bluuebunny/crossref_metadata_2025 huggingface dataset:
JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs
Authors: Aggarwal Dimple , West Kristy L , Zern Tosca L , Shrestha Sudeep , Vergara-Jimenez Marcela , Fernandez Maria Luz
Published: September 2005

Background

Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver.

Methods

Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism.

Results

Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment.

Conclusion

These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.
Medical concepts related to individual risk are better explained with "plausibility" rather than "probability"
Authors: Grossi Enzo
Published: September 2005

Background

The concept of risk has pervaded medical literature in the last decades and has become a familiar topic, and the concept of probability, linked to binary logic approach, is commonly applied in epidemiology and clinical medicine. The application of probability theory to groups of individuals is quite straightforward but can pose communication challenges at individual level. Few articles by the way have tried to focus the concept of "risk" at the individual subject level rather than at population level.

Discussion

The author has reviewed the conceptual framework which has led to the use of probability theory in the medical field in a time when the principal causes of death were represented by acute disease often of infective origin.

In the present scenario, in which chronic degenerative disease dominate and there are smooth transitions between health and disease the use of fuzzy logic rather than binary logic would be more appropriate. The use of fuzzy logic in which more than two possible truth-value assignments are allowed overcomes the trap of probability theory when dealing with uncertain outcomes, thereby making the meaning of a certain prognostic statement easier to understand by the patient.

At individual subject level the recourse to the term plausibility, related to fuzzy logic, would help the physician to communicate to the patient more efficiently in comparison with the term probability, related to binary logic. This would represent an evident advantage for the transfer of medical evidences to individual subjects.
A qualitative study of the impact of the implementation of advanced access in primary healthcare on the working lives of general practice staff
Authors: Ahluwalia Sanjiv , Offredy Maxine
Published: September 2005

Background

The North American model of 'advanced access' has been emulated by the National Primary Care Collaborative in the UK as a way of improving patients' access in primary care. The aim of this study was to explore the impact of the implementation of advanced access on the working lives of general practice staff.

Methods

A qualitative study design, using semi-structured interviews, was conducted with 18 general practice staff: 6 GPs, 6 practice managers and 6 receptionists. Two neighbouring boroughs in southeast England were used as the study sites. NUD*IST computer software assisted in data management to identify concepts, categories and themes of the data. A framework approach was used to analyse the data.

Results

Whilst practice managers and receptionists saw advanced access as having a positive effect on their working lives, the responses of general practitioners (GPs) were more ambivalent. Receptionists reported improvements in their working lives with a change in their role from gatekeepers for appointments to providing access to appointments, fewer confrontations with patients, and greater job satisfaction. Practice managers perceived reductions in work stress from fewer patient complaints, better use of time, and greater flexibility for contingency planning. GPs recognised benefits in terms of improved consultations, but had concerns about the impact on workload and continuity of care.

Conclusion

AA has improved working conditions for receptionists, converting their perceived role from gatekeeper to access facilitator, and for practice managers as patients were more satisfied. GP responses were more ambivalent, as they experienced both positive and negative effects.
Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma
Authors: Théoleyre S , Mori K , Cherrier B , Passuti N , Gouin F , Rédini F , Heymann D
Published: September 2005

Background

Osteosarcoma is the most common type of primary bone tumor. The use of aggressive chemotherapy has drastically improved the prognosis of the patients with non-metastatic osteosarcomas, however the prognosis of the patients with metastasis is still very poor. Then, new and more effective treatments for curing osteosarcoma, such as immunotherapy are needed. Tumor-infiltrating lymphocytes (TIL) have been involved in the control of tumor development and already assessed with success for the treatment of several cancers including melanoma. While TIL represent a fascinating therapeutic approach in numerous malignant pathologies, there is few report concerning adult bone-associated tumors including osteosarcoma.

Methods

Human TIL were isolated and characterized (phenotype, lytic activity) from twenty-seven patients with bone-associated tumors (osteosarcoma, Ewing's sarcoma, giant cell tumor, chondrosarcoma, plasmocytoma and bone metastases). Similar experiments were performed using rat osteosarcoma model.

Results

While TIL with a main CD4+ profile were easily isolated from most of the tumor samples, only TIL extracted from osteosarcoma were cytotoxic against allogeneic tumor cells. In all cases, TIL lytic activity was significantly higher compared to autologous peripheral blood leukocytes. Similar data were observed in rat osteosarcoma model where TIL were characterized by a main CD4+ profile and high lytic activity against allogeneic and autologous tumor cells. Moreover, rat TIL expansion was not accompanied by refractoriness to further activation stimulus mainly by tumor antigens.

Conclusion

These results demonstrated that TIL therapy could be a very efficient strategy for the treatment of adult osteosarcoma.
Differential expression of MUC genes in endometrial and cervical tissues and tumors
Authors: Hebbar Vidya , Damera Gautam , Sachdev Goverdhan P
Published: September 2005

Background

Mucin glycoprotein's are major components of mucus and are considered an important class of tumor associated antigens. The objective of this study was to investigate the expression of human MUC genes (MUC1, MUC2, MUC5B, MUC5AC and MUC8) in human endometrium and cervix, and to compare and quantitate the expression of MUC genes in normal and cancerous tissues.

Methods

Slot blot techniques were used to study the MUC gene expression and quantitation.

Results

Of the five-mucin genes studied, MUC1, MUC5B and MUC8 showed high expression levels in the normal and cancerous endometrial and cervical tissues, MUC2 and MUC5AC showed considerably lower expression. Statistically, higher levels of MUC1, MUC5B and MUC8 were observed in endometrial adenocarcinomas compared to normal tissues. In contrast, only MUC1 levels increased with no significant changes in expression of MUC5B and MUC8 in cervical tumors over normal cervical tissues.

Conclusion

Endometrial tumors showed increased expression of MUC1, MUC5B and MUC8 over normal tissues. Only MUC1 appears to be increase, in cervical tumors. All the studied tissues showed high and consistent expression of MUC8 mRNA. Low to neglible levels of MUC2 and MUC5AC were observed in all studied endometrial and cervical tissues.
Ethnic variations in orthodontic treatment need in London schoolchildren
Authors: Alkhatib Mhd Nour , Bedi Raman , Foster Claire , Jopanputra Pooja , Allan Sue
Published: September 2005

Background

The study was carried out to determine the prevalence of orthodontic treatment need in children from minority ethnic groups and compare the need to the white population. The second objective was to explore variations in agreement between subjective and objective treatment need in a multiethnic context using the aesthetic component of Orthodontic Treatment Need Index (IOTN AC).

Methods

A cross-sectional study in North West London, 14 schools were randomly selected from the 27 schools in the two boroughs of Harrow and Hillingdon. Comparison between objective and subjective treatment need was carried out using IOTN AC index. Clinical orthodontic treatment need was also recorded using the dental health component of Orthodontic Treatment Need Index (IOTN DHC).

Results

2,788 children were examined and completed the questionnaire. 16% of the study population were already wearing appliances or had finished orthodontic treatment. Of the remaining children; 15% had definite need for treatment using the dental health component of the IOTN. There was no significant variation in the need for orthodontic treatment between different ethnic backgrounds (P > 0.05) whether using the AC or DHC components of the IOTN index. However, poor agreement was detected between professional and subjective assessment of ethnic minority of orthodontic treatment need using IOTN AC index.

Conclusion

Orthodontic treatment need in children of ethnic minorities does not differ significantly from the vast majority of white children. However treatment need based on aesthetic index continues to vary in all ethnic groups from the professional aesthetic assessment
Community concepts of malaria-related illness with and without convulsions in southern Ghana
Authors: Ahorlu Collins K , Koram Kwadwo A , Ahorlu Cynthia , de Savigny Don , Weiss Mitchell G
Published: September 2005

Background

Malaria, both with or without convulsions, is a serious hardship for people living in endemic areas, especially in sub-Saharan Africa. Community references to malaria, however, may encompass other conditions, which was collectively designated malaria-related illness (MRI). Inasmuch as the presence or absence of convulsions reportedly affects timely help-seeking for malaria, a local comparison of these conditions is needed to inform malaria control.

Methods

Vignette-based EMIC interviews (insider-perspective interviews) for MRI with convulsions (convulsion positive, MRI-CP) and without convulsions (convulsion negative, MRI-CN) were developed to study relevant features of MRI-related experience, meaning and behaviour in two rural communities in Ghana. These semi-structured interviews elicited both qualitative narrative and categorical codes for quantitative analysis. Interviews with 201 respondents were conducted.

Results

The conditions depicted in the vignettes were well recognized by respondents and named with various local terms. Both presentations were considered serious, but MRI-CP was more frequently regarded potentially fatal than MRI-CN. More than 90.0% of respondents in both groups acknowledged the need to seek outside help. However, significantly more respondents advised appropriate help-seeking within 24 (p = 0.01) and 48 (p = 0.01) hours for MRI-CP. Over 50.0% of respondents responding to questions about MRI-CP identified MRI-CN as a cause of convulsions.

Conclusion

Local comparison of MRI-CP and MRI-CN based on vignettes found a similar profile of reported categories of perceived causes, patterns of distress, help-seeking and preventive measures for both presentations. This differs from previous findings in sub-Saharan Africa, which assert communities regard the two conditions to be unrelated. The perceived relationships should be acknowledged in formulating strategies to control malaria through timely help-seeking and treatment to reduce childhood mortality.
Atomic force microscopy: a powerful tool for high-resolution imaging of spermatozoa
Authors: Kumar Sunil , Chaudhury Koel , Sen Prasenjit , Guha Sujoy K
Published: September 2005

Atomic force microscopy (AFM) has emerged as the only technique capable of real-time imaging of the surface of a living cell at nano-resolution. Since AFM provides the advantage of directly observing living biological cells in their native environment, this technique has found many applications in pharmacology, biotechnology, microbiology, structural and molecular biology, genetics and other biology-related fields. AFM has also proved to be a valuable tool for reproductive biologists. An exhaustive review on the various applications of AFM to sperm cells is presented. AFM has been extensively applied for determining the structural and topological features of spermatozoa. Unstained, unfixed spermatozoa in their natural physiological surroundings can be imaged by this technique which provides valuable information about the morphological and pathological defects in sperm cells as three-dimensional images with precise topographical details. Sperm head defects and the acrosome at the tip of the head responsible for fertilization, can be examined and correlated with the lack of functional integrity of the cell. Considerable amount of work is reported on the structural details of the highly condensed chromatin in sperm head using AFM. Detailed information on 3D topographical images of spermatozoa acquired by AFM is expected to provide a better understanding of various reproductive pathways which, in turn, can facilitate improved infertility management and/or contraceptive development.
The effect of patient characteristics on variability in pain and function over two years in early knee osteoarthritis
Authors: Paradowski Przemyslaw T , Englund Martin , Lohmander L Stefan , Roos Ewa M
Published: September 2005

Background

Large variations in pain and function are seen over time in subjects at risk for and with radiographic knee osteoarthritis (OA). We hypothesized that this variation may be related not only to knee OA but also to patient characteristics. The objective of this study was to investigate the influence of age, gender, and body mass index (BMI) on clinically relevant change in pain and function over two years in subjects at high risk for or with knee OA.

Methods

We assessed 143 individuals (16% women, mean age 50 years [range 27–83]) twice; 14 and 16 years after isolated meniscectomy. Subjects completed one disease-specific questionnaire, the Knee injury and Osteoarthritis Outcome Score (KOOS) and one generic measure, the SF-36. Individuals with a BMI between 25 and 29.9 were considered overweight, while individuals with a BMI of 30 or more were considered obese.

Results

Subjects aged 46–56 (the middle tertile) were more likely to change (≥10 points on a 0–100 scale) in the KOOS subscale Activities of Daily Living (ADL) than younger subjects (odds ratio [OR] 4.5, 95% confidence interval [95% CI] 1.5–13.0). Essentially the same result was obtained after adjusting for baseline values. Overweight or obesity was a risk factor for clinically relevant change for knee pain (OR 2.4, 95% CI 1.0 – 5.8, OR 4.0, 95% CI 1.2 – 13.6) and obesity for change in ADL (OR 4.3, 95% CI 1.2 – 15.4). The results did not remain significant when adjusted for the respective baseline value. Being symptomatic was strongly associated with increased variation in pain and function while presence or absence of radiographic changes did not influence change over two years in this cohort.

Conclusion

In a population highly enriched in early-stage and established knee OA, symptomatic, middle-aged, and overweight or obese subjects were more likely to vary in their knee function and pain over two years. The natural course of knee pain and function may be associated with subject characteristics such as age and BMI.
Quality of Life determinants in women with breast cancer undergoing treatment with curative intent
Authors: Pandey Manoj , Thomas Bejoy Cherian , SreeRekha Padmakumar , Ramdas Kunnambath , Ratheesan Kuttan , Parameswaran Sankarannair , Mathew Beela S , Rajan Balakrishnan
Published: September 2005

Background

The diagnosis of breast cancer and its subsequent treatment has significant impact on the woman's physical functioning, mental health and her well-being, and thereby causes substantial disruption to quality of life (QOL). Factors like patient education, spousal support and employment status, financial stability etc., have been found to influence QOL in the breast cancer patient. The present study attempts to identify the determinants of QOL in a cohort of Indian breast cancer patients.

Patients and methods

Functional Assessment of Cancer Therapy-Breast (FACT-B) Version 4 Malayalam was used to assess quality of life in 502 breast cancer patients undergoing treatment with curative intent. The data on social, demographic, disease, treatment, and follow-up were collected from case records. Data was analysed using Analysis of Variance (ANOVA) and multinomial logistic regression.

Results

The mean age of the patients was 47.7 years with 44.6% of the women being pre-menopausal. The FACT-B mean score was 90.6 (Standard Deviation [SD] = 18.4). The mean scores of the subscales were – Physical well-being 19.6 (SD = 4.7), Social well-being 19.9 (SD = 5.3), Emotional well-being 14 (SD = 4.9), Functional well-being 13.0 (SD = 5.7), and the Breast subscale 23.8 (SD = 4.4). Younger women (<45 years), women having unmarried children, nodal and/or metastatic disease, and those currently undergoing active treatment showed significantly poorer QOL scores in the univariate analysis. However multivariate analysis indicated that the religion, stage, pain, spouse education, nodal status, and distance travelled to reach the treatment centre as indicative of patient QOL.

Conclusion

QOL derangements are common in breast cancer patients necessitating the provisions for patient access to psychosocial services. However, because of the huge patient load, a screening process to identify those meriting intervention over the general population would be a viable solution.
Effect of rabbit doe-litter separation on 24-hour changes of luteinizing hormone, follicle stimulating hormone and prolactin release in female and male suckling pups
Authors: Cano Pilar , Jiménez-Ortega Vanesa , P Álvarez Maria , Alvariño Mario , Cardinali Daniel P , Esquifino Ana I
Published: September 2005

Background

The daily pattern of nursing of the rabbit pup by the doe is the most important event in the day for the newborn and is neatly anticipated by them. Such anticipation presumably needs a close correlation with changes in hormones that will allow the pups to develop an appropriate behavior. Although a number of circadian functions have been examined in newborn rabbits, there is no information on 24-h pattern of gonadotropin release or on possible sex-related differences in gonadotropin or prolactin (PRL) release of pups. This study examined the 24-h changes of plasma luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) in 11 days old suckling female and male rabbits left with the mother or after short-term (i.e., 48 h) doe-litter separation.

Methods

Animals were kept under controlled light-dark cycles (16 h – 8 h; lights on at 08:00 h). On day 9 post partum, groups of 6–7 female or male rabbit pups were separated from their mothers starting at 6 different time intervals in the 24 h cycle. Pups were killed 48 h after separation. At each time interval groups of male or female pups that stayed with the mother were killed as controls. Plasma, LH, FSH and PRL levels were measured by specific radioimmunoassays.

Results

In pups kept with their mother plasma FSH and LH maxima occurred at the first and second part of the light phase (at 13:00 and 17:00 – 21:00 h, respectively) (females) or as two peaks for each of the hormones (at 13:00 and 01:00 h) (males). PRL release was similar in female and male rabbit pups kept with their mother, showing a 24-h pattern with two peaks, at 13:00 and 01:00 h, respectively. Mean 24-h values of gonadotropins and PRL did not differ between sexes. Isolation of pups for 48 h augmented circulating gonadotropin and PRL levels and distorted hormone 24-h pattern to a similar extent in both sexes.

Conclusion

Significant sex differences in 24-h changes in LH and FSH, but not in PRL, release occurred in rabbit pups kept with the doe. Separation of newborn pups from their mother augmented circulating gonadotropin and PRL levels and disrupted 24-h rhythmicity of gonadotropin and PRL release similarly in both sexes. The effect of pups' isolation can be attributed either to a modification of the circadian pacemaker or to a masking effect on some of its output overt rhythms.
Estrogen regulation of testicular function
Authors: Akingbemi Benson T
Published: September 2005

Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i) localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta) in tissues of the reproductive tract; ii) analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii) investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.
Technical efficiency of public district hospitals and health centres in Ghana: a pilot study
Authors: Osei Daniel , d'Almeida Selassi , George Melvill O , Kirigia Joses M , Mensah Ayayi Omar , Kainyu Lenity H
Published: September 2005

Background

The Government of Ghana has been implementing various health sector reforms (e.g. user fees in public health facilities, decentralization, sector-wide approaches to donor coordination) in a bid to improve efficiency in health care. However, to date, except for the pilot study reported in this paper, no attempt has been made to make an estimate of the efficiency of hospitals and/or health centres in Ghana. The objectives of this study, based on data collected in 2000, were: (i) to estimate the relative technical efficiency (TE) and scale efficiency (SE) of a sample of public hospitals and health centres in Ghana; and (ii) to demonstrate policy implications for health sector policy-makers.

Methods

The Data Envelopment Analysis (DEA) approach was used to estimate the efficiency of 17 district hospitals and 17 health centres. This was an exploratory study.

Results

Eight (47%) hospitals were technically inefficient, with an average TE score of 61% and a standard deviation (STD) of 12%. Ten (59%) hospitals were scale inefficient, manifesting an average SE of 81% (STD = 25%). Out of the 17 health centres, 3 (18%) were technically inefficient, with a mean TE score of 49% (STD = 27%). Eight health centres (47%) were scale inefficient, with an average SE score of 84% (STD = 16%).

Conclusion

This pilot study demonstrated to policy-makers the versatility of DEA in measuring inefficiencies among individual facilities and inputs. There is a need for the Planning and Budgeting Unit of the Ghana Health Services to continually monitor the productivity growth, allocative efficiency and technical efficiency of all its health facilities (hospitals and health centres) in the course of the implementation of health sector reforms.
Data from necropsy studies and in vitro tissue studies lead to a model for allometric scaling of basal metabolic rate
Authors: Painter Page R
Published: September 2005

Background

The basal metabolic rate (BMR) of a mammal of mass M is commonly described by the power function αM

β
where α and β are constants determined by linear regression of the logarithm of BMR on the logarithm of M (i. e., β is the slope and α is the intercept in regression analysis). Since Kleiber's demonstration that, for 13 measurements of BMR, the logarithm of BMR is closely approximated by a straight line with slope 0.75, it has often been assumed that the value of β is exactly 3/4 (Kleiber's law).

Results

For two large collections of BMR data (n = 391 and n = 619 species), the logarithm of BMR is not a linear function of the logarithm of M but is a function with increasing slope as M increases. The increasing slope is explained by a multi-compartment model incorporating three factors: 1) scaling of brain tissue and the tissues that form the surface epithelium of the skin and gastrointestinal tract, 2) scaling of tissues such as muscle that scale approximately proportionally to body mass, and 3) allometric scaling of the metabolic rate per unit cell mass. The model predicts that the scaling exponent for small mammals (body weight < 0.2 kg) should be less than the exponent for large mammals (> 10 kg). For the simplest multi-compartment model, the two-compartment model, predictions are shown to be consistent with results of analysis using regression models that are first-order and second-order polynomials of log(M). The two-compartment model fits BMR data significantly better than Kleiber's law does.

Conclusion

The F test for reduction of variance shows that the simplest multi-compartment allometric model, the two-compartment model, fits BMR data significantly better than Kleiber's law does and explains the upward curvature observed in the BMR.
Mutations affecting cleavage at the p10-capsid protease cleavage site block Rous sarcoma virus replication
Authors: Vana Marcy L , Chen Aiping , Boross Peter , Weber Irene , Colman Dalbinder , Barklis Eric , Leis Jonathan
Published: September 2005

A series of amino acid substitutions (M239F, M239G, P240F, V241G) were placed in the p10-CA protease cleavage site (VVAM*PVVI) to change the rate of cleavage of the junction. The effects of these substitutions on p10-CA cleavage by RSV PR were confirmed by measuring the kinetics of cleavage of model peptide substrates containing the wild type and mutant p10-CA sites. The effects of these substitutions on processing of the Gag polyprotein were determined by labeling Gag transfected COS-1 cells with 35S-Met and -Cys, and immunoprecipitation of Gag and its cleavage products from the media and lysate fractions. All substitutions except M239F caused decreases in detectable Gag processing and subsequent release from cells. Several of the mutants also caused defects in production of the three CA proteins. The p10-CA mutations were subcloned into an RSV proviral vector (RCAN) and introduced into a chick embryo fibroblast cell line (DF-1). All of the mutations except M239F blocked RSV replication. In addition, the effects of the M239F and M239G substitutions on the morphology of released virus particles were examined by electron microscopy. While the M239F particles appeared similar to wild type particles, M239G particles contained cores that were large and misshapen. These results suggest that mutations affecting cleavage at the p10-CA protease cleavage site block RSV replication and can have a negative impact on virus particle morphology.
Ethnopharmacological survey of different uses of seven medicinal plants from Mali, (West Africa) in the regions Doila, Kolokani and Siby
Authors: Togola Adiaratou , Diallo Drissa , Dembélé Seydou , Barsett Hilde , Paulsen Berit Smestad
Published: September 2005

An ethnopharmacological survey was carried out to collect information on the use of seven medicinal plants in rural areas in the nearby regions of Bamako, Mali. The plants were Opilia celtidifolia, Anthocleista djalonensis, Erythrina senegalensis, Heliotropium indicum, Trichilia emetica, Piliostigma thonningii and Cochlospermum tinctorium

About 50 medical indications were reported for the use of these plants in traditional medicine. The most frequent ailments reported were malaria, abdominal pain and dermatitis. The highest number of usages was reported for the treatment of malaria (22%). The majority of the remedies were prepared from freshly collected plant material from the wild and from a single species only. They were mainly taken orally, but some applications were prepared with a mixture of plants or ingredients such as honey, sugar, salt, ginger and pepper. Decoction of the leaves was the main form of preparation (65%) and leaf powder was mostly used for the preparation of infusions (13%). The part of the plants most frequently used was the leaves. There was a high degree of informant consensus for the species and their medicinal indications between the healers interviewed.

The results of this study showed that people are still dependent on medicinal plants in these rural areas of Mali.
Targeted therapy against Bcl-2-related proteins in breast cancer cells
Authors: Emi Manabu , Kim Ryungsa , Tanabe Kazuaki , Uchida Yoko , Toge Tetsuya
Published: September 2005

Introduction

Bcl-2 and Bcl-xL confer resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We examined the relationship between the expression of Bcl-2 and Bcl-xL and chemosensitivity of breast cancer cells, with the aim of developing specific targeted therapy.

Methods

Four human breast cancer cell lines were examined, and the effects of antisense (AS) Bcl-2 and AS Bcl-xL phosphorothioate oligodeoxynucleotides (ODNs) on chemosensitivity were tested in vitro and in vivo. Chemosensitivity was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, and the antitumor effect was assessed in vivo by the success of xenograft transplantation into athymic mice.

Results

Treatment with AS Bcl-2 and Bcl-xL ODNs resulted in a sequence-specific decrease in protein expression, compared with controls. Treatment of BT-474, ZR-75-1, and MDA-MB-231 cells with AS Bcl-2 increased chemosensitivity to doxorubicin (DOX), mitomycin C (MMC), paclitaxel (TXL), and docetaxel (TXT). Transfection of the Bcl-2 gene into MDA-MB-453 cells decreased sensitivity to DOX and MMC. Treatment of MDA-MB-231, BT-474, and ZR-75-1 cells with AS Bcl-xL increased chemosensitivity to DOX, MMC and taxanes to a smaller extent than AS Bcl-2. This occurred in the setting of increased Bax and cleaved poly(ADP-ribose) polymerase, as well as decreased Bcl-2 and pAkt. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, which was attenuated by methylation of the CpG motifs of AS Bcl-2; however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Bcl-2 and Bcl-xL, to a smaller extent, are major determinants of chemosensitivity in breast cancer cells.

Conclusion

Targeted therapy against Bcl-2 protein with the use of AS ODNs might enhance the effects of chemotherapy in patients with breast cancer.
Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials
Authors: Rubinstein Lawrence V. , Korn Edward L. , Freidlin Boris , Hunsberger Sally , Ivy S. Percy , Smith Malcolm A.
Published: September 2005

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.
Pretreatment Quality of Life and Functional Status Assessment Significantly Predict Survival of Elderly Patients With Advanced Non—Small-Cell Lung Cancer Receiving Chemotherapy: A Prognostic Analysis of the Multicenter Italian Lung Cancer in the Elderly Study
Authors: Maione Paolo , Perrone Francesco , Gallo Ciro , Manzione Luigi , Piantedosi FrancoVito , Barbera Santi , Cigolari Silvio , Rosetti Francesco , Piazza Elena , Robbiati Sergio Federico , Bertetto Oscar , Novello Silvia , Migliorino Maria Rita , Favaretto Adolfo , Spatafora Mario , Ferraù Francesco , Frontini Luciano , Bearz Alessandra , Repetto Lazzaro , Gridelli Cesare
Published: September 2005

Purpose

To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non—small-cell lung cancer treated with chemotherapy.

Patients and Methods

Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm.

Results

Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival.

Conclusions

Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non—small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.
Darbepoetin Alfa for the Treatment of Chemotherapy-Induced Anemia: Disease Progression and Survival Analysis From Four Randomized, Double-Blind, Placebo-Controlled Trials
Authors: Hedenus Michael , Vansteenkiste Johan , Kotasek Dusan , Austin Matthew , Amado Rafael G.
Published: September 2005

Purpose

To determine the effect of darbepoetin alfa (DA) on progression-free survival (PFS) and overall survival (OS) in patients with chemotherapy-induced anemia (CIA).

Patients and Methods

Two 16-week randomized, double-blind, placebo-controlled phase III studies of weekly DA in anemic patients with lung cancer (n = 314) or lymphoproliferative malignancies (LPMs; n = 344) undergoing chemotherapy were analyzed with prospectively defined long-term PFS and OS end points. Short-term effects of DA on PFS and OS were analyzed by including two additional 16-week dose-finding, double-blind, placebo-controlled studies in anemic patients with multiple tumor types (n = 405) and LPMs (n = 66).

Results

Median follow-up is 15.8 months (lung cancer) and 32.6 months (LPM). Median duration of PFS was comparable between DA and placebo: 5.1 months (95% CI, 4.1 to 6.9 months) versus 4.4 months (95% CI, 3.7 to 5.3 months) for lung cancer and 14.2 months (95% CI, 12.2 to 17.5 months) versus 15.9 months (95% CI, 13.1 to 19.0 months) for LPMs. The estimated hazard ratio (HR) of death related to DA use for lung cancer was 0.77 (95% CI, 0.59 to 1.01) and 1.26 (95% CI, 0.92 to 1.71) for LPMs. In the pooled analyses of all four studies (n = 1,129), no differences in PFS or OS were observed between DA and placebo (HR = 0.92; 95% CI, 0.78 to 1.07; and HR = 0.95; 95% CI, 0.78 to 1.16, respectively).

Conclusion

Treatment with DA does not seem to influence PFS or OS in patients with CIA. Prospective, randomized clinical trials will provide additional insights into the effects of DA on PFS and OS in specific tumor types.
Phase II to III Study Comparing Doxorubicin and Docetaxel With Fluorouracil, Doxorubicin, and Cyclophosphamide As First-Line Chemotherapy in Patients With Metastatic Breast Cancer: Results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre
Authors: Bontenbal Marijke , Creemers Geert-Jan , Braun Hans J. , de Boer Auke C. , Janssen Jos Th. , Leys Rieneke B. , Ruit Jan B. , Goey Swan Hoo , van der Velden Paul C. , Kerkhofs Leon G. , Schothorst Kristel L. , Schmitz Paul I. , Bokma Hansje J. , Verweij Jaap , Seynaeve Caroline
Published: September 2005

Purpose

To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC).

Patients and Methods

Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m2 and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks.

Results

A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively.

Conclusion

In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.
Phase I Trial of Temozolomide Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma
Authors: Quinn Jennifer A. , Desjardins Annick , Weingart Jon , Brem Henry , Dolan M. Eileen , Delaney Shannon M. , Vredenburgh James , Rich Jeremy , Friedman Allan H. , Reardon David A. , Sampson John H. , Pegg Anthony E. , Moschel Robert C. , Birch Robert , McLendon Roger E. , Provenzale James M. , Gururangan Sridharan , Dancey Janet E. , Maxwell Jill , Tourt-Uhlig Sandra , Herndon James E. , Bigner Darell D. , Friedman Henry S.
Published: September 2005

Purpose

We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG.

Patients and Methods

For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined.

Results

The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression.

Conclusion

This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.
Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens
Authors: Zia Mohammad I. , Siu Lillian L. , Pond Greg R. , Chen Eric X.
Published: September 2005

Purpose

To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies.

Methods

We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies.

Results

Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were “positive.” The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for “positive” phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083).

Conclusion

Promising results from phase II studies frequently do not translate into “positive” phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.
Proliferation Marker Ki-67 in Early Breast Cancer
Authors: Urruticoechea Ander , Smith Ian E. , Dowsett Mitch
Published: September 2005

Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer. Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67. The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake. High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios. However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs.
Prognostic Value of Extracapsular Tumor Spread for Locoregional Control in Premenopausal Patients With Node-Positive Breast Cancer Treated With Classical Cyclophosphamide, Methotrexate, and Fluorouracil: Long-Term Observations From International Breast Cancer Study Group Trial VI
Authors: Gruber Günther , Bonetti Marco , Nasi M. Laura , Price Karen N. , Castiglione-Gertsch Monica , Rudenstam Carl-Magnus , Holmberg Stig B. , Lindtner Jurij , Golouh Rastko , Collins John , Crivellari Diana , Carbone Antonino , Thürlimann Beat , Simoncini Edda , Fey Martin F. , Gelber Richard D. , Coates Alan S. , Goldhirsch Aron
Published: September 2005

Purpose

We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive lymph nodes (LN1-3+).

Patients and Methods

We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of “classical” CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years.

Results

In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate ± distant failure (LRF ± distant failure) within 10 years was estimated at 19% (± 2%) without ECS, versus 27% (± 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy.

Conclusion

Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.