bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women
Authors: Abbas Aamer , Fadel Paul J. , Wang Zhongyun , Arbique Debbie , Jialal Ishwarlal , Vongpatanasin Wanpen
Published: July 2004

Objectives—

Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women.

Methods and Results—

In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 μg per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women.

Conclusions—

Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes.
Hepatic Lipase, Lipoprotein Metabolism, and Atherogenesis
Authors: Santamarina-Fojo Silvia , González-Navarro Herminia , Freeman Lita , Wagner Elke , Nong Zengxuan
Published: July 2004

The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis.
Mast Cells in Neovascularized Human Coronary Plaques Store and Secrete Basic Fibroblast Growth Factor, a Potent Angiogenic Mediator
Authors: Lappalainen Helena , Laine Petri , Pentikäinen Markku O. , Sajantila Antti , Kovanen Petri T.
Published: July 2004

Objective—

Intraplaque neovascularization and hemorrhage may facilitate plaque progression. We studied expression of basic fibroblast growth factor (bFGF), a potent angiogenic mediator, by mast cells (MCs) in human coronary plaques with increasing degrees of atherosclerosis.

Methods and Results—

Normal and atherosclerotic coronary segments were collected from 30 autopsied subjects. Immunohistochemical methods were used to detect MCs, bFGF, and microvessels. Both adventitial and intimal MCs showed intracytoplasmic granular staining for bFGF, and bFGF-positive extracellular granules were observed close to the MCs. Increased numbers of bFGF-positive MCs were detected in neovascularized areas of plaques, and there was a positive correlation between numbers of bFGF-positive MCs and microvessels in both the intima and adventitia. In plaques, the highly neovascularized areas contained increased numbers of bFGF-positive MCs compared with the adjacent nonvascularized areas, where only few MCs were present. Importantly, the proportion of intimal MCs expressing bFGF increased with increasing severity of atherosclerosis.

Conclusions—

The present work reveals a novel source of bFGF in human coronary arteries, the intimal and adventitial MCs. The association of bFGF-positive MCs with microvessels and with the severity of atherosclerosis suggests that coronary MCs, by releasing bFGF, may play a role in angiogenesis and progression of coronary plaques.
Modifications in the Biophysical Properties of Connexin43 Channels by a Peptide of the Cytoplasmic Loop Region
Authors: Seki Akiko , Duffy Heather S. , Coombs Wanda , Spray David C. , Taffet Steven M. , Delmar Mario
Published: July 2004

Connexin43 (Cx43) channels reside in at least 3 states: closed, open, or residual. It is hypothesized that the residual state results from the interaction of an intracellular “gating element” with structures at the vestibule of the pore. Recently, we showed in vitro that there is an intramolecular interaction of the carboxyl-terminal domain (referred to as “CT”) with a region in the cytoplasmic loop of Cx43 (amino acids 119 to 144; referred to as “L2”). Here, we assessed whether the L2 region was able to interact with the gating particle in a functional channel. Cx43 channels were recorded in the presence of a peptide corresponding to the L2 region, delivered via the patch pipette. This manipulation did not modify unitary conductance, but decreased the frequency of transitions into the residual state, prolonged open time, and altered the voltage dependence of the channel in a manner analogous to that observed after truncation of the CT domain. The latter correlated with the ability of the peptide to bind to the CT domain, as determined by mirror resonance spectroscopy. Overall, we propose that the L2 acts as a “receptor” that interacts with a flexible intracellular gating element during channel gating. The full text of this article is available online at http://circres.ahajournals.org.
Intracerebral Transplantation of Porcine Choroid Plexus Provides Structural and Functional Neuroprotection in a Rodent Model of Stroke
Authors: Borlongan Cesar V. , Skinner Steve J.M. , Geaney Marilyn , Vasconcellos Alfred V. , Elliott Robert B. , Emerich Dwaine F.
Published: July 2004

Background and Purpose—

Choroid plexus (CP) secretes a cocktail of neurotrophic factors. In the present study, CP from neonatal pigs was encapsulated within alginate microcapsules for in vitro and in vivo neuroprotective studies.

Methods—

In vitro studies involved serum deprivation of rat embryonic cortical neurons and treatment with a range of concentrations of conditioned media from CP. For in vivo studies, rats received a 1-hour middle cerebral artery occlusion followed by intracranial transplantation of encapsulated or unencapsulated CP, empty capsules, or no transplant. Behavioral testing was conducted on days 1 to 3 after transplantation. Cerebral infarction was analyzed using 2,3,5-triphenyl-tetrazolium chloride staining at 3 days after transplantation.

Results—

Conditioned media from CP produced a significant dose-dependent protection of serum-deprived cortical neurons. Enzyme-linked immunosorbent assay confirmed secretion of GDNF, BDNF, and NGF from CP. Parallel in vivo studies showed that CP transplants improved behavioral performance and decreased the volume of infarction. Both encapsulated and unencapsulated CP transplants were effective; however, more robust benefits accompanied encapsulated transplants.

Conclusions—

These data are the first to demonstrate the neuroprotective potential of transplanted CP and raise the intriguing possibility of using these cells as part of the treatment regimen for stroke and other neurological disorders.
THE SURA OF THE POETS, QUR'AN XXVI: FINAL CONCLUSIONS
Authors: Shahīd Irfan
Published: July 2004

The crucial verses in the Qur'an (XXVI, 224-227) for understanding the theme of Islam and poetry have been re-examined in the light of recent publications and have reinforced the conclusion that the key word " al-ghawuna " in verse 224 signifies not erring human beings, but demons, " shayatin." More importantly, verse 227 has been shown to involve not the poets' mendacity as such, but their inability to produce anything that can compare with the Qur'an, declared inimitable, " mu'jiz ." The traditional interpretation of verse 226, that poets are liars, has been traced through Islamic cultural history.
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation
Authors: Jin Yinzhu , Mazza Cinzia , Christie Jacinda R. , Giliani Silvia , Fiorini Maurilia , Mella Patrizia , Gandellini Francesca , Stewart Donn M. , Zhu Qili , Nelson David L. , Notarangelo Luigi D. , Ochs Hans D.
Published: July 2004

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. X-linked thrombocytopenia (XLT) is an allelic variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia. WAS and XLT are caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene which encodes a 502-amino acid protein, named WASP. WASP is thought to play a role in actin cytoskeleton organization and cell signaling. Here, we report the identification of 141 unique mutations, 71 not previously reported, from 227 WAS/XLT families with a total of 262 affected members. When possible we studied the effects of these mutations on transcription, RNA splicing, and protein expression. By analyzing a large number of patients with WAS/XLT at the molecular level we identified 5 mutational hotspots in the WASP gene and have been able to establish a strong association between genotype and phenotype. (Blood. 2004;104:4010-4019)
A GTPase-activating protein binds STAT3 and is required for IL-6–induced STAT3 activation and for differentiation of a leukemic cell line
Authors: Tonozuka Yukio , Minoshima Yukinori , Bao Ying Chun , Moon Yuseok , Tsubono Yohei , Hatori Tomonori , Nakajima Hideaki , Nosaka Tetsuya , Kawashima Toshiyuki , Kitamura Toshio
Published: July 2004

We previously identified a guanosine triphosphatase (GTPase)–activating protein (GAP) male germ cell Rac GAP (MgcRacGAP) that enhanced interleukin-6 (IL-6)–induced macrophage differentiation of murine M1 leukemia cells. Later, MgcRacGAP was found to play crucial roles in cell division. However, how MgcRacGAP enhanced IL-6–induced differentiation remained elusive. Here we show that MgcRacGAP enhances IL-6–induced differentiation through enhancement of signal transducer and activator of transcription–3 (STAT3) activation. MgcRacGAP, Rac, and STAT3 formed a complex in IL-6–stimulated M1 cells, where MgcRacGAP interacted with Rac1 and STAT3 through its cysteine-rich domain and GAP domain. In reporter assays, the wild-type MgcRacGAP enhanced transcriptional activation of STAT3 while a GAP-domain deletion mutant (ΔGAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependent transcription. Intriguingly, M1 cells expressing ΔGAP had no effect on the differentiation signal of IL-6, while forced expression of MgcRacGAP rendered M1 cells hyperresponsive to the IL-6–induced differentiation. Moreover, knockdown of MgcRacGAP by RNA interference profoundly suppressed STAT3 activation, implicating MgcRacGAP in the STAT3-dependent transcription. All together, our data not only reveal an important role for MgcRacGAP in STAT3 activation, but also demonstrate that MgcRacGAP regulates IL-6–induced cellular differentiation in which STAT3 plays a pivotal role.
Distinct roles of ADP receptors in von Willebrand factor–mediated platelet signaling and activation under high flow
Authors: Mazzucato Mario , Cozzi Maria Rita , Pradella Paola , Ruggeri Zaverio M. , De Marco Luigi
Published: July 2004

We have investigated the role of adenosine diphosphate (ADP) receptors in the adhesion, activation, and aggregation of platelets perfused over immobilized von Willebrand factor (VWF) under high shear stress. Blocking P2Y1 prevented stable platelet adhesion and aggregation, indicative of a complete inhibition of αIIbβ3 activation, and decreased the duration of transient arrests from 5.9 seconds ± 2.8 seconds to 1.2 seconds ± 0.8 seconds; in contrast, blocking P2Y12 inhibited only the formation of larger aggregates. Moreover, blocking P2Y1 decreased the proportion of platelets showing early intracytoplasmic Ca++ elevations (α/β peaks) from 20.6% ± 1.6% to 14.6% ± 1.5% (P < .01), and the corresponding peak ion concentration from 1543 nM ± 312 nM to 1037 nM ± 322 nM (P < .05); it also abolished the Ca++ elevations seen in firmly attached platelets (γ peaks). Blocking P2Y12 had no effect on these parameters, and did not enhance the effect of inhibiting P2Y1. Inhibition of phospholipase C had similar consequences as the blocking of P2Y1, whereas inhibition of Src family kinases abolished both type α/β and γ Ca++ oscillations, although the former effect required a higher inhibitor concentration. Our results demonstrate that, under elevated shear stress conditions, ADP signaling through P2Y1 may contribute to the initial stages of platelet adhesion and activation mediated by immobilized VWF, and through P2Y12 to sustained thrombus formation.
Expression and analysis of a split premature termination codon in FGG responsible for congenital afibrinogenemia: escape from RNA surveillance mechanisms in transfected cells
Authors: Neerman-Arbez Marguerite , Germanos-Haddad Myrna , Tzanidakis Konstantinos , Vu Dung , Deutsch Samuel , David Armelle , Morris Michael A. , de Moerloose Philippe
Published: July 2004

Congenital afibrinogenemia, the most severe form of fibrinogen deficiency, is characterized by the complete absence of fibrinogen. The disease is caused by mutations in 1 of the 3 fibrinogen genes FGG, FGA, and FGB, clustered on the long arm of human chromosome 4. The majority of cases are due to null mutations in the FGA gene although one would expect the 3 genes to be equally implicated. However, most patients studied so far are white, and therefore the identification of causative mutations in non-European families is necessary to establish if this finding holds true in all ethnic groups. In this study, we report the identification of a novel nonsense mutation (Arg134Xaa) in the FGG gene responsible for congenital afibrinogenemia in 10 patients from Lebanon. Expression studies in COS-7 cells demonstrated that the Arg134Xaa codon, which is encoded by adjacent exons (TG-intron 4-A) affected neither mRNA splicing nor stability, but led to the production of an unstable, severely truncated fibrinogen γ chain that is not incorporated into a functional fibrinogen hexamer.
8-Cl-Adenosine enhances 1,25-dihydroxyvitamin D3-induced growth inhibition without affecting 1,25-dihydroxyvitamin D3-stimulated differentiation of primary mouse epidermal keratinocytes
Authors: Bollag Wendy B , Zhong Xiaofeng , Josephson Sarah
Published: July 2004

Background

Epidermal keratinocytes continuously proliferate and differentiate to form the mechanical and water permeability barrier that makes terrestrial life possible. In certain skin diseases, these processes become dysregulated, resulting in abnormal barrier formation. In particular, skin diseases such as psoriasis, actinic keratosis and basal and squamous cell carcinomas are characterized by hyperproliferation and aberrant or absent differentiation of epidermal keratinocytes. We previously demonstrated that 8-Cl-adenosine (8-Cl-Ado) can induce keratinocyte growth arrest without inducing differentiation.

Results

To determine if this agent might be useful in treating hyperproliferative skin disorders, we investigated whether 8-Cl-Ado could enhance the ability of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a known keratinocyte differentiating agent and a clinical treatment for psoriasis, to inhibit keratinocyte growth. We found that low concentrations of 8-Cl-Ado and 1,25(OH)2D3 appeared to act additively to reduce proliferation of primary mouse epidermal keratinocytes. However, another agent (transforming growth factor-beta) that triggers growth arrest without inducing differentiation also coincidentally inhibits differentiation elicited by other agents; inhibition of differentiation is suboptimal for treating skin disorders, as differentiation is often already reduced. Thus, we determined whether 8-Cl-Ado also decreased keratinocyte differentiation induced by 1,25(OH)2D3, as measured using the early and late differentiation markers, keratin 1 protein levels and transglutaminase activity, respectively. 8-Cl-Ado did not affect 1,25(OH)2D3-stimulated keratin 1 protein expression or transglutaminase activity.

Conclusions

Our results suggest that 8-Cl-Ado might be useful in combination with differentiating agents for the treatment of hyperproliferative disorders of the skin.
Discovery of induced point mutations in maize genes by TILLING
Authors: Till Bradley J , Reynolds Steven H , Weil Clifford , Springer Nathan , Burtner Chris , Young Kim , Bowers Elisabeth , Codomo Christine A , Enns Linda C , Odden Anthony R , Greene Elizabeth A , Comai Luca , Henikoff Steven
Published: July 2004

Background

Going from a gene sequence to its function in the context of a whole organism requires a strategy for targeting mutations, referred to as reverse genetics. Reverse genetics is highly desirable in the modern genomics era; however, the most powerful methods are generally restricted to a few model organisms. Previously, we introduced a reverse-genetic strategy with the potential for general applicability to organisms that lack well-developed genetic tools. Our TILLING (Targeting Induced Local Lesions IN Genomes) method uses chemical mutagenesis followed by screening for single-base changes to discover induced mutations that alter protein function. TILLING was shown to be an effective reverse genetic strategy by the establishment of a high-throughput TILLING facility and the delivery of thousands of point mutations in hundreds of Arabidopsis genes to members of the plant biology community.

Results

We demonstrate that high-throughput TILLING is applicable to maize, an important crop plant with a large genome but with limited reverse-genetic resources currently available. We screened pools of DNA samples for mutations in 1-kb segments from 11 different genes, obtaining 17 independent induced mutations from a population of 750 pollen-mutagenized maize plants. One of the genes targeted was the DMT102 chromomethylase gene, for which we obtained an allelic series of three missense mutations that are predicted to be strongly deleterious.

Conclusions

Our findings indicate that TILLING is a broadly applicable and efficient reverse-genetic strategy. We are establishing a public TILLING service for maize modeled on the existing Arabidopsis TILLING Project.
Shoulder posture and median nerve sliding
Authors: Julius Andrea , Lees Rebecca , Dilley Andrew , Lynn Bruce
Published: July 2004

Background

Patients with upper limb pain often have a slumped sitting position and poor shoulder posture. Pain could be due to poor posture causing mechanical changes (stretch; local pressure) that in turn affect the function of major limb nerves (e.g. median nerve). This study examines (1) whether the individual components of slumped sitting (forward head position, trunk flexion and shoulder protraction) cause median nerve stretch and (2) whether shoulder protraction restricts normal nerve movements.

Methods

Longitudinal nerve movement was measured using frame-by-frame cross-correlation analysis from high frequency ultrasound images during individual components of slumped sitting. The effects of protraction on nerve movement through the shoulder region were investigated by examining nerve movement in the arm in response to contralateral neck side flexion.

Results

Neither moving the head forward or trunk flexion caused significant movement of the median nerve. In contrast, 4.3 mm of movement, adding 0.7% strain, occurred in the forearm during shoulder protraction. A delay in movement at the start of protraction and straightening of the nerve trunk provided evidence of unloading with the shoulder flexed and elbow extended and the scapulothoracic joint in neutral. There was a 60% reduction in nerve movement in the arm during contralateral neck side flexion when the shoulder was protracted compared to scapulothoracic neutral.

Conclusion

Slumped sitting is unlikely to increase nerve strain sufficient to cause changes to nerve function. However, shoulder protraction may place the median nerve at risk of injury, since nerve movement is reduced through the shoulder region when the shoulder is protracted and other joints are moved. Both altered nerve dynamics in response to moving other joints and local changes to blood supply may adversely affect nerve function and increase the risk of developing upper quadrant pain.
Investigating the utility of combining Φ29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArray™ genotyping
Authors: Pask Rebecca , Rance Helen E , Barratt Bryan J , Nutland Sarah , Smyth Deborah J , Sebastian Meera , Twells Rebecca CJ , Smith Anne , Lam Alex C , Smink Luc J , Walker Neil M , Todd John A
Published: July 2004

Background

Sustainable DNA resources and reliable high-throughput genotyping methods are required for large-scale, long-term genetic association studies. In the genetic dissection of common disease it is now recognised that thousands of samples and hundreds of thousands of markers, mostly single nucleotide polymorphisms (SNPs), will have to be analysed. In order to achieve these aims, both an ability to boost quantities of archived DNA and to genotype at low costs are highly desirable. We have investigated Φ29 polymerase Multiple Displacement Amplification (MDA)-generated DNA product (MDA product), in combination with highly multiplexed BeadArray™ genotyping technology. As part of a large-scale BeadArray genotyping experiment we made a direct comparison of genotyping data generated from MDA product with that from genomic DNA (gDNA) templates.

Results

Eighty-six MDA product and the corresponding 86 gDNA samples were genotyped at 345 SNPs and a concordance rate of 98.8% was achieved. The BeadArray sample exclusion rate, blind to sample type, was 10.5% for MDA product compared to 5.8% for gDNA.

Conclusions

We conclude that the BeadArray technology successfully produces high quality genotyping data from MDA product. The combination of these technologies improves the feasibility and efficiency of mapping common disease susceptibility genes despite limited stocks of gDNA samples.
Premorbid adjustment in first-episode non-affective psychosis: Distinct patterns of pre-onset course
Authors: Larsen Tor K. , Friis Svein , Haahr Ulrik , Johannessen Jan Olav , Melle Ingrid , Opjordsmoen Stein , Rund Bjørn Rishovd , Simonsen Erik , Vaglum Per , McGlashan Thomas H.
Published: July 2004

Background

Knowledge about premorbid development in psychosis can shed light upon theories about aetiology and schizophrenic heterogeneity, and form a basis for early detection initiatives.

Aims

To identify and validate patterns of premorbid functioning in first-episode psychosis.

Method

The Premorbid Adjustment Scale was used to examine 335 patients.

Results

Social and academic function constituted fairly independent dimensions. Cluster analysis identified groups varying both in level and course. Patients with a stable social course compared with a deteriorating one had a shorter duration of untreated psychosis, were older, had more friends and less negative symptoms. Good childhood academic function correlated with more education, more meaningful activities and better working memory. Patients with a stable academic course were older at admission.

Conclusions

Patterns of premorbid development suggest both neuro-developmental and neuroregressive pathways to illness.
There is only one functional somatic syndrome
Authors: Wessely Simon , White Peter D.
Published: July 2004

Functional somatic symptoms and syndromes are a major health issue. They are common, costly, persistent and may be disabling. Most of the current literature pertains to specific syndromes defined by medical subspecialties. Indeed, each medical subspecialty seems to have at least one somatic syndrome. These include: irritable bowel syndrome (gastroenterology); chronic pelvic pain (gynaecology); fibromyalgia (rheumatology); non-cardiac chest pain (cardiology); tension headache (neurology); hyperventilation syndrome (respiratory medicine) and chronic fatigue syndrome (infectious disease). In 1999, Wessely and colleagues concluded on the basis of a literature review that there was substantial overlap between these conditions and challenged the acceptance of distinct syndromes as defined in the medical literature (Wessely et al, 1999). They proposed the concept of a general functional somatic syndrome. But is there any empirical evidence for such a general syndrome? Is it even a useful concept? Five years on, Professor Simon Wessely, King's College London, revisits this debate. He is opposed by Dr Peter White from St Bartholomew's Hospital and Queen Mary School of Medicine and Dentistry, London.
What are the benefits of evidence-based supported employment for patients with first-episode psychosis?
Authors: Rinaldi Miles , Mcneil Karen , Firn Mike , Koletsi Marsha , Perkins Rachel , Singh Swaran P.
Published: July 2004

Aims and Method

To examine the effectiveness of integrating evidence-based supported employment into an early intervention service for young people with first-episode psychosis. Demographic, clinical and vocational data were collected over a 12-month period to evaluate the effect on vocational outcomes at 6 months and 12 months of the employment of a vocational specialist, and to assess model fidelity.

Results

Following vocational profiling and input from the vocational specialist and the team, there were significant increases in the proportion of clients engaged in work or educational activity over the first 6 months of the intervention, and in a subsample over a second 6-month period. The evidence-based Supported Employment Fidelity Scale was used to measure the degree of implementation, which scored 71, signifying ‘good implementation’.

Clinical Implications

The results suggest that implementing evidence-based supported employment within an early intervention service increases employment and education opportunities for patients within the service.
A study of clozapine and long-term hospitalisation rates
Authors: Woodall Alan A. , Menkes David B. , Trevelyan Thomas R. , Lanceley Colin P.
Published: July 2004

Aims and Method

The aim of the study was to investigate the use of clozapine in treatment-resistant schizophrenia and its impact on hospitalisation rates when prescribed in accordance with National Institute for Clinical Excellence (NICE) guidelines. Case records were examined of patients admitted to the psychiatric unit of Glan Clwyd Hospital between 1996 and 2001.

Results

Of 59 patients identified as having treatment-resistant schizophrenia, 83% had been considered for clozapine, 48% were taking clozapine, 20% had refused the drug and 15% had stopped taking it because of side-effects. The mean annual hospitalisation rate for patients receiving clozapine for a minimum of 3 years was 13.5 days, markedly lower than those not receiving this drug (34.0 days, P=0.03). Older patients were less likely to have been offered clozapine (P=0.006).

Clinical Implications

This study supports the NICE guidelines recommending clozapine for patients with treatment-resistant disease. Clozapine is offered less often to older patients; factors influencing this require investigation.
Low glycaemic index diet in patients prescribed clozapine: pilot study
Authors: Smith Helen , White Tom
Published: July 2004

Aims and Method

This study aimed to investigate the potential benefits of a low glycaemic index diet in patients with schizophrenia taking clozapine. Seven patients consented to participate in a 5-week pilot study. Measurements were taken of body weight, random blood glucose and cholesterol levels.

Results

The mean weight loss per patient was 2.9 kg in 4 weeks. Random blood glucose levels reduced from a mean of 5.3 mmol/l at the beginning of the study to 4.7 mmol/l at the end.

Clinical Implications

A low glycaemic index diet may possibly reduce the substantial cardiovascular risk in patients receiving antipsychotic medication.
Lessons learned from a failed research project
Authors: Vaidya Girish
Published: July 2004

There has been a significant emphasis on research experience in the years of specialist registrar training (Royal College of Psychiatrists, 1998). It has also been acknowledged that in reality many specialist registrars find it difficult to start a research project and complete it within the 3 years of specialist registrar training (Allsopp et al, 2002). There have been various suggestions about how the ‘research day’ can be used more gainfully – in acquiring skills in evidence-based medicine (Ramchandani et al, 2001); or in preparing to be a consultant.
Using Health-Related Quality of Life Measures to Predict Cardiac Function in Survivors Exposed to Anthracyclines
Authors: Ginsberg Jill P. , Cnaan Avital , Zhao Huaqing , Clark Bernard J. , Paridon Stephen M. , Chin Alvin J. , Rychik Jack , Hogarty Alexa N. , Barber Gerald , Rutkowski Monika , Kimball Thomas R. , DeLaat Cynthia , Steinherz Laurel J. , Silber Jeffrey H.
Published: July 2004

Purpose

As the number of pediatric cancer survivors increases, so does the number of survivors previously exposed to anthracyclines as part of their cancer therapy. Because screening is costly, some have suggested that health-related quality of life (HRQL) measures might be useful in focusing screening tests on those patients with cases most likely to display positive findings. This study reports on the predictive ability of HRQL measures to detect patients with abnormalities on serial cardiac testing.

Methods

Using 127 patients from the ACE-Inhibitor after Anthracycline (AAA) Trial, this study compared serial measures of the Short Form-36 (SF-36; for ages > 13 years) and Child Health Questionnaire-Child Form 87 (CHQ-CF87; for ages ≤ 13 years) to serial cardiac performance tests including echocardiographic shortening fraction, left ventricular end systolic wall stress (LVESWS), LVESWS-index, and maximal cardiac index (MCI; a measure of cardiac output at peak exercise).

Results

Generally, there was no clinically or statistically significant correlation between any HRQL measure and any cardiac function measure except between MCI and vitality and physical functioning. For each of these measures, the correlation between MCI was statistically significant (P < .006), but each HRQL subscale could explain no more than 7% of the variation in MCI. HRQL measures were not predictive of any other cardiac function measure.

Conclusion

HRQL measures should not be used in isolation as a screen for cardiac function abnormalities in patients exposed to anthracylines who already have a mild degree of ventricular dysfunction. Patient history appears to be no substitute for cardiac testing in this cohort.
Utility of Fine-Needle Aspiration As a Diagnostic Technique in Lymphoma
Authors: Hehn Sean T. , Grogan Thomas M. , Miller Thomas P.
Published: July 2004

Purpose

To evaluate, from a clinician's perspective, the sensitivity and specificity of fine-needle aspiration (FNA) as a technique for the diagnosis of lymphoma.

Patients and Methods

Medical records of 470 new patients seen in one lymphoma specialist's clinic from January 1998 through December 2002 were reviewed. Ninety-nine (21%) of the 470 patients underwent a total of 115 FNA procedures, which were assessed by more than 70 different pathologists in 32 different pathology departments. Subsequent excisional biopsies were performed in 67 of these patients and interpreted by a single hematopathology group without independent review.

Results

Of 115 FNA procedures, 93 were completed for the initial evaluation of lymphoma and 22 were done for assessment of relapsed disease. Of the 93 FNA attempts at initial diagnosis, only 27 (29%) were given a specific and complete histologic diagnosis using an accepted classification system (Working Formulation, Revised European-American Classification of Lymphoid Neoplasms, WHO). For the 22 FNAs done for recurrent disease, only nine (41%) were classified using an accepted system. Sixty-seven (72%) of the 93 FNAs performed for the evaluation of initial disease had subsequent excisional biopsies. Among these paired comparisons, only eight (12%) of 67 FNA diagnoses were correlated with the subsequent excisional biopsy diagnosis. Immunophenotyping was completed on 24 of the 67 paired FNAs. Seven of the 24 FNAs with immunophenotyping (29%) were correlated with subsequent histology on excisional biopsy. Only one (2%) of 43 FNA diagnoses, based on morphology alone, was correlated with subsequent excisional biopsy diagnosis.

Conclusion

Overall, FNA for lymphoma diagnosis is not helpful, not cost effective, and in addition may misguide treatment.
Duration of Response to Second-Line, Platinum-Based Chemotherapy for Ovarian Cancer: Implications for Patient Management and Clinical Trial Design
Authors: Markman Maurie , Markman Jonathan , Webster Kenneth , Zanotti Kristine , Kulp Barbara , Peterson Gertrude , Belinson Jerome
Published: July 2004

Purpose

Limited information is available regarding the influence of the duration of a prior response on the length of a subsequent response to platinum chemotherapy in recurrent ovarian cancer.

Patients and Methods

We retrospectively reviewed the medical records of women with ovarian cancer treated at the Cleveland Clinic from 1993 through April 2003 who received two or more platinum-based regimens for recurrence of the malignancy. Patients were considered to have responded to second-line therapy if they satisfied specific criteria, including favorable effects on both measurable or assessable disease.

Results

A total of 211 platinum-based regimens were administered to 176 women with recurrent ovarian cancer during this time period, with a response being observed in 125 treatment episodes (59%). Only four (3%) of 121 currently assessable secondary responses were of longer duration than the prior response in a specific individual. In three of these four cases, the platinum-based regimen used in the second-line approach included a drug that had not been used in that patient's primary chemotherapy program.

Conclusion

The length of a prior response to platinum-based therapy in ovarian cancer is highly predictive of the upper limit of the duration of response to a subsequent platinum program, assuming the same or similar drugs are used. Knowledge of this clinical parameter may assist in developing optimal management for an individual patient and may potentially be exploited in clinical trial designs examining novel maintenance strategies with both cytotoxic and cytostatic agents in women who achieve a secondary response to a platinum-based regimen.
Differential Prognostic Impact of Comorbidity
Authors: Read William L. , Tierney Ryan M. , Page Nathan C. , Costas Irene , Govindan Ramaswamy , Spitznagel Edward L.J. , Piccirillo Jay F.
Published: July 2004

Purpose

Cancer patients with concurrent comorbid conditions have worse outcomes than patients with no comorbidities. We hypothesized that the prognostic impact of comorbidities would be greatest for patients with cancers associated with a long natural history and least in patients with aggressive cancers.

Patients and Methods

Using the Barnes-Jewish Hospital Oncology Data Services cancer registry, we grouped 11,558 patients with breast, lung, colon, or prostate cancer by morphologic stage at diagnosis and then determined the 1-year overall survival rate for each group. Overall, severity of comorbidity was assessed from chart review and classified into one of four groups: none, mild, moderate, or severe. The relative prognostic impact of comorbidity was measured by the hazard ratio and adjusted for the prognostic impact of age, race, and sex.

Results

One-year overall survival rate ranged from 20% for 1,005 patients with distant spread of lung cancer to 98% for 3,325 patients with localized prostate cancer. Adjusted hazard ratio of moderate/severe comorbidity (relative to none/mild) ranged from 1.04 to 4.48. The correlation between overall survival rate and severity of comorbidity was statistically significant (r2 = 0.56; P < .001). The proportion of variance in outcome explained by comorbidity ranged from less than 1% to almost 9%, depending on tumor site and stage.

Conclusion

Concurrent comorbidities had the greatest prognostic impact among groups with the highest survival rate and the least impact in groups with the lowest survival rate. These findings can be used to help determine the role comorbidity information should play in studies of cancer outcomes.
Assessing Quality of Life During Chemotherapy for Pleural Mesothelioma: Feasibility, Validity, and Results of Using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module
Authors: Nowak Anna K. , Stockler Martin R. , Byrne Michael J.
Published: July 2004

Purpose

To assess the feasibility and validity of using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (QLQ-LC13) to describe health-related quality of life (HRQL) in patients with pleural mesothelioma undergoing combination chemotherapy, to identify the most impaired aspects of HRQL, and to assess the impact of chemotherapy on HRQL.

Patients and Methods

Fifty-three patients received cisplatin on day 1 and gemcitabine on days 1, 8, and 15 of a 28-day cycle for a maximum of six cycles. HRQL was assessed using the EORTC QLQ-C30 and QLQ-LC13.

Results

Compliance was 100% at baseline but subsequently decreased. At baseline, role function and social function were the most impaired domains, and the worst-rated symptoms were fatigue, dyspnea, pain, insomnia, appetite loss, and cough. Dyspnea, pain, insomnia, and cough improved with chemotherapy, although functional domains and chemotherapy-related symptoms deteriorated. Fatigue remained unchanged. Few patients reported hemoptysis. Functional domains and symptoms scales from the QLQ-C30 demonstrated predictive validity for survival. The predictive value of QLQ-LC13 pain scores was improved by combining three pain items into a single score. Dyspnea scores were correlated strongly with lung function as measured by forced vital capacity.

Conclusion

This study supports the validity of the EORTC QLQ-C30 and LC13 as outcome measures for trials of chemotherapy in mesothelioma. Although the most prominent symptoms reported were concordant with clinical experience, impairments in role and social function and insomnia were worse than expected. Future research should focus on how best to apply, analyze, and interpret existing, validated HRQL instruments in mesothelioma research and practice, not on the development of new ones.
High Levels of Circulating Insulin-Like Growth Factor-I Increase Prostate Cancer Risk: A Prospective Study in a Population-Based Nonscreened Cohort
Authors: Stattin Pär , Rinaldi Sabina , Biessy Carine , Stenman Ulf-Håkan , Hallmans Göran , Kaaks Rudolf
Published: July 2004

Purpose

Insulin-like growth factor-I (IGF-I) stimulates proliferation and inhibits apoptosis in prostate cancer cells, and IGF-I has been associated with increased prostate cancer risk in some, but not all, epidemiologic studies.

Subjects and Methods

We extended our previous case-control study nested in the Northern Sweden Health and Disease Cohort, a population-based cohort from a region where little prostate specific antigen (PSA) screening is done. Levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured in prediagnostic blood samples from a total of 281 men who were subsequently diagnosed with prostate cancer after recruitment (median, 5 years after blood collection) and from 560 matched controls.

Results

Logistic regression analyses showed increases in prostate cancer risk with increasing plasma peptide levels, up to an odds ratio (OR) for top versus bottom quartile of IGF-I of 1.67 (95% CI, 1.02 to 2.71; P trend = .05), which was attenuated after adjustment for IGFBP-3 to an OR of 1.47 (95% CI, 0.81 to 2.64; P trend = .32). For men younger than 59 years at recruitment, OR for top versus bottom quartile of IGF-I was 4.12 (95% CI, 1.01 to 16.70; P trend = .002), which was significantly stronger than for men older than 59 years (P interaction = .006). For men with advanced cancer, OR for top versus bottom quartile of IGF-I was 2.87 (95% CI, 1.01 to 8.12; P trend = .10).

Conclusion

Our data add further support for IGF-I as an etiologic factor in prostate cancer and indicate that circulating IGF-I levels measured at a comparatively young age may be most strongly associated with prostate cancer risk.
Role of the Insulin-Like Growth Factor I Decline in the Induction of Atrogin-1/MAFbx during Fasting and Diabetes
Authors: Dehoux Mischael , Van Beneden Ronald , Pasko Nevi , Lause Pascale , Verniers Josiane , Underwood Louis , Ketelslegers Jean-Marie , Thissen Jean-Paul
Published: July 2004

In catabolic conditions, atrogin-1/MAFbx, a muscle-specific ubiquitin-ligase required for muscle atrophy, is increased, and concentrations of IGF-I, a growth factor known to have antiproteolytic action, are reduced. To define the relationship between the decline in IGF-I and the induction of atrogin-1/MAFbx, we studied the effect of IGF-I replacement on atrogin-1/MAFbx mRNA in rats fasted for 51 h and in rats made diabetic with streptozotocin (STZ). Fasting produced a 5.8-fold increase in atrogin-1/MAFbx (P < 0.001). This was attenuated to a 2.5-fold increase by injections of IGF-I (P < 0.05 vs. fasting). Animals with STZ-induced diabetes experienced a 15.1-fold increase in atrogin-1/MAFbx (P < 0.001). Normalization of their circulating IGF-I concentrations by IGF-I infusion blunted the induction of atrogin-1/MAFbx to 6.3-fold (P < 0.05 vs. STZ diabetes without IGF-I). To further delineate the regulation of atrogin-1/MAFbx by IGF-I, we studied a model of cultured muscle cells. We observed that IGF-I produced a time- and dose-dependent reduction of atrogin-1/MAFbx mRNA, with a 50% effective dose of 5 nm IGF-I, a physiological concentration. The degradation rate of atrogin-1/MAFbx mRNA was not affected by IGF-I, suggesting that the reduction of atrogin-1/MAFbx mRNA by IGF-I is a transcriptional effect. Exposure of muscle cells in culture to dexamethasone increased atrogin-1/MAFbx mRNA with a 50% effective dose of 10 nm, a pharmacological concentration. In the presence of dexamethasone, IGF-I at physiological concentrations retained its full inhibitory effect on atrogin-1/MAFbx mRNA. We conclude that IGF-I inhibits atrogin-1/MAFbx expression and speculate that this effect might contribute to the antiproteolytic action of IGF-I in muscle.
Novel Expression of Gonadotropin Subunit Genes in Oocytes of the Gilthead Seabream (Sparus aurata)
Authors: Wong Ten-Tsao , Zohar Yonathan
Published: July 2004

It is widely believed that FSH and LH, which are known to play key roles in controlling the production of functional oocytes in vertebrates, are synthesized and secreted exclusively by the anterior pituitary. Here we present evidence for the novel expression of FSHβ, LHβ, and the common glycoprotein-α (Cgα) in the gilthead seabream ovary. Using in situ hybridization and immunocytochemistry, FSHβ was detected in primary-growth and secondary-growth-I oocytes, LHβ was found in secondary-growth oocytes, and Cgα was observed in both primary and secondary-growth oocytes. Northern blot analyses demonstrated that Fshβ transcript is 0.6 kb in both pituitary and ovary, whereas the ovarian Lhβ transcript (1.1 kb), unexpectedly, is longer than the known pituitary Lhβ transcript (0.6 kb). Sequence analyses revealed that ovarian Lhβ is driven by a different promoter than pituitary Lhβ, which generates an additional 459 bases at the distal portion of the 5′-untranslated region of the ovarian Lhβ. Furthermore, using in vitro ovarian fragment incubation, we demonstrated that mammalian GnRH analog agonist enhanced the expression of ovarian Fshβ (up to 2.7-fold), Lhβ (up to 1.4-fold), Cgα (up to 1.8-fold), and the secretion of ovarian LH (up to 2.2-fold). In contrast, GnRH antagonist, analog E, suppressed the secretion of ovarian LH. Our findings suggest that a GnRH-gonadotropin axis is present in the gilthead seabream ovary and that FSH and LH, the well-characterized pituitary hormones, may have prominent novel roles in teleost intraovarian communication between oocytes and ovarian follicle cells.
Susceptibility Rather than Resistance to Hyperthyroidism Is Dominant in a Thyrotropin Receptor Adenovirus-Induced Animal Model of Graves’ Disease as Revealed by BALB/c-C57BL/6 Hybrid Mice
Authors: Chen Chun-Rong , Aliesky H. , Pichurin P. N. , Nagayama Y. , McLachlan S. M. , Rapoport B.
Published: July 2004

We investigated why TSH receptor (TSHR) adenovirus immunization induces hyperthyroidism more commonly in BALB/c than in C57BL/6 mice. Recent modifications of the adenovirus model suggested that using adenovirus expressing the TSHR A subunit (A-subunit-Ad), rather than the full-length TSHR, and injecting fewer viral particles would increase the frequency of hyperthyroidism in C57BL/6 mice. This hypothesis was not fulfilled; 65% of BALB/c but only 5% of C57BL/6 mice developed hyperthyroidism. TSH binding inhibitory antibody titers were similar in each strain. Functional TSHR antibody measurements provided a better indication for this strain difference. Whereas thyroid-stimulating antibody activity was higher in C57BL/6 than BALB/c mice, TSH blocking antibody activity was more potent in hyperthyroid-resistant C57BL/6 mice. F1 hybrids (BALB/c × C57BL/6) responded to A-subunit-Ad immunization with hyperthyroidism and TSHR antibody profiles similar to those of the hyperthyroid-susceptible parental BALB/c strain. In contrast, ELISA of TSHR antibodies revealed that the IgG subclass distribution in the F1 mice resembled the disease-resistant C57BL/6 parental strain. Because the IgG subclass distribution is dependent on the T helper 1/T helper 2 cytokine balance, this paradigm can likely be excluded as an explanation for susceptibility to hyperthyroidism. In summary, our data for BALB/c, C57BL/6, and F1 strains suggest that BALB/c mice carry a dominant gene(s) for susceptibility to induction of a thyroid-stimulating antibody/TSH blocking antibody balance that results in hyperthyroidism. Study of this genetic influence will provide useful information on potential candidate genes in human Graves’ disease.
Lateral diffusion of Toll-like receptors reveals that they are transiently confined within lipid rafts on the plasma membrane
Authors: Triantafilou Martha , Morath Siegfried , Mackie Alan , Hartung Thomas , Triantafilou Kathy
Published: July 2004

The innate immune system utilises pattern recognition receptors in order to recognise microbial conserved molecular patterns. The family of Toll-like receptors (TLRs) has been shown to act as the main pattern recognition receptors for the innate immune system. Using biochemical as well as fluorescence imaging techniques, TLR2 and TLR4 were found to be recruited within microdomains upon stimulation by bacterial products. Furthermore their lateral diffusion in the cell membrane as determined by fluorescence recovery after photobleaching revealed that upon stimulation by bacterial products TLRs encounter barriers to their lateral movement, thus supporting the notion that specialised domains on the plasma membrane facilitate the innate recognition.