bluuebunny/crossref_metadata_2025 huggingface dataset:
The applicability of quality-of-life assessment in palliative care: comparing two quality-of-life measures
Authors: Pratheepawanit N , Salek M S , Finlay I G
Published: May 2003

Two self-administered quality-of-life measures, the McGill Quality of Life Questionnaire (MQOL) and the Patient Evaluated Problem Scores (PEPS) were compared in patients receiving palliative care. The MQOL is a multidimensional questionnaire consisting of 16 items in five quality-of-life (QOL) domains: physical symptoms, physical well-being, psychological, existential and support domains. The PEPS is an individualized questionnaire asking patients to identify and rate major problems affecting their QOL. Both questionnaires were completed by 36 patients during outpatient clinic visits in three palliative care settings in Wales. Of those patients who stated their questionnaire preference 60% favoured MQOL due to its comprehensiveness, while others (28%) preferred PEPS due to its simplicity. The MQOL showed excellent internal consistency ([.alpha] = 0.90). The intrapatient analysis of answers from both questionnaires showed that MQOL was better than PEPS in reporting physical symptoms and support domain, while PEPS detected more psychosocial issues. The MQOL overall QOL score correlated highly with its existential domain ( rs = 0.57, P < 0.0005) and the PEPS overall quality of life ( rs = 0.77, P < 0.0005). Similarly, the PEPS overall QOL correlated well with MQOL total score ( rs = 0.76, P < 0.0005) and existential domain of the MQOL ( rs = 0.63, P < 0.0005). The findings support the importance of an existential domain in assessing the QOL of this population. Both MQOL and PEPS were found to be relevant and acceptable in advanced cancer patients receiving palliative care. However, with its favourable psychometric properties MQOL may be more suitable for QOL assessment in this population.
The use of interpleural analgesia using bupivacaine for pain relief in advanced cancer
Authors: Amesbury Brendan , O'Riordan Jane , Dolin Simon
Published: May 2003

The use of interpleural analgesia is described in six patients with a variety of advanced malignancies suffering from pain uncontrolled by opioids. The benefits and complications of the technique are discussed including management of the catheters at home and the measurement of plasma bupivacaine concentrations. Interpleural analgesia can provide good analgesia in a small, selected population of patients with otherwise uncontrolled pain of malignant origin.
Percutaneous endoscopic duodenostomy: the relief of obstruction in advanced gastric carcinoma
Authors: Dresner S M , Wayman J , Lovel T , Hayes N , Griffin S M
Published: May 2003

Nausea and vomiting in patients with advanced gastric malignancy and mechanical obstruction are distressing and difficult to manage. We describe a patient with linitis plastica and gastric stasis who was treated with a percutaneous endoscopic duodenostomy as the stomach could not be used for percutaneous endoscopic gastrostomy (PEG) formation. A ConfloTM PEG tube was inserted into the second part of the duodenum using the Ponsky–Gauderer technique without complication. The patient experienced excellent symptomatic relief and tolerated enteral nutrition extremely well, regaining some weight. This manoeuvre can produce effective symptom palliation allowing the patient to be managed at home during the terminal phase of their illness.
A longitudinal evaluation of a communication skills programme
Authors: Wilkinson Susie , Bailey Koren , Aldridge Judith , Roberts Anita
Published: May 2003

Communication is an essential component of palliative care, but patients and their families are often dissatisfied with their interactions with health professionals. Communication difficulties are also a recognized stress factor among health professionals. Education and training, however, are said to improve communication skills. A communication skills training programme for 110 nurses has demonstrated statistically significant improvements in the nurses' skills, but no long-term effect was evaluated. This paper presents the results of the long-term follow-up study. Of the 110 nurses contacted, 20% refused to participate, 45% agreed and 35% did not respond; 33 nurses returned usable data.

The mean length of time since completing the original study was 2.5 years. Since completion of the original course there was no statistically significant deterioration or improvement in eight of the nine areas of assessment skills evaluated. In the area of psychological assessment there was a statistically significant improvement, and overall the nurses maintained their skills and improved in this area. The results suggest that over time the nurses became more confident in the emotional areas of care as a result of the training.

The two key elements of the training were audio-tape recordings and feedback, which raised self-awareness, and experiential workshops covering ways of handling difficult situations. Whether a similar training effect could be achieved by a short 3–5-day course on communication skills needs addressing, because the integrated training skills course evaluated here is costly. Preliminary evidence suggests that the 3–5-day course may not be as effective, so the increased costs associated with the integrated training skills course may be wisely spent if it improves the quality of nurse–patient interaction as evidence here suggests.
The progress of awareness and acceptance of dying assessed in cancer patients and their caring relatives
Authors: Hinton John
Published: May 2003

Awareness and acceptance of dying were assessed weekly by semistructured interviews in a randomized sample of 76 hospice cancer patients and caring relatives. During the final eight weeks of the study, patients' awareness showed only slight increase (about 42% fully certain) while relatives' certainty clearly progressed (from 53% to 81% certain). Depression was linked with greater awareness in relatives but not patients. Patients were more anxious if death seemed probable rather than certain or no more than possible. Acceptance usually increased, with 51% of patients and 69% of relatives becoming nearly/fully accepting. Many individuals diverged from the average progress of awareness and acceptance; 18% of patients and 24% of relatives showed fluctuating or falling acceptance.

Patients' and relatives' levels of awareness were positively correlated ( r = 0.46), as was acceptance ( r = 0.47). Relatives accepted more if patients were over 70 years, weak, unable to concentrate or had a quality of life index (QLI) below five, but patients were more accepting if female and if the QLI was above five. Pain did not increase acceptance. Acceptance was described in terms of death's inevitability, faith and spiritual values, life's diminishing rewards, completing life, final benefits, humour, sharing, etc. Individuals often used more than one concept.

Generalizing exact figures from this sample needs caution, but some patterns of progress, possible influential factors and ways of acceptance may apply widely.
Coeliac plexus block using computed tomography guidance
Authors: Perello Antoni , Ashford Nicholas S , Dolin Simon J
Published: May 2003

Coeliac plexus blocks have been used successfully in the treatment of abdominal pain in advanced cancer and in benign chronic abdominal pain. However, concern remains about occasional potentially serious complications. One possible way to reduce the risks of this procedure may be to improve imaging during the procedure. We report a series of 38 coeliac plexus blocks carried out under computer tomographic (CT) guidance, mostly using the anterior approach. The technique is described. Effectiveness and side-effect rates were similar to other reported series. There were no major complications. Analysis of contrast spread would indicate that anterior preaortic or bilateral contrast spread is necessary to obtain pain relief. Our experience would indicate that routine CT guidance can be a simple aid to coeliac plexus block, and can be achieved easily in a district general hospital. Improved imaging allows accurate needle placement, while avoiding vital structures such as the aorta and pleura. Accurate placement may also allow the use of reduced volumes of neurolytic drugs.
Patient and carer preference for, and satisfaction with, specialist models of palliative care: a systematic literature review
Authors: Wilkinson E K , Salisbury C , Bosanquet N , Franks P J , Kite S , Lorentzon M , Naysmith A
Published: May 2003

This systematic literature review examined the impact of specialist models of palliative care on consumer satisfaction, opinion and preference over the past 20 years. From the literature search, 83 relevant papers were identified. Research findings from North America did not reveal any reliable or consistent trends, and this was due primarily to methodological flaws in the research. In the UK, consumers are more satisfied with all types of palliative care, whether provided by inpatient units or in the community, than with palliative care provided by general hospitals. Even though research findings consistently indicate that consumers appreciate the psychosocial climate in hospices, this research was based on small-scale local studies which were mainly focused on a single hospice. The dearth of high quality, comprehensive research was notable on the impact on consumer preference, opinion or satisfaction of hospice home care services, and other forms of palliative care in the community. It was concluded that further research is needed into consumer priorities for patients dying of noncancer diseases, and into the possible impact of patient characteristics on consumer satisfaction, opinion and preference for specialist models of palliative care.
Identifying the concerns of informal carers in palliative care
Authors: Payne S , Smith P , Dean S
Published: May 2003

The purpose of this preliminary study was to identify the perceived support needs of informal carers (families and friends) of cancer patients receiving palliative care in the community. Changes in policy mean that increasing numbers of palliative care patients receive the majority of their care at home. This potentially places heavy demands on families and friends. Thirty-nine informal carers were recruited from two areas in southern England. Data were obtained on psychological morbidity (General Health Questionnaire), and caregiving burden (Carer Strain Index), and a semistructured interview was used to elicit data on perceptions of caring. Results indicate that 33 (84%) reported above normal levels of psychological distress and 16 (41%) experienced high levels of strain related to caregiving. Younger age and being female were found to be correlated with psychological morbidity and strain. Participants also reported life restrictions, emotional distress and limited support.
Feasibility of using postal questionnaires to examine carer satisfaction with palliative care: a methodological assessment
Authors: Jacoby Ann , Lecouturier Jan , Bradshaw Colin , Lovel Tim , Eccles Martin
Published: May 2003

This paper reports on the methodological findings from a project which examined the feasibility of using a postal questionnaire to assess lay carer satisfaction with palliative care. The focus of this paper is the process of questionnaire development and its psychometric evaluation. The questionnaire was derived from an interview schedule used in previous national surveys of care for the dying, and was refined through qualitative work with recently bereaved lay carers. It was then tested in a postal survey of 355 lay carers identified from death registration certificates. Overall response rates were low, but significantly enhanced by the use of a single reminder sent 3 weeks after the initial mailshot. The analysis indicated that in the majority of cases the person targeted to receive the questionnaire was the most appropriate informant. Psychometric evaluation of the questionnaire against five criteria was encouraging, with low item nonresponse and ineligible response, and some evidence of discriminatory power, reliability, and face and content validity. Postal approaches appear to represent an acceptable means of assessing user satisfaction with palliative care, compared with more resource-intensive methods.
Development of a breathlessness assessment guide for use in palliative care
Authors: Corner Jessica , O'Driscoll Majella
Published: May 2003

The complex nature of breathlessness in advanced cancer makes it a difficult symptom to understand and control. Measurement instruments applied to breath-lessness have thus far failed to consider the multivariant components of this symptom. This study developed a breathlessness assessment guide for use in the clinical practice setting, that may be completed by any member of the health care team. The guide aims to encourage breathlessness to be addressed as a multidimensional problem, in which the emotional experience of breathlessness is inseparable from the sensory experience and the causative biological mechanisms. This guide provides the foundation for understanding the symptom of breathlessness in advanced cancer, and in turn promotes the development of management strategies to deal with this complex symptom.
Unlicensed uses for medication in a palliative care unit
Authors: Atkinson Clea V , Kirkham Stephen R
Published: May 2003

The aim of this study was to review the extent of drug use for unlicensed purposes in a palliative care unit. We carried out a prospective study of all patients with advanced malignancy admitted to a 10-bed specialist palliative care unit over a 4-month period. Prescriptions were assessed and compared with licensed prescribing indications. Seventy-six patients were included in the study; 689 prescriptions were made using 84 drugs to treat 34 different symptoms. Fifteen per cent of prescribing events were for unlicensed indications. We conclude that drugs are frequently used in the palliative care setting for purposes unsupported by product licences, although usually backed by literature. These drugs are often prescribed for symptoms which are difficult to control.
Prospective study of symptom control in 133 cases of palliative care inpatients in Shatin Hospital
Authors: Lo R S K , Ding A , Chung T K , Woo J
Published: May 2003

We report a prospective study assessing the prevalence and severity of physical and nonphysical symptoms, and the benefits from treatment and intervention, in advanced cancer patients presenting to a local palliative care unit in Hong Kong. Patients were assessed by a modified version of the support team assessment schedule (STAS). The study highlighted some symptoms which needed better control, and also reinforced the team morale by demonstrating aspects where there was definite improvement. In general, the STAS was found to be practicable and acceptable by our patients and staff. The most important benefit gained from the study was the successful dissemination of the concept of audit and quality assurance throughout the unit, which is essential for continuous improvement in the future.
The impact of different models of specialist palliative care on patients' quality of life: a systematic literature review
Authors: Salisbury C , Bosanquet N , Wilkinson E K , Franks P J , Kite S , Lorentzon M , Naysmith A
Published: May 2003

This study set out to systematically review the research evidence about the impact of alternative models of specialist palliative care on the quality of life of patients. Eighty-six relevant papers were identified and reviewed, including 22 descriptive and 27 comparative studies. We found few comparative trials of reasonable quality. There was some evidence that in-patient palliative care provided better pain control than home care or conventional hospital care, but this research was dated and open to criticism. Research on palliative home care teams and co-ordinating nurses has demonstrated limited impact on quality of life over conventional care for patients dying at home. These negative findings may be due to the limitations of the assessment tools used. There is a need for larger studies to provide clear evidence as to whether specialist palliative care services provide improvements in patients' quality of life. This review does not exclude the possibility that models of care might be justifiable on other grounds such as patient preference or cost-effectiveness.
Chemotherapy-induced moderate to severe anemia in intermediate-grade non-Hodgkin’s lymphoma patients
Authors: Caggiano Vincent , Tannous Rima E. , Gupta Sanjay , Fridman Moshe
Published: May 2003

This study investigated the incidence of anemia in chemotherapy-treated intermediate-grade non-Hodgkin’s lymphoma (IGNHL) patients. A historic case series design was used. The study data were obtained from 12 oncology practices that participated in the Oncology Practice Pattern Study (OPPS). The analysis focused on 353 IGNHL patients with normal baseline (prechemotherapy) hemoglobin (Hb) (≥12.0 g/dL). These patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone combination) therapy (at some point) from 1993 through 1999. Anemia was found to be prominent during chemotherapy. About 24% of the patients with a normal baseline Hb level dropped below 10.0 g/dL and 49% dropped to 10.0 -11.9 g/dL, at some point during chemotherapy. As anemia treatment data were unavailable, it is likely that some of these patients received therapy to boost their Hb levels, rendering our results conservative. A logistic regression model revealed that in patients with normal baseline Hb, age ≥60, female gender, lower baseline Hb level, and lymphoma histology classified as the Working Formulation (WF) E or H were significant predictors of a drop in Hb below 10.0 g/dL during chemotherapy. Chemo-therapy-induced anemia is frequently observed in lymphoma patients. It is possible to identify adverse baseline patient characteristics associated with higher risk of chemotherapy-induced anemia and carefully monitor such patients. Additional studies in community oncology practice are warranted to validate these findings and improve our understanding of the problems of anemia in chemotherapy treated non-Hodgkin’s lymphoma (NHL) patients.
Dexamethasone prophylaxis for paclitaxel hypersensitivity
Authors: Gilbar Peter , Ridge Alison
Published: May 2003

Objective. To evaluate single-dose intravenous (IV) dexamethasone as a viable alternative to the standard two-dose oral protocol and as a method for the administration of corticosteroid prophylaxis in the prevention of paclitaxel-induced hypersensitivity reactions (HSR).

Method. A retrospective analysis of pharmacy dispensing and medical records was undertaken to ascertain those patients who had received IV corticosteroid prophylaxis, details of therapy and incidence of HSR. A comprehensive literature review was also undertaken to determine the incidence of HSR to paclitaxel in patients receiving a similar IV dexamethasone premedication protocol.

Results. Thirty-five patients received prophylactic dexamethasone 20 mg IV, given 30 minutes before paclitaxel infusion. Patients also received promethazine 25 mg IV and ranitidine 50 mg IV. No HSR were reported. A number of studies were identified in which IV corticosteroid prophylaxis was used, including retrospective analyses, a prospective report, clinical studies involving paclitaxel employing IV corticosteroids as part of the premedication regimen, and comparative retrospective studies. Only one study described IV corticosteroid therapy adversely.

Conclusions. For the safe administration of paclitaxel, premedication with corticosteroids, and H1 and H2 receptor antagonists, is essential. The administration of IV dexamethasone 20 mg, given 30 minutes before paclitaxel infusion, is an appealing and practical alternative to the standard oral prophylactic regimen and offers benefits to patients in terms of compliance, convenience, ease of administration and flexibility.
Ca2+-Induced Ca2+ Release in the Pancreatic β-Cell: Direct Evidence of Endoplasmic Reticulum Ca2+ Release
Authors: Graves Thomas K. , Hinkle Patricia M.
Published: May 2003

The role of the Ca2+-induced Ca2+ release channel (ryanodine receptor) in MIN6 pancreatic β-cells was investigated. An endoplasmic reticulum (ER)-targeted “cameleon” was used to report lumenal free Ca2+. Depolarization of MIN6 cells with KCl led to release of Ca2+ from the ER. This ER Ca2+ release was mimicked by treatment with the ryanodine receptor agonists caffeine and 4-chloro-m-cresol, reversed by voltage-gated Ca2+ channel antagonists and blocked by treatment with antagonistic concentrations of ryanodine. The depolarization-induced rise in cytoplasmic Ca2+ was also inhibited by ryanodine, which did not alter voltage-gated Ca2+ channel activation. Both ER and cytoplasmic Ca2+ changes induced by depolarization occurred in a dose-dependent manner. Glucose caused a delayed rise in cytoplasmic Ca2+ but no detectable change in ER Ca2+. Carbamyl choline caused ER Ca2+ release, a response that was not altered by ryanodine. Taken together, these results provide strong evidence that Ca2+-induced Ca2+ release augments cytoplasmic Ca2+ signals in pancreatic β-cells.
Dehydroepiandrosterone Modulates Endothelial Nitric Oxide Synthesis Via Direct Genomic and Nongenomic Mechanisms
Authors: Simoncini Tommaso , Mannella Paolo , Fornari Letizia , Varone Gaetano , Caruso Antonella , Genazzani Andrea R.
Published: May 2003

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones in humans, and their levels progressively decline with age. Epidemiological studies suggest that DHEA/DHEAS concentrations may be inversely related to cardiovascular risk, but disagreement exists on this issue. Preliminary studies show that DHEA regulates vascular function, but few data have been published on the mechanisms. We show that DHEA administration to human endothelial cells triggers nitric oxide synthesis, due to enhanced expression and stabilization of endothelial nitric oxide synthase (eNOS). Additionally, DHEA rapidly activates eNOS, through a nontranscriptional mechanism that depends on ERK1/2 MAPK, but not on phosphatidylinositol 3-kinase/Akt. DHEA is not converted to estrogens or androgens by endothelial cells, and its genomic and nongenomic effects are not blocked by antagonists of the estrogen, progesterone, glucocorticoid, or androgen receptors, suggesting that DHEA acts through a specific receptor. Oral DHEA administration to ovariectomized Wistar rats dose-dependently restores aortic eNOS levels and eNOS activity, confirming the effects of DHEA in vivo. Our present data suggest that DHEA may have direct genomic and nongenomic effects on the vascular wall that are not mediated by other steroid hormone receptors, leading to eNOS activation and induction.
Diazoxide Attenuates Glucose-Induced Defects in First-Phase Insulin Release and Pulsatile Insulin Secretion in Human Islets
Authors: Song Soon H. , Rhodes Christopher J. , Veldhuis Johannes D. , Butler Peter C.
Published: May 2003

Humans with type-2 diabetes mellitus (TTDM) have hyperglycemia (∼11 mm) and impaired glucose-mediated insulin secretion characterized by impaired first-phase insulin release (FPIR) and pulsatile insulin release. Culture of islets from nondiabetic humans in very high glucose concentrations (∼20–30 mm) for 96 h causes impaired FPIR. We sought to determine 1) whether human islets cultured at a glucose concentration of approximately 11 mm (comparable to TTDM) recapitulates impaired insulin secretion in TTDM, specifically impaired FPIR and insulin pulse mass with an increased proinsulin/insulin (PI/I) secretion ratio; and 2) whether these changes can be attenuated by addition of diazoxide to islets cultured with 11 mm glucose. Islets cultured with 11 mm glucose for 96 h had 75% depleted insulin stores (P < 0.05), decreased FPIR and insulin pulse mass (P < 0.05), and an approximately 3-fold increase in the ratio of PI/I islet content and in secretion ratio (P < 0.05). Addition of diazoxide to islets cultured with 11 mm glucose decreased insulin secretion during static incubation, leading to relative preservation of insulin stores and enhanced insulin secretion during subsequent perifusion; FPIR increased by 162% (P < 0.05) and insulin pulse mass by 150% (P < 0.05) vs. no diazoxide. The mean islet PI/I content and islet PI/I secretion ratio were also decreased by approximately 70% (P < 0.05) by prior addition of diazoxide to islets during culture with 11 mm glucose. FPIR and insulin pulse mass were related to islet insulin stores (P < 0.001 for FPIR and P < 0.001 for pulse amplitude). In conclusion, the pattern of defects of insulin secretion present in TTDM (impaired FPIR and pulsatile insulin secretion, increased PI/I ratio) can be recapitulated in human islets cultured with 11 mm glucose for 96 h. These defects can be at least partially offset by concurrent inhibition of insulin secretion by diazoxide, which also preserves insulin stores. Defective insulin secretion in TTDM may be, at least in part, due to depletion of available insulin stores secondary to chronic increased demand (insulin resistance and hyperglycemia) in the setting of a decreased β-cell mass.
Characterization of the Androgen-Regulated Prostate-Specific T Cell Receptor γ-Chain Alternate Reading Frame Protein (TARP) Promoter
Authors: Cheng Wing-Shing , Giandomenico Valeria , Pastan Ira , Essand Magnus
Published: May 2003

TARP (T cell receptor γ-chain alternate reading frame protein) is uniquely expressed in males in prostate epithelial cells and prostate cancer cells. Here we demonstrate that TARP expression is regulated by testosterone at the transcriptional level through specific binding of androgen receptor to an androgen response element in the proximal TARP promoter. We further demonstrate that the promoter specifically initiates reporter gene expression in TARP-positive prostate cancer cell lines. To develop a regulatory sequence for prostate-specific gene expression, we constructed a chimeric sequence consisting of the TARP promoter and the prostate-specific antigen (PSA) enhancer. We found that in the prostatic adenocarcinoma cell line LNCaP, the transcriptional activity of the regulatory sequence consisting of a TARP promoter and PSA enhancer is 20 times higher than the activity of a regulatory sequence consisting of the PSA promoter and PSA enhancer. Thus, our studies define a regulatory sequence that may be used to restrict expression of therapeutic genes to prostate cancer cells and may therefore play a role in prostate cancer gene therapy.
Identification of a Putative Autocrine Bone Morphogenetic Protein-Signaling Pathway in Human Ovarian Surface Epithelium and Ovarian Cancer Cells
Authors: Shepherd Trevor G. , Nachtigal Mark W.
Published: May 2003

Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily of cytokines that are involved in development, differentiation, and disease. In an analysis of normal ovarian surface epithelium (OSE) and ovarian cancer (OC) cells, we observed BMP4 mRNA expression and found that primary OC cells produce mature BMP4. In addition, each member of the downstream signaling pathway was expressed in primary OSE and OC cells. Smad1 was phosphorylated and underwent nuclear translocation in normal OSE and OC cells upon treatment with BMP4. Interestingly, the BMP target genes ID1 and ID3 were up-regulated 10- to 15-fold in primary OC cells, compared with a 2- to 3-fold increase in normal OSE. The growth of several primary OC cells was relatively unaltered by BMP4 treatment; however, long-term BMP4 treatment of primary OC cells resulted in decreased cell density as well as increased cell spreading and adherence. These data demonstrate the existence and putative function of BMP signaling in normal OSE and OC cells, and thus the continued examination of BMP4 signaling in the regulation of these two processes will be critical to further our current understanding of the role of BMP biology in OC pathogenesis.
Effect of severe protein-calorie malnutrition on the penetration kinetics of trimethoprim and sulfamethoxazole to the deep tissues of Wistar rats
Authors: Lares-Asseff Ismael , Pérez Maria Gabriela , Camacho Guadalupe A , Toledo Aleiandra R , Guillé Maria del Carmen López Adrián J , Sosa Martha G
Published: May 2003

This study shows the effect that severe malnourishment has on the kinetics of antibiotic penetration in tissues. A total of 104 male Wistar rats, 21 days old, were randomly divided into eight groups. Five groups of experimental rats were severely malnourished (SM) and three further groups were considered well-nourished control groups (WN). A single dose of trimethoprim–sulfamethoxazole (TMP-SMX) was administered intraperitoneally. Blood samples were taken by heart puncture and five organs were extracted 0–24 h after the administration of the drug. HPLC was used to assess the amount of trimethoprim and sulfamethoxazole in fluids. The elimination half-life for trimethoprim from plasma was longer in SM rats with a median of 3.15 h; in WN rats, it was 0.390 h. Clearance was slower in SM rats: 646.72 mL μg−1 h−1 vs 3036.38 mL μg−1 h−1 in WN rats (P < 0.05). Tissue penetration was much higher for trimethoprim, with penetration indexes of 0.80–5.66 in WN rats, compared with 0.35–2.14 in SM rats. In the case of sulfamethoxazole, penetration indexes were 0.029–1.13 for WN and 0.075–0.657 for SM rats. Similarly, the penetration ratio to muscle and heart tissue was lower in SM rats. However, penetration to kidney, lung, liver and spleen was greater in SM rats. It is evident that severe SM decreases the capacity of trimethoprim more importantly than sulfamethoxazole biotransformation.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit vascular smooth muscle cell proliferation via differential effects on the cell cycle
Authors: Brooks Gavin , Yu Xue-Mei , Wang Yuequn , Crabbe M James C , Shattock Michael J , Harper Jane V
Published: May 2003

Abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of both atherosclerosis and restenosis. Recent studies suggest that high-dose salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in-vitro and in-vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAIDs) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains to be shown. In this study, we demonstrate that the NSAIDs aspirin, sodium salicylate, diclofenac, ibuprofen, indometacin and sulindac induce a dose-dependent inhibition of proliferation in rat A10 VSMCs in the absence of significant cytotoxicity. Flow cytometric analyses showed that exposure of A10 cells to diclofenac, indometacin, ibuprofen and sulindac, in the presence of the mitotic inhibitor, nocodazole, led to a significant G0/G1 arrest. In contrast, the salicylates failed to induce a significant G1 arrest since flow cytometry profiles were not significantly different from control cells. Cyclin A levels were elevated, and hyperphosphorylated p107 was present at significant levels, in salicylate-treated A10 cells, consistent with a post-G1/S block, whereas cyclin A levels were low, and hypophosphorylated p107 was the dominant form, in cells treated with other NSAIDs consistent with a G1 arrest. The ubiquitously expressed cyclin-dependent kinase (CDK) inhibitors, p21 and p27, were increased in all NSAID-treated cells. Our results suggest that diclofenac, indometacin, ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase, whereas the growth inhibitory effect of salicylates probably affects the late S and/or G2/M phases. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit in the treatment of certain vasculoproliferative disorders.
Direct, differential-equation-based in-vitro–in-vivo correlation (IVIVC) method
Authors: Buchwald Peter
Published: May 2003

A new, differential equation-based in-vitro–in-vivo correlation (IVIVC) method is proposed that directly relates the time-profiles of in-vitro dissolution rates and in-vivo plasma concentrations by using one-or multi-compartment pharmacokinetic models and a corresponding system of differential equations. The rate of in-vivo input is connected to the rate of in-vitro dissolution through a general functional dependency that allows for time scaling and time shifting. A multiplying factor that accounts for the variability of absorption conditions as the drug moves along is also incorporated. Two data sets incorporating slow-, medium-, and fast-release formulations were used to test the applicability of the method, and predictive powers were assessed with a leave-one-formulation-out approach. All fitted parameters had realistic values, and good or acceptable fits and predictions were obtained as measured by plasma concentration mean squared errors and percent AUC errors. Introduction of step-down functions that account for the transit of the dosage form past the intestinal sites of absorption proved useful. By avoiding the integral transforms used in the existing deconvolution- or convolution-based IVIVC models, the present method can provide increased transparency, improved performance, and greater modelling flexibility.
Can the USP paddle method be used to represent in-vivo hydrodynamics?
Authors: Scholz Annette , Kostewicz Edmund , Abrahamsson Bertil , Dressman Jennifer B
Published: May 2003

Experiments in-vitro and in dogs were conducted to find in-vitro hydrodynamic conditions that can be used to represent gastrointestinal motility patterns. Specifically, the dissolution performance of micronised and coarse-grade felodipine (a poorly soluble, neutral, lipophilic drug) was studied in a biorelevant medium in the USP paddle apparatus at various paddle speeds. Ratios of percentage dissolved (slower:faster rev min−1) were calculated pairwise. These ratios were then compared with AUC ratios obtained in a corresponding pharmacokinetic study in Labradors, in which the absorption of both the micronised and coarse-grade felodipine had been compared under two gastrointestinal hydrodynamic conditions. Using a paddle speed combination of 75 and 125 rev min−1 to represent the motility patterns in response to administration of normal saline and 5% glucose, respectively, the in-vitro ratios (75:125 rev min−1 dissolution ratio was 91% for the micronised and 46% for the coarse-grade powder) showed good agreement with the pharmacokinetic data (saline-to-glucose absorption ratio was 98% for the micronised and 46% for the coarse-grade powder). It was concluded that, provided an appropriate composition is chosen for the dissolution test, the USP paddle apparatus can be used to reflect variations in hydrodynamic conditions in the upper gastrointestinal tract.
Quantitative structure–activity relationship (QSAR) analysis of cationic complexes of heart perfusion imaging agents and subsequent proposition of two different uptake mechanisms
Authors: Zhang Huabei , Li Bo , Dai Mei
Published: May 2003

Some physicochemical and quantum-chemical discriptors of two series of cationic complexes of heart perfusion imaging agents ([99mTc1(NO)Cl(PL)2]+ and [99mTc-Mine]+ series) have been obtained using a semi-empirical quantum mechanics method — ZINDO/1. Quantitative structure–activity relationships (QSARs) between these descriptors and heart uptake were investigated by multiple linear regression analysis method, as the result of which, several equations were obtained. Fairly complete new heart uptake mechanisms, redox mechanism for [99mTc1(NO)Cl(PL)2]+ series and passively transport mechanism for [99mTc-Mine]+ series are proposed based on the results shown in the equations.
Thiomersal enhances the binding of histamine to the H1 receptor, but not histamine-stimulated inositol phosphate formation
Authors: Jain Vandana , McWilliams Emma , Young Michael
Published: May 2003

Thiomersal (thimerosal) was a weak inhibitor of the binding of [3H]mepyramine to histamine H1 receptors in guinea-pig cerebellar membranes (11 ± 1% inhibition at 10 μm, 32 ± 3% inhibition at 300 μm). However, in the concentration range 3–30 μm, thiomersal enhanced the binding of histamine to the H1 receptor, as reflected by the displacement of curves of histamine inhibition of [3H]mepyramine binding to lower concentrations, without any change in the Hill coefficient. The ratio of the IC50 values (the concentration giving 50% inhibition) in the absence and presence of thiomersal increased from 1.8 with 3 μm to 3.6 with 30 μm thiomersal. There was no consistent effect of thiomersal at concentrations of 30 μm and below on curves of mepyramine inhibition of [3H]mepyramine binding. In the presence of 10 μm thiomersal histamine-induced accumulation of inositol phosphates in U373 MG astrocytoma cells was partially inhibited (37 ± 8% inhibition of the maximum response), without any significant change in the EC50 (the concentration giving the half maximal response) for histamine. Thus although histamine binding was potentiated by thiomersal, there was no potentiation of an H1 receptor-mediated functional response.
Transcriptional regulation ofmitfaaccounts for the sox10 requirement in zebrafish melanophore development
Authors: Elworthy Stone , Lister James A. , Carney Tom J. , Raible David W. , Kelsh Robert N.
Published: May 2003

The transcription factor Sox10 is required for the specification, migration and survival of all nonectomesenchymal neural crest derivatives including melanophores. sox10-/- zebrafish lack expression of the transcription factor mitfa, which itself is required for melanophore development. We demonstrate that the zebrafish mitfa promoter has sox10 binding sites necessary for activity in vitro, consistent with studies using mammalian cell cultures that have shown that Sox10 directly regulates Mitf expression. In addition, we demonstrate that these sites are necessary for promoter activity in vivo. We show that reintroduction of mitfa expression in neural crest cells can rescue melanophore development in sox10-/- embryos. This rescue of melanophores in sox10-/- embryos is quantitatively indistinguishable from rescue in mitfa-/- embryos. These findings show that the essential function of sox10 in melanophore development is limited to transcriptional regulation of mitfa. We propose that the dominant melanophore phenotype in Waardenburg syndrome IV individuals with SOX10 mutations is likely to result from failure to activate MITF in the normal number of melanoblasts.
Development of theDrosophilamushroom bodies: elaboration,remodeling and spatial organization of dendrites in the calyx
Authors: Zhu Sijun , Chiang Ann-Shyn , Lee Tzumin
Published: May 2003

One Drosophila mushroom body (MB) is derived from four indistinguishable cell lineages, development of which involves sequential generation of multiple distinct types of neurons. Differential labeling of distinct MB clones reveals that MB dendrites of different clonal origins are well mixed at the larval stage but become restricted to distinct spaces in adults. Interestingly, a small dendritic domain in the adult MB calyx remains as a fourfold structure that, similar to the entire larval calyx, receives dendritic inputs from all four MB clones. Mosaic analysis of single neurons demonstrates that MB neurons, which are born around pupal formation, acquire unique dendritic branching patterns and consistently project their primary dendrites into the fourfold dendritic domain. Distinct dendrite distribution patterns are also observed for other subtypes of MB neurons. In addition,pruning of larval dendrites during metamorphosis allows for establishment of adult-specific dendrite elaboration/distribution patterns. Taken together,subregional differences exist in the adult Drosophila MB calyx, where processing and integration of distinct types of sensory information begin.
ArabidopsisMSI1 is required for epigenetic maintenance of reproductive development
Authors: Hennig Lars , Taranto Patti , Walser Marcel , Schönrock Nicole , Gruissem Wilhelm
Published: May 2003

WD40 repeat proteins similar to yeast MSI1 are conserved in animals and plants, in which they participate in complexes involved in chromatin metabolism. Although MSI1-like proteins are well characterised biochemically,their function in the development of multicellular eukaryotes is not well understood. We constructed Arabidopsis plants in which the AtMSI1 protein level was altered. Strong ectopic expression of AtMSI1 produced no visible altered phenotype, but reduction of AtMSI1 dramatically affected development. The primary shoot apical meristem was unable to develop organs after the transition to flowering. Flowers that developed on floral shoots from axillary meristems experienced a progressive loss of floral morphology,including a reduction in size of the petals and stamens and the development of carpel-like sepals. Ovule development was disrupted in all flowers, resulting in complete female sterility. Molecular analysis of the mutant plants revealed that AtMSI1 is required to maintain the correct temporal and organ-specific expression of homeotic genes, including AGAMOUS and APETALA2. In contrast, FAS1 and FAS2, which together with AtMSI1 form the chromatin assembly complex CAF-1, are not required for repression of these genes. Therefore, AtMSI1 has specific functions in addition to CAF-1-mediated chromatin assembly. Efficient formation of heterochromatin, but not methylation of centromeric DNA repeats, depends on AtMSI1 presence demonstrating a key role of AtMSI1 in maintenance of chromatin structure.
The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum
Authors: Chi Candace L. , Martinez Salvador , Wurst Wolfgang , Martin Gail R.
Published: May 2003

Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO),which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1-/- embryos, the mes/met is deleted by the 30 somite stage (∼E10) (McMahon, A. P. and Bradley, A.(1990) Cell 62,1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage (∼E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18, and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes,and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met.
TheC. elegansG-protein-coupled receptor SRA-13 inhibits RAS/MAPK signalling during olfaction and vulval development
Authors: Battu Gopal , Hoier Erika Froehli , Hajnal Alex
Published: May 2003

In C. elegans, the RAS/MAPK pathway is used in different tissues to regulate various cell fate decisions. Several positive and negative regulators tightly control the activity of the RAS/MAPK pathway at different steps. We demonstrate a link between a G-protein-coupled receptor signalling pathway and the RAS/MAPK cascade. SRA-13, a member of the SRA family of chemosensory receptors, negatively regulates RAS/MAPK signalling during vulval induction and the olfaction of volatile attractants. Epistasis analysis indicates that SRA-13 inhibits the RAS/MAPK pathway at the level or upstream of MAPK. In both tissues, the vulval precursor cells and the chemosensory neurones, SRA-13 acts through the GPA-5 Gα protein subunit, suggesting a common mechanism of crosstalk. Moreover, we find that vulval induction is repressed by food withdrawal during larval development and that SRA-13 activity is required for the suppression of vulval induction in response to food starvation. Thus, SRA-13 may serve to adapt the activity of the RAS/MAPK pathway to environmental conditions.
TheXenopusLIM-homeodomain protein Xlim5 regulates the differential adhesion properties of early ectoderm cells
Authors: Houston Douglas W. , Wylie Christopher
Published: May 2003

One of the earliest lineage restriction events in embryogenesis is the specification of the primary germ layers: ectoderm, mesoderm and endoderm. In Xenopus, germ layer specification occurs prior to gastrulation and requires the transcription factor VegT both for the cellautonomous specification of endoderm and the generation of mesoderm-inducing signals. In the absence of VegT, ectoderm is formed in all regions of the embryo. In this work, we show that VegT-depleted vegetal cells (prospective endoderm) behave like animal cells in sorting assays and ectopically express early markers of ectoderm. To gain insight into how ectoderm is specified, we looked for candidate ectoderm-specific genes that are ectopically expressed in VegT-depleted embryos, and examined the role of one of these, the LIM homeobox gene Xlim5, in ectoderm development. We show that overexpression of Xlim5 in prospective endoderm cells is sufficient to impair sorting of animal cells from vegetal cells but is not sufficient (at similar doses) to induce ectoderm-specific genes. In whole embryos, Xlim5 causes vegetal cells to segregate inappropriately to other germ layers and express late differentiation markers of that germ layer. Inhibition of Xlim5 function using an Engrailed repressor construct or a morpholino oligonucleotide causes loss of animal cell adhesion or delay in neural fold morphogenesis,respectively, without significantly affecting early ectoderm gene expression. Taken together, our results provide evidence that a primary role for Xlim5 is to specifically regulate differential cell adhesion behaviour of the ectoderm.
A Novel Three-dimensional Rhombic Network Self-assembled by the First Reported cis-[Mn(4,4′-azpy)2(H2O)4]2+ Cations through Hydrogen Bonding Interactions
Authors: Li Baolong , Li Baozong , Lang Jianping , Zhang Yong
Published: May 2003

A novel complex [Mn(4,4′-azpy)2(H2O)4](ClO4)2·2(4,4′-azpy)·0.5(H2O) was synthesized and characterized. It is composed of the first example cis-[Mn(4,4′-azpy)2(H2O)4]2+ cations. Three-dimensional rhombic network is formed through hydrogen bonding interactions between coordinated water and mono-coordinated 4,4′-azpy and noncoordinated 4,4′-azpy.
(Salen)ruthenium-catalyzed Desymmetrization of meso-Diols (2). Apical Ligand Effect on Enantioselectivity
Authors: Shimizu Hideki , Katsuki Tsutomu
Published: May 2003

Enantiotopos-selectivity of aerobic oxidation of meso-diols using chiral (nitrosyl)Ru(salen) complexes as catalyst was found to be dependent on the nature of their apical ligand. The oxidation with complex 5 possessing an apical hydroxo ligand as the catalyst showed moderate to good enantioselectivity (up to 80% ee).
A Novel TTP Donor Containing a PROXYL Radical for Magnetic Molecular Conductors
Authors: Fujiwara Hideki , Lee Ha-Jin , Kobayashi Hayao , Fujiwara Emiko , Kobayashi Akiko
Published: May 2003

A TTP donor containing a stable PROXYL radical was synthesized to develop conducting-magnetic bifunctional materials and its structure and physical properties were investigated. Furthermore its cation radical salts were prepared and revealed their conducting and magnetic properties.