb levels rose transiently in one-tenth of the patients, but the prevalence of demonstrable TgAbs decreased to <10% after 3 years. The median serum half-life of TgAbs in treated DTC patients was 10 weeks. At initial examination (when all patients still had residual thyroid tissue and 17 had metastases), rising TgAb levels were correlated with the inability to detect Tg in 4, 30 and 73% of the patients, when initial TgAbs were <6, 6–50 or >50 U/ml respectively. While the Tg recovery test was valid for all patients, an in vitro dilution assay with TgAb serum reduced Tg values by up to 32%.

Conclusions: The development and course of TgAbs in DTC patients cannot be predicted by initial or residual tumour volume, TgAb or Tg levels. The presence of TgAbs, even in low concentrations, may cause Tg underestimation despite valid recovery tests in DTC patients.
p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells
Authors: Corrèze C , Blondeau J-P , Pomérance M
Published: July 2005

Objective: Thyrotropin activates the cAMP pathway in thyroid cells, and stimulates cell cycle progression in cooperation with insulin or insulin-like growth factor-I. Because p38 mitogen-activated protein kinases (p38 MAPKs) were stimulated by cAMP in the FRTL-5 rat thyroid cell line, we investigated (i) the effect of the specific inhibition of p38 MAPKs on FRTL-5 cell proliferation and (ii) the mechanism of action of p38 MAPKs on cell cycle control, by studying the expression and/or the activity of several cell cycle regulatory proteins in FRTL-5 cells.

Methods: DNA synthesis was monitored by incorporation of [3H]thymidine into DNA and the cell cycle distribution was assessed by fluorescence-activated cell sorter analysis. Expression of cell cycle regulatory proteins was determined by Western blot analysis. Cyclin-dependent kinase 2 (Cdk2) activity associated to cyclin E was immunoprecipitated and was measured by anin vitrokinase assay.

Results: SB203580, an inhibitor of α and β isoforms of p38 MAPKs, but not its inactive analog SB202474, inhibited DNA synthesis and the G1-S transition induced by forskolin plus insulin. SB203580 inhibited specifically p38 MAPK activity but not other kinase activities such as Akt and p70-S6 kinase. Treatment of FRTL-5 cells with SB203580 decreased total and cyclin E-associated Cdk2 kinase activity stimulated with forskolin and insulin. However, inhibition of p38 MAPKs by SB203580 was without effect on total cyclin E and Cdk2 levels. The decrease in Cdk2 kinase activity caused by SB203580 treatment was not due to an increased expression of p21Cip1or p27Kip1inhibitory proteins. In addition, SB203580 affected neither Cdc25A phosphatase expression nor Cdk2 Tyr-15 phosphorylation. Inhibition of p38 MAPKs decreased Cdk2-cyclin E activation by regulating the subcellular localization of Cdk2 and its phosphorylation on Thr-160.

Conclusions: These results indicate that p38 MAPK activity is involved in the regulation of cell cycle progression in FRTL-5 thyroid cells, at least in part by increasing nuclear Cdk2 activity.