bluuebunny/crossref_metadata_2025 huggingface dataset:
Age Differences in the Heritability of Mean and Intraindividual Variation of Psychological Distress
Authors: Neiss Michelle , Almeida David M.
Published: December 2003

Background: An important question in the study of intraindividual variability is whether the same explanatory mechanisms govern between person variation and within person variation. Objective: This paper investigates genetic and environmental influences on affect across varying time frames and genetic and environmental influences on within person variation in affect. Methods: Twin participants aged 25–74 years provided information on their affective experiences over monthly, weekly, and daily recall periods. Questionnaires and daily telephone interviews were used to assess frequency of negative emotions. Results: Monthly, weekly, and daily reports of negative affect all showed modest genetic influence. Monthly and daily measures also demonstrated modest shared environmental influence. Sibling resemblance in within-person variation in affect was accounted for entirely by shared environment. Tests for age differences in magnitude of genetic and environmental effects revealed that genetic influences on monthly reports of affect were greater among older adults, but genetic influences on daily affective experiences were lower among older adults. Conclusions: Lowered heritability in daily affect among older adults contradicts standard behavior genetic expectations, and is consistent with the proposition that older adults gain skills in emotion regulation.
Aging and Attenuated Processing Robustness
Authors: Li Shu-Chen , Huxhold Oliver , Schmiedek Florian
Published: December 2003

Background: Within-person, across-time variations in processes and performance are intrinsic to all aspects of human functioning. Objective: This article starts with a brief taxonomy of intraindividual dynamics. There are adaptive as well as non-adaptive types of intraindividual variations that unfold with different degrees of reversibility on different time scales and involve either single, or systems of, functions. Methods: Empirical findings regarding aging and a specific type of intraindividual variation, namely attenuated processing robustness, are then presented with respect to cognitive and sensorimotor functioning. Results: In both domains of functioning, old adults exhibit less robust functioning with a greater amount of week-to-week, day-to-day, or trial-by-trial fluctuations in their cognitive, walking, and postural control performances. Conclusion: Currently, the causes for the attenuation of processing robustness in cognitive and sensorimotor functioning are not well understood. Neurocomputational models are useful tools for exploring the tripartite relationships between the aging of neural information-processing fidelity, and cognitive, and sensorimotor processes.
Gender Differences in Level and Change in Cognitive Functioning
Authors: Aartsen Marja J. , Martin Mike , Zimprich Daniel
Published: December 2003

Background: Gender differences in level of cognitive functioning are frequently observed, but little is known about gender differences in rate of decline of cognitive functioning. Objective: The present study aims to describe variability between and within men and women specified for four different cognitive abilities at baseline, and variability in change in these abilities among men and women over 6 years. Methods: We started with a study sample of 1,132 men and 1,175 women, with a measurement interval of 3 years. At wave 3 of the study, 1,552 of the respondents from wave 1 were still present. Differences in level and rate of change were estimated with latent change models. Results: Women have higher levels of memory functioning then men, but no gender differences were observed for speed or non-verbal reasoning changes. Conclusion: In spite of evidence for a stronger age-related atrophy of the brain structure of men, no gender differences in decline of cognitive functions could be observed.
MMSE Cross-Domain Variability Predicts Cognitive Decline in Centenarians
Authors: Kliegel Matthias , Sliwinski Martin
Published: December 2003

Background: Early detection of dementia is one of the key issues in cognitive gerontology. However, so far the detection of early stages in cognitive decline has been rather unreliable. One central limitation of current assessment strategies is that they rely on information about a person’s level of performance obtained from a single assessment. Objective: In the first part of the present paper, we propose three strategies for overcoming this limitation by using information from several measurement occasions to improve diagnostic reliability. Methods: In the second part, we present one exemplary empirical analysis of one of these approaches reporting data from the Heidelberg Centenarian Study. Results: In this sample of very old individuals tested at baseline and at a follow-up 18 months later, the intra-individual cross-domain variability across MMSE subscales [1]at baseline predicted cognitive decline (i.e. change in an external cognitive functioning rating from baseline to follow-up) much better than baseline mean MMSE scores. Conclusions: In conclusion, we discuss the advantage of performance varibility as a predictor for cognitive decline.
Escitalopram: Superior to Citalopram or a Chiral Chimera?
Authors: Svensson Staffan , Mansfield Peter R.
Published: December 2003

Background: Escitalopram is the active isomer of the antidepressant citalopram. In theory single-isomer drugs may be superior but few have been found to have clinically significant advantages. The manufacturer claims that escitalopram has more efficacy and a faster onset of effect than citalopram. The purpose of this study was to assess how far these claims are justified. Methods: Relevant trial reports were requested from H. Lundbeck A/S and the Swedish drug regulatory authority. The trials consisted of a pooled analysis of 1,321 patients from one unpublished, one partly published and one published eight-week trial, as well as a 24-week trial with 357 patients published as a poster. The studies compared escitalopram with placebo and/or citalopram in outpatients aged ≧18 years who met specified criteria for depression. The trials’ quality was assessed with Moncrieff et al.’s quality assessment instrument and the results compared with the claims from the advertisements. Results: The advertising claims are not justified because they are based on secondary outcomes, non-intention-to-treat analyses and arbitrarily defined subgroups. The subgroup results are inconsistent. Methodological flaws in the trials could account for the differences found. Even if the differences claimed were real they appear too small to justify higher prices. Conclusions: On the evidence available to us the manufacturer’s claims of superiority for escitalopram over citalopram are unwarranted. The Swedish and Danish drug regulatory authorities reached similar conclusions. This highlights the need for wider dissemination of national authorities’ statements to other countries affected by the European Union’s mutual recognition procedure.
A Randomized Clinical Trial of the Treatment Effects of Massage Compared to Relaxation Tape Recordings on Diffuse Long-Term Pain
Authors: Hasson Dan , Arnetz Bengt , Jelveus Lena , Edelstam Bo
Published: December 2003

Background: Long-term musculoskeletal pain is a common problem in primary health care settings that is difficult to treat. Two common treatments are mental relaxation and massage. Scientific studies show contradictory results. Furthermore, many studies lack long-term follow-up even though it is a chronic disorder. The purpose of this randomized clinical trial was to assess possible effects of massage as compared to listening to relaxation tapes in conditions of ‘diffuse’ and long-term musculoskeletal pain. Methods: 129 patients from primary health care suffering from long-term musculoskeletal pain were randomized to either a massage or mental relaxation group, and assessed before, during and after treatment. Results: During treatment there was a significant improvement in the three main outcome measures: self-rated health, mental energy, and muscle pain only in the massage group as compared to the relaxation group. However, at the 3-month post-treatment follow-up, there was a significant worsening in the outcome measures (time × group effect p < 0.05) back to initial rating levels in the massage group as compared to no changes in the relaxation group. Conclusion: Massage, but not mental relaxation, is beneficial in attenuating diffuse musculoskeletal symptoms. Beneficial effects were registered only during treatment. This lack of long-term benefits could be due to the short treatment period or treatments such as these do not address the underlying causes of pain. Future studies of long-term pain should include longer treatment periods and post-treatment follow-up. It might also be worthwhile assessing the long-term benefits from booster treatment after the initial intense treatment period.
A Method for Rating Charts to Identify and Classify Patients with Medically Unexplained Symptoms
Authors: Smith Robert C. , Korban Elie , Kanj Mohammed , Haddad Robert , Lyles Judith S. , Lein Catherine , Gardiner Joseph C. , Hodges Annemarie , Dwamena Francesca C. , Coffey John , Collins Clare
Published: December 2003

Background: As part of conducting a randomized control trial (RCT) to treat chronically high utilizing patients with medically unexplained symptoms (MUS), we developed the chart rating method reported here to identify and classify MUS subjects. Method: Intended at this point only as a research tool, the method is comprehensive, uses explicit guidelines, and requires clinician raters. It distinguishes primary organic disease patients from those with primary MUS, quantifies medical comorbidities in primary MUS patients, and also distinguishes subgroups among MUS patients that we call somatization (resembles DSM-IV somatoform disorders) and minor acute illness (MAI) which differs from DSM-IV somatoform definitions. Scoring rules are used to generate the diagnoses above. The rules may be set according to the investigator’s needs, from highly sensitive to highly specific. Results: We found high levels of agreement with the gold standard for MUS vs. organic disease (97.6%) and among raters for the key individual chart elements rated (92–96%). The method identified 206 MUS subjects and the extent of their medical comorbidities for entry into a RCT. It also identified somatization and MAI; the latter supports the validity of this newly reported MAI syndrome. Conclusion: We concluded that this method offered research potential for identifying MUS patients, for quantifying their medical comorbidities, and for classifying MUS subgroups.
Coping Strategies of Women with Breast Cancer: A Comparison of Patients with Healthy and Benign Controls
Authors: Anagnostopoulos Fotios , Vaslamatzis Gregoris , Markidis Marios
Published: December 2003

Background: Cancer has an enormous impact on the patient, triggering fears of suffering, disability and death. Still, little research has been published which investigates the coping strategies adopted by cancer patients, when attempting to deal with their serious health threat. Moreover, it is often not clarified whether the selected coping strategies are used exclusively by cancer patients, or whether other groups of women facing benign breast diseases or having health worries regarding their breasts share similar coping strategies. This study attempts to identify those coping strategies that distinguish breast cancer patients from non-malignant controls. Methods: A sample of 180 breast cancer patients was assessed on how it coped with health threats. The control group was composed of 268 women who were diagnosed as having either a benign disease or were disease free. The Ways of Coping Questionnaire was administered in order to record the frequency of the coping strategies used under the health conditions. Univariate analyses were conducted to compare mean scores in coping strategies among the diagnostic groups. Multivariate analyses were performed to identify those variables that distinguish one group from the other. Results: Compared with women with benign breast disease and those who were disease free, breast cancer patients significantly infrequently exhibited attributions of blame to self, whereas they did not differ from controls in other ways of coping such as self-isolation, passive acceptance, seeking social support, problem-focused coping, positive reappraisal, distancing, and wishful thinking. Conclusion: Our results may suggest that under the conditions of a cancer diagnosis, patients do not tend to assign responsibility on themselves and their character, since they possibly need to avoid guilt, low self-esteem, and social distance, and to maintain a potential to invest in the adjustment process.
A Self-Administered Version of a Brief Measure of Suffering: First Aspects of Validity
Authors: Rumpf Hans-Jürgen , Löntz Werner , Uesseler Susanne
Published: December 2003

Background: Measuring the impact of illness is important for several reasons. Recently, a new instrument was introduced using a pictorial approach in measuring the perception of suffering caused by illness: the Pictorial Representation of Illness Measure (PRISM). The aim of the present study was to introduce a self-administered version of PRISM and to provide some first data on its validity. Method: A postal survey was conducted in subjects with the chronic depigmentation disorder vitiligo. Participants were members of the German vitiligo association. The response rate was 60.6%. Data of 333 respondents completing the PRISM were used for analysis. Besides illness-related measures, psychological variables were assessed with the following instruments: Satisfaction with Life Scale (SWLS), five-item version of the Mental Health Inventory, adaptation of the Skindex-29, a quality-of-life measure for skin diseases. Results: Only 2.9% did not fill in the PRISM. Self-illness separation correlated as predicted with some illness-related variables. The distance was significantly larger in subjects whose depigmentation was no longer spreading. Significant correlations were also found with mental health (0.50), satisfaction with life (–0.28), perceived impairment of outward appearance (–0.65), and the Skindex subscales ‘emotions’ (–0.66) and ‘functioning’ (–0.67). Conclusion: Data suggest that PRISM can be self-administered. Measures of convergent validity confirm the usefulness of the new measure.
PRISM: Enmeshment of Illness and Self-Schema
Authors: Denton Fiona , Sharpe Louise , Schrieber Leslie
Published: December 2003

Background: The Pictorial Representation of Illness and Self Measure (PRISM) is a recently developed tool purported to assess burden of suffering due to illness. The nature of the PRISM task suggests a conceptual link to the illness self-schema construct hypothesised to be present in some individuals with chronic illness. This study investigates the relationship between PRISM and schema as measured by cognitive bias. Methods: 43 patients with systemic lupus erythematosus (SLE) completed an information-processing task involving endorsement of positive and negative illness words as descriptors of themselves, followed by free recall of the words. The outcome measures were endorsement and recall bias for negative illness words. Patients also completed the PRISM task and were assessed on other physical and psychological variables. Results: PRISM did not correlate significantly with age, depression, functional impairment or disease activity. In a multiple regression analysis, only recall bias made an independent contribution to PRISM. Conclusions: Illness self-schema appears to play a significant role in determining the way in which SLE patients complete the PRISM task. This is discussed in light of a schema enmeshment model recently proposed in the cognitive bias literature.
Neuroendocrinology of Neurodegenerative Diseases
Authors: González de Aguilar Jose-Luis , René Frédérique , Dupuis Luc , Loeffler Jean-Philippe
Published: December 2003

The nervous system plays a key role in the regulation of neuroendocrine axes and, in turn, the released neurohormones modulate the activity of different brain regions. Neurodegenerative diseases, which are known to affect specific neuronal populations, may provoke neuroendocrine dysfunctions that alter the intimate relationship between both systems. In addition, these modifications may influence the progression of the neurodegenerative process. In the present review, we summarise some of the endocrine changes characterising three major neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Special attention is focused on the contribution of disease transgenic models to elucidate such alterations.
Brain Renin-Angiotensin System
Authors: Baltatu Ovidiu , Bader Michael
Published: December 2003

The existence of a brain renin-angiotensin system (RAS) was postulated 30 years ago. Since then our knowledge on the biology of the brain RAS has advanced considerably. The brain RAS has been found to be involved in the modulation of cardiovascular and fluid-electrolyte homeostasis, generally complementing the classical roles of the endocrine RAS. The RAS has additionally been implicated in other brain-specific functions, such as memory, cognition and stress. During the last years, the development of transgenic technologies allowed to get further insight into the functionality and relevance of the brain RAS. This paper is attempting to summarize our recent experience from transgenic animals.
Role of K+ Channels in Frequency Regulation of Spontaneous Action Potentials in Rat Pituitary GH3 Cells
Authors: Lee Suk-Ho , Lee Eun Hae , Ryu Shin Young , Rhim Hyewhon , Baek Hye-Jung , Lim Wonil , Ho Won-Kyung
Published: December 2003

The frequency of spontaneous action potentials (SAP) is important in the regulation of hormone secretion. The decrease in K+ conductance is known as a primary mechanism for increasing SAP frequency. To investigate the nature of K+ channels that contribute to the frequency regulation of the SAP in rat clonal pituitary GH3 cells, the effect of various K+ channel blockers on the SAP and membrane currents were recorded using the patch-clamp technique. A classical inward rectifying K+ channel blocker, Cs+ (5 mM), caused an increase in firing frequency and depolarization in after-hyperpolarization (AHP) voltage. An ether-a-go-go(erg) type K+ channel blocker, E-4031 (5 µM), caused no significant effect on the SAP. Tetraethylammonium (TEA, 10 mM) decreased firing frequency and increased the duration of SAP. These effects were not changed by the presence of high concentration of Ca2+ buffer (10 mM EGTA or BAPTA) in pipette solutions. In voltage-clamp experiments, Cs+ and E-4031 did not affect outwardly rectifying K+ currents, but significantly inhibited inwardly rectifying K+ currents recorded in isotonic K+ solution. However, the kinetics of Cs+-sensitive current and E-4031-sensitive current were distinctive: the time to peak was more immediate and the decay rate was slower in Cs+-sensitive current than in E-4031-sensitive current. These results imply that Cs+ and E-4031 inhibit the distinct components of inwardly rectifying K+ currents, and that the contribution of the Cs+-sensitive current can be immediate on repolarization and can last more effectively over pacemaking potential range than E-4031-sensitive current.
Modulatory Effects of Leptin on Leydig Cell Function of Normal and Hyperleptinemic Rats
Authors: Giovambattista Andrés , Suescun María O. , Nessralla Claudio C.D.L. , França Luiz R. , Spinedi Eduardo , Calandra Ricardo S.
Published: December 2003

Neonatal L-monosodium glutamate (MSG) administration in rats induces several neuroendocrine and metabolic disruptions. Leptin, the adipocyte product, modulates several neuroendocrine systems including the hypothalamic-pituitary-gonadal (HPG) axis in mammals. The aim of the present study was to determine whether MSG-induced chronic hyperleptinemia could play any relevant role in the hypogonadism developed by male rats when examined in adulthood. We found that 120-day-old MSG male rats displayed significant hyperleptinemia, hypogonadism, and undisturbed basic testis structure and spermatogenesis. In vitro studies in purified Leydig cells from normal (CTR) and MSG-damaged rats revealed that basal and human chorionic gonadotropin (hCG)-stimulated 17-hydroxy-progesterone (17-HO-P4), Δ4-androstenedione (Δ4A) and testosterone (T) secretions were significantly lower in MSG than in CTR cells. Exposure to murine leptin (mleptin, 10–8M) significantly inhibited hCG-elicited T secretion by CTR cells after 180 min incubation. While mleptin significantly inhibited hCG-stimulated Δ4A output and the Δ4A:17-OH-P4 ratio of secretion, conversely, it failed to modify the ratio T:Δ4A release by CTR Leydig cells. Interestingly, the effects of mleptin found on CTR Leydig cells were absent in MSG Leydig cells. Finally, endogenous hyperleptinemia was associated with a significant decrease in Leydig cell expression of Ob-Rb mRNA in MSG rats. In summary, this study demonstrates that: (1) mleptin inhibited testicular steroidogenesis in CTR rats; (2) MSG-treated rats showed lower in vitro 17-OH-P4, Δ4A and T production under basal and post-hCG stimulation conditions; (3) purified Leydig cells from MSG-treated rats displayed resistance to the inhibitory action of mleptin on T release, and (4) endogenous leptin exerts a modulatory effect on Leydig cell Ob-Rb mRNA expression. The inhibitory effect of leptin on testicular function is thus abrogated in MSG-damaged rats. The testicular leptin-resistance developed by MSG rats seems to be due to early chronic exposure of Leydig cells to high leptin circulating levels, which in turn down-regulate testicular Ob-Rb expression. It remains to be determined whether the testicular dysfunction of MSG rats can be reversed after correction of hyperleptinemia or whether it is an irreversible effect of the hypothalamic lesion.
Effect of Dihydrotestosterone on Pituitary Follicle-Stimulating Hormone Isoforms in Adult Male Rats Treated with a Gonadotropin-Releasing Hormone Antagonist
Authors: Rulli Susana B. , Zitta Karina , Calandra Ricardo S. , Campo Stella
Published: December 2003

The effect of androgens on the oligosaccharide structure of follicle-stimulating hormone (FSH) isoforms was studied in adult male rats treated with a potent gonadotropin-releasing hormone (GnRH) antagonist. Animals were castrated (Cx), and 24 h later were treated with physiological doses of either testosterone propionate (T) or dihydrotestosterone propionate (DHT) (0.25 mg/rat in corn oil, daily, s.c.) for 7 days. The antiandrogen flutamide (F; 5 mg/day/rat, twice a day, s.c.) was administered to either Cx-T or Cx-DHT rats to block androgen action. The GnRH antagonist Org 30276 (Ant; 1 mg/kg/day, s.c.) was injected to both Cx- and Cx-DHT treated rats. FSH serum levels reached normal values in Cx rats treated with either T or DHT, whereas those treated with F retained Cx conditions. Both Cx-Ant and Cx-Ant-DHT treated animals presented normal serum FSH levels. Concanavalin A affinity chromatography was used to isolate pituitary FSH isoforms according to their carbohydrate inner structure. An increased proportion of FSH isoforms bearing complex-type oligosaccharides was observed in Cx rats treated with T or DHT, whereas the proportion of these isoforms was reduced in Cx and Cx-T-F or Cx-DHT-F rats. These results demonstrate that functional androgens are needed to complete the oligosaccharide processing of FSH. In addition, the proportion of the different pituitary FSH isoforms after DHT replacement was equivalent to that found when GnRH action was blocked, indicating that androgens are involved in the regulation of carbohydrate incorporation to the FSH molecule by acting mainly at the pituitary level, independently of GnRH action.
Recurrence Rate and Prognosis of Patients with Hepatocellular Carcinoma That Developed after Elimination of Hepatitis C Virus RNA by Interferon Therapy
Authors: Ikeda Kenji , Kobayashi Masahiro , Saitoh Satoshi , Someya Takashi , Hosaka Tetsuya , Akuta Norio , Suzuki Fumitaka , Tsubota Akihito , Suzuki Yoshiyuki , Arase Yasuji , Kumada Hiromitsu
Published: December 2003

Background: Although hepatocellular carcinoma does develop after sustained response to interferon (IFN) in patients with chronic hepatitis C, details on the clinical prognosis have not been elucidated yet. Patients and Methods: Among 12 patients with liver cancer arising after hepatitis C virus (HCV) elimination, 10 patients with potentially curative ablation were prospectively analyzed. Matched control patients were chosen from a patient list of surgical resection on the basis of age, sex, cancer stage, and severity of liver disease. Control patients were recruited with a ratio of 1:4, and all the control patients had positive HCV-RNA. Results: One (10.0%) of 10 patients with virus elimination and 31 (77.5%) of 40 control patients eventually developed cancer recurrence during the same follow-up period. Cancer recurrence rates of the 10 cases and 40 controls were 10.0 and 55.3% at the 3rd year, and 10.0 and 72.2% at the 5th year, respectively. The recurrence rate in the 10 cases of virus elimination was significantly lower than that of control patients (p = 0.012). Conclusion: Although hepatocellular carcinogenesis after elimination of HCV-RNA by IFN treatment did rarely occur, the recurrence rate after radical therapy was significantly lower than that of untreated or non-responsive patients.
Effective Combination Chemotherapy with Bimonthly Docetaxel and Cisplatin with or without Hematopoietic Growth Factor Support in Patients with Advanced Gastroesophageal Cancer
Authors: Schüll Birgit , Kornek Gabriela V. , Schmid Katharina , Raderer Markus , Hejna Michael , Lenauer Alfred , Depisch Dieter , Lang Fritz , Scheithauer Werner
Published: December 2003

Purpose: A phase II trial was performed to determine the antitumor efficacy and tolerance of combined docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer. Patients and Methods: Thirty-seven patients with histologically confirmed metastatic gastroesophageal cancer were entered in this trial. Treatment consisted of 4-weekly courses of docetaxel 50 mg/m2 and cisplatin 50 mg/m2 both given on day 1 and 15. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1,000–2,000/µl), a 5-day course of human granulocyte colony-stimulating factor (G-CSF) 5 µg/kg/day was given subcutaneously; in addition, if hemoglobin was <12.0 mg/dl, erythropoietin 10,000 IU was administered subcutaneously 3 times per week. Results: The confirmed overall response rate (intent-to-treat) was 46%, including 4 complete responses (11%) and 13 partial responses (35%). Eleven patients (30%) had stable disease and 9 (24%) progressed while on treatment. The median time to response was 3 months, the median time to progression was 7 months and the median overall survival time was 11.5 months with 16 (43%) patients currently alive. Hematologic toxicity was common, though WHO grade 4 neutropenia occurred only in 3 patients. Nonhematologic adverse reaction were usually mild to moderate; grade 3 toxicities included alopecia in 5 patients (14%), infection in 1 (3%), neutrotoxicity in 2 (5%) and anaphylaxis in 1 patient. Conclusion: Our data suggest that the combination of docetaxel and cisplatin with or without G-CSF and/or erythropoietin has a promising therapeutic index in patients with advanced gastroesophageal cancer.
Phase II Trial of Weekly Paclitaxel in Previously Untreated Advanced Non-Small-Cell Lung Cancer
Authors: Yasuda Kazuhito , Igishi Tadashi , Kawasaki Yuji , Yamamoto Mitsunobu , Kato Kazuhiro , Matsumoto Shingo , Kotani Masahiro , Sako Takanori , Shigeoka Yasushi , Sugitani Akinori , Histuda Yutaka , Shimizu Eiji
Published: December 2003

Objective: New effective therapy is desirable for outpatients with advanced non-small-cell lung cancer (NSCLC). Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for chemotherapy-naive NSCLC. Methods: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and no prior therapy were enrolled. We administered weekly infusions of 80 mg/m2 paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, we treated each patient for a minimum of four cycles. Results: Of 35 patients enrolled, 17 patients achieved partial response, although no complete responses were observed (response rate 49%; 95% confidence interval 32–66%). The median survival time was 55 weeks (range 6–93 weeks). Grade 3 or 4 leukopenia occurred in only 1 patient (3%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2, 26 and 3%, respectively). Serious toxicity, observed in 2 patients (6%), was interstitial pneumonia, and 1 patient died from sequela. Conclusion: Low-dose weekly paclitaxel is a promising therapy for advanced NSCLC with high effectiveness and low toxicity.
Changes in the Activation and Reconstitution of Lymphocytes Resulting from Total-Body Irradiation Correlate with Slowed Tumor Growth
Authors: Miller Glen M. , Kim Dong W. , Andres Melba L. , Green Lora M. , Gridley Daila S.
Published: December 2003

Alterations in cytokine secretion, activation marker expression, and immune cell concentrations were investigated at sequential time points following delivery of total-body irradiation (TBI) to C57BL/6 mice (n = 64) in the Lewis lung tumor model. Significantly slower tumor growth was observed when a 3-Gy dose of TBI was administered 2 h prior to tumor implantation (p < 0.05). The antitumor effect was correlated with an increased CD4:CD8 T cell ratio and heightened leukocyte blastogenesis. TBI was also found to induce an expansion of natural killer (NK) cells in the blood and spleen of tumor-bearing animals 10 days after irradiation (2.8 × 106 NK cells/spleen in test mice compared to 8.9 × 105 NK cells/spleen in normal control animals). However, no significant differences were found in NK cell levels within the tumor tissue. Enhanced production of interleukin (IL)-12 and IL-18 from spleen supernatants was consistent with an augmentation of the NK cell response. Significant reductions in transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor, both of which are associated with immune suppression, were also noted. Furthermore, TBI induced changes in expression of CD25 and CD71 activation markers, suggesting that radiation may alter tumor surveillance. Taken together, the relative percentages and activation status of immune cell compartments support the conclusion that these TBI-induced changes function to slow tumor progression.
Low-Dose Thalidomide Treatment for Advanced Hepatocellular Carcinoma
Authors: Hsu Chiun , Chen Chiung-Nien , Chen Li-Tzong , Wu Chen-Yao , Yang Pei-Ming , Lai Ming-Yang , Lee Po-Huang , Cheng Ann-Lii
Published: December 2003

Objective: To analyze the efficacy of oral thalidomide in the treatment of advanced hepatocellular carcinoma (HCC). Methods: Sixty-eight patients with unresectable and nonembolizable HCC were consecutively enrolled in a compassionate treatment program of oral thalidomide. Tumor response and treatment-related toxicity were prospectively followed. Thalidomide was given at a starting dose of 200 mg per day. The dose was gradually escalated in 100-mg steps up to 600 mg per day if no limiting toxicities developed. Results: Sixty-three patients were evaluable for response. One complete and 3 partial responses, defined by World Health Organization criteria, were seen, with a response rate of 6.3% (95% CI 0–12.5). The duration of response was 50+, 24.6, 11.6+ and 8.7+ weeks, respectively. All 4 responders had a dramatic decrease in α-fetoprotein (α-FP) levels. Another 6 of the 42 patients with elevated α-FP levels before treatment had a more than 50% decrease in their α-FP levels after thalidomide treatment. Totally 10 patients had an objective response to thalidomide. The median overall survival for all of the 68 patients was 18.7 weeks (95% CI 11.8– 25.6) with a 1-year survival rate of 27.6%. The median overall survival of the 10 patients with an objective response to thalidomide was 62.4 weeks (95% CI 31.2–93.6 weeks). All responders responded at a dose equal to or less than 300 mg per day. Toxicities of thalidomide were generally manageable, and only 16, 6, and 0 patients developed grade 2, 3, and 4 toxicities, respectively. Conclusion: Low-dose thalidomide is safe and induces unequivocal tumor response in a minority of patients with advanced HCC.
Prevention of Intrahepatic Metastasis by Curcumin in an Orthotopic Implantation Model
Authors: Ohashi Yasukata , Tsuchiya Yasunori , Koizumi Keiichi , Sakurai Hiroaki , Saiki Ikuo
Published: December 2003

Curcumin has been shown to have potent anti-metastatic activity, however, its mechanism of action is still unclear. Here, we analyzed the anti-metastatic mechanism using hepatocellular carcinoma, CBO140C12 cells. Daily oral administration of curcumin suppressed intrahepatic metastasis in a dose-dependent manner, whereas the growth of implanted tumors was not affected. We next examined the effect of curcumin on several metastatic properties in vitro. Curcumin inhibited the invasion of tumor cells through Matrigel-coated filters and the production of MMP-9. In addition, curcumin significantly inhibited adhesion and haptotactic migration to fibronectin and laminin without affecting the expression of integrins on the cell surface. Furthermore, the formation of actin stress fibers was affected by treatment with curcumin. These results suggested that curcumin suppressed the intrahepatic metastasis mediated by the inhibiton of several metastatic properties, in which the functional alteration of cytoskeletal organization, at least in part, could play an important role.
Anaplastic Oligodendrogliomas: Prognostic Factors for Tumor Recurrence and Survival
Authors: Puduvalli Vinay K. , Hashmi Masood , McAllister Leslie D. , Levin Victor A. , Hess Kenneth R. , Prados Michael , Jaeckle Kurt A. , Yung W.K. Alfred , Buys Saundra S. , Bruner Janet M. , Townsend Jeannette J. , Davis Richard , Sawaya Raymond , Kyritsis Athanassios P.
Published: December 2003

Objectives: Anaplastic oligodendrogliomas (AO) are uncommon primary brain tumors whose natural history, prognosis, and optimal management are not yet fully understood. However, they are associated with a better prognosis and response to multimodality therapy based on specific molecular changes. In this multicenter retrospective study, we analyzed the clinical characteristics of patients with AO to identify prognostic factors that influence time to progression (TTP) and survival. Methods: A retrospective search of the brain tumor databases of three institutions (the University of Texas M. D. Anderson Cancer Center, the University of California at San Francisco, and the University of Utah) for patients between 1977 and 1995 with histologically confirmed AO identified a cohort of 106 patients that was further analyzed in this study. Initial treatment included surgery alone (n = 12) or surgery followed by one of the following: radiotherapy (RT) alone (n = 49), chemotherapy alone (n = 4), chemotherapy followed by RT (n = 10), RT followed by chemotherapy (n = 20), and others (n = 11). Results: The median age at diagnosis was 43 years, and the median Karnofsky performance score (KPS) was 90. The overall median survival was 7.3 years, and the 5-year survival rate was 62%. Univariate analysis of several clinical variables showed that only age (p < 0.0001) and KPS (p = 0.04) correlated significantly with survival. Fifty patients had disease progression after initial therapy. The median TTP was 48 months. Age at diagnosis was the only variable that correlated significantly with TTP. Conclusions: A trend towards longer survival with a greater extent of resection was evident. The relative efficacy of various treatment modalities could not be definitively determined because of the heterogeneity of the therapies used. Overall, patients with AO have a better prognosis after therapy compared with those who have other malignant gliomas.
The Myelodysplastic Syndromes: A Matter of Life or Death
Authors: Parker Jane E. , Mufti Ghulam J.
Published: December 2003

Apoptosis is upregulated in early myelodysplastic syndromes (MDS) and may contribute to the peripheral cytopenias commonly observed. Conversely, leukemic progression is associated with abrogation of programmed cell death (PCD). The stage of hematopoietic cell maturation at which defects in PCD arise and the underlying causes of apoptosis dysregulation remain unknown. This paper outlines the apoptotic process in normal hematopoietic cells and summarizes current data regarding the role, potential causes and clinical implications of altered apoptosis in MDS.
p53 Alterations in Myeloid Leukemia
Authors: Boyapati Anita , Kanbe Eiki , Zhang Dong-Er
Published: December 2003

Although most solid tumors contain inactivating mutations of the p53 tumor suppressor, hematological malignancies do not contain frequent alterations in the p53 gene (<20%). How these tumors arise in the presence of a super tumor suppressor like p53 remains to be elucidated. Given the number of downstream effectors of p53, it is likely that critical targets of p53 are inactivated in leukemia, bypassing the requirement for p53 gene mutations in these tumors. This review describes new biochemical and transcriptional activities of p53 as well as the status of p53 in acute myelogenous leukemia and chronic myelogenous leukemia.
Apoptosis Induced by Molecular Targeting Therapy in Hematological Malignancies
Authors: Adachi Souichi , Leoni Lorenzo M. , Carson Dennis A. , Nakahata Tatsutoshi
Published: December 2003

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the bcr-abl fusion protein in CML, and was superior to IFN-α plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in bcr-abl-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular Bcr-Abl protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-trans-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-α (PML/RARα) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
Biology and Clinical Application of Neural Stem Cells
Authors: Shimazaki Takuya
Published: December 2003

Neural stem cells, which exist in various regions of the CNS throughout the mammalian lifespan, can be expanded and induced to differentiate into neurons and glia in vitro and in vivo. Because of these characteristics, there has been increasing interest in the identification and characterization of neural stem cells and neural progenitor cells both for basic developmental biology studies and for therapeutic applications to the damaged brain. Transplantation of neural stem cells or their derivatives into a host brain and the proliferation and differentiation of endogenous stem cells by pharmacological manipulations are potential treatments for many neurodegenerative diseases and brain injuries, such as Parkinson’s disease, brain ischemia and spinal cord injury. Continued progress in neural stem cell research is providing a new future for brain repair.
Potential of Human Embryonic Stem Cells in Regenerative Medicine
Authors: Passier Robert
Published: December 2003

Stem cells can give rise to more stem cells or differentiate into more specialized cells. In the last 5 years not only have researchers succeeded in isolating human embryonic stem (hES) cell lines but also in identifying adult stem cells with possible pluripotent differentiation capacity. The shortage of donor organs or tissues for regenerative medicine has further stimulated research into the capacity of stem cells to differentiate into different cells and their use in replacement therapy in diseases such as Parkinson’s, diabetes, rheumatoid arthritis and myocardial infarction. Current problems and recent progress with respect to hES cells and their potential use for clinical applications will be discussed. The potential of adult stem cells for differentiation and tissue repair is reviewed elsewhere.
The Neurobiology of Female Puberty
Authors: Ojeda Sergio R. , Prevot Vincent , Heger Sabine , Lomniczi Alejandro , Dziedzic Barbara , Mungenast Alison
Published: December 2003

In this review, studies are described indicating that the increase in pulsatile release of gonadotropin releasing hormone that signals the initiation of puberty requires both changes in transsynaptic communication and the activation of glia-to-neuron signaling pathways. The major players in the transsynaptic control of puberty are neurons that utilize excitatory and inhibitory amino acids as transmitters. Glial cells employ a combination of trophic factors and small cell-cell signaling molecules to regulate neuronal function and thus promote sexual development. A neuron-to-glia signaling pathway mediated by excitatory amino acids serves to coordinate the simultaneous activation of transsynaptic and glia-to-neuron communication required for the advent of sexual maturity.
Mutations Affecting Gonadotropin Secretion and Action
Authors: Huhtaniemi Ilpo
Published: December 2003

A number of mutations are known to disturb the development and function of the hypothalamic-pituitary-gonadal axis. They affect hypothalamic-pituitary-gonadal function at multiple levels, from the migration of gonadotropin releasing hormone neurons to the hypothalamus right through to gonadotropin action in the ovary and testis. Most of the mutations are inactivating, causing various forms of hypogonadism. Exceptions are the activating mutations of the luteinizing hormone receptor, causing male-limited gonadotropin-independent precocious puberty. The human mutations and genetically modified animal models have clarified the molecular pathogenesis of hypogonadism and such disorders can now be diagnosed using molecular biological techniques, enabling selection of specific treatments and appropriate counselling of patients and their families.
Peroxisome Proliferator-Activated Receptor-γ and Insulin Action: Insights from Human Genetics
Authors: Chatterjee V. Krishna K.
Published: December 2003

Peroxisome proliferator-activated receptor-γ (PPARγ), an orphan nuclear receptor, mediates adipocyte differentiation and is the cellular target for the thiazolidinedione group of insulin-sensitizing antidiabetic agents. We screened this receptor gene in a cohort of subjects with severe insulin resistance and have identified heterozygous missense mutations in several individuals from three families. Functional studies indicate that the receptor mutants are transcriptionally impaired and inhibit wild type PPARγ action in a dominant-negative manner. The clinical phenotype of patients includes partial lipodystrophy, early-onset hypertension, dyslipidaemia and hepatic steatosis. Factors which contribute to the severe insulin resistance in affected individuals include diminished body fat mass, impaired lipid flux in adipose tissue and reduced circulating levels of adiponectin. In a large kindred of five individuals with severe insulin resistance, we have identified frameshift/premature stop mutations in PPARγ and the muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A). The frameshift PPARγ mutant exhibits complete loss of function with no dominant-negative activity; the PPP1R3A truncation mutant is mislocalized intracellularly. Individuals harbouring either gene defect alone have normal circulating insulin levels, but a combination of both genetic abnormalities co-segregates with severe insulin resistance.
Molecular Basis for the Treatment of Achondroplasia
Authors: Yamanaka Yoshitaka , Ueda Koso , Seino Yoshiki , Tanaka Hiroyuki
Published: December 2003

Achondroplasia (ACH), the most common form of short-limbed dwarfism, and its related disorders are caused by constitutively activated point-mutated fibroblast growth factor receptor 3 (FGFR3). Recent studies have provided a large body of evidence to prove chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes. In the present study, we analyzed apoptosis using a chondrogenic cell line, ATDC5, expressing the FGFR3 mutants causing ACH and thanatophoric dysplasia, which is a more severe neonatal lethal form comprising type I and type II. We found that the introduction of these mutated FGFR3s into ATDC5 cells decreased mRNA expression of parathyroid hormone-related peptide (PTHrP) and induced apoptosis. Importantly, replacement of PTHrP prevented the apoptotic changes in ATDC5 cells expressing ACH mutant. Insulin-like growth factor (IGF)-I, which is an important mediator of growth hormone (GH), also reduced apoptosis in ATDC5 cells expressing ACH mutant. IGF-I prevented apoptosis through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, indicating the mechanisms by which GH treatment improves disturbed bone growth in ACH.
Skeletal Dysplasia, Growth Hormone Treatment and Body Proportion: Comparison with Other Syndromic and Non-Syndromic Short Children
Authors: Hagenäs Lars , Hertel Thomas
Published: December 2003

Skeletal dysplasias comprise a diverse group of conditions that usually compromise both linear growth and body proportions. It is of theoretical interest to evaluate the effect of GH treatment on linear growth, body proportion and final height in the different skeletal dysplasias. Reported experience of GH treatment in short children with skeletal dysplasia is sparse and often limited to short treatment periods and knowledge of its effects on final height and body proportion is generally lacking. Formal studies are almost all confined to achondroplasia as the most common entity. First-year response is typically a 2–3 cm increase in growth velocity in prepubertal children, or a gain of about 0.5 SDS or less in relative height from a baseline level of –4 to –5 SDS. GH treatment for up to 5 years in achondroplasia can produce a total height gain of about 1 SDS. Apart from achondroplasia, treatment of hypochondroplasia and dyschondrosteosis with GH has been reported in a small number of patients. Long-term data are, however, lacking. Of theoretical interest is that in many syndromic or non-syndromic short-statured children body proportion, i.e. trunk to leg length ratio, does not seem to be dependent on the degree of GH sufficiency and does not seem to be changed by GH treatment. GH treatment, at least in the prepubertal period, does seem to influence degree of disproportion.