bluuebunny/crossref_metadata_2025 huggingface dataset:
The 14‐Alkyl‐ and 14‐Alkenyl‐5β‐methylindolomorphinan Series Provide δ‐Selective Partial Opioid Agonists
Authors: Grundt Peter , Martinez‐Bermejo Fernando , Lewis John W. , Husbands Stephen M.
Published: March 2003

A series of 14β‐alkyl‐ and 14β‐alkenyl‐5β‐methylindolomorphinans was synthesized and evaluated in opioid binding and functional assays. While being relatively nonselective in binding assays, the 14‐cinnamyl and 14‐isopentyl members showed selective opioid δ‐receptor partial agonist activity in [35S]GTPγS assays.
The Composition of Keto Aldoses in Aqueous Solution as Determined by NMR Spectroscopy
Authors: Köpper Sabine , Freimund Stefan
Published: March 2003

Keto aldoses usually form complex mixtures of equilibrating isomers in solution. This is due to the two different positions that may be used for ring closure in dicarbonyl sugars. The composition of various 2‐keto aldoses 1–5 and 8, the 3‐keto aldose 2‐deoxy‐D‐erythro‐hexos‐3‐ulose (9), and the ketose 1‐deoxy‐D‐ribulose (10) in aqueous solution has been determined by NMR spectroscopy. The investigated keto aldoses form equilibria containing three to fifteen isomers. Among various furanose and pyranose ring structures stemming from 1,4‐, 1,5‐, 2,5‐, and 2,6‐cyclization, bicyclic forms were also found in several cases. The 2‐keto aldoses mainly exist as hydrated isomers in H2O. Therefore, these forms and their proportions were compared to forms found in two homomorphous aldoses and one homomorphous ketose as model compounds. Besides the NMR data, also the composition of the 2‐keto aldoses agreed with the average of forms found in the model compounds, a finding that might eventually be useful for deducing the composition of other keto aldoses.
Nonenzymatic Oligomerization of Ribonucleotides: Towards in vitro Selection Experiments
Authors: Hey Marcus , Hartel Christian , Göbel Michael W.
Published: March 2003

Inspired by the polymerase chain reaction, orthogonal primer–template pairs have been applied in template‐controlled oligomerization experiments with Orgel's imidazole‐activated ribonucleotide‐5′‐phosphates. Variation of the linker length allowed us to monitor the extension of both primers simultaneously on a DNA sequencer. Sets of hexapyrimidine primers were found that are capable of inducing the reciprocal synthesis of each other's binding site. Considerable cross‐inhibition by different monomers was observed. However, this effect is a function of primer sequence and can disappear in favorable cases. With random sequences introduced into the templates, selection experiments are within reach. First results are reported below.
Photochemical Synthesis of Highly Functionalized Cyclopropyl Ketones
Authors: Wessig Pablo , Mühling Olaf
Published: March 2003

A series of di‐ and trisubstituted cyclopropyl ketones 11 were prepared by irradiation of ketones 3 and 5, which bear a leaving group adjacent to the carbonyl C‐atom. The required ketones 3 could be easily synthesized either by functionalization of ketones 1 with a hypervalent iodine reagent, 2, or by O‐sulfonylation of α‐hydroxy ketones 7. The nitrates 5 were obtained by treatment of the corresponding α‐bromo ketones with AgNO3. The irradiation of 3 and 5 must be performed in the presence of an acid scavenger (1‐methyl‐1H‐imidazole) to obtain the cyclopropanes 11 in good yields. The synthetic efficiency of the method was, among other things, demonstrated by the preparation of a highly strained bicyclo[2.1.0]pentane 11i in good yield. The mechanism of the photochemical cyclization was investigated by means of photokinetic measurements, as well as by quantum‐chemical calculations. It was shown that the presence of the leaving group substantially influences all steps of the photochemical reaction cascade. The X‐ray crystal structures of 11j and exo‐11k were also determined.
Acceleration of the Baylis–Hillman Reaction in the Presence of Ionic Liquids
Authors: Kim Eun Jin , Ko Soo Y. , Song Choong Eui
Published: March 2003

The Baylis–Hillman reaction is accelerated in the presence of ionic liquids. Of various 1‐butyl‐3‐methylimidazolium (bmim)‐based ionic liquids tested, [bmim][PF6] has been found to result in the highest rate increase. In the company of Lewis acid and H‐bond‐donor additives, the reaction rates further improve, albeit only modestly. A preparatively useful Baylis–Hillman procedure prescribes the use of [bmim][PF6] with La(OTf)3 and 2,2′2″‐nitrilotris[ethanol], in which the net effect of the ionic liquid is to bring about a more than twofold rate increase over the otherwise same reaction in MeCN.
Modafinil affects mood, but not cognitive function, in healthy young volunteers
Authors: Randall Delia C. , Shneerson John M. , Plaha Komal K. , File Sandra E.
Published: March 2003

Modafinil is a selective wakefulness‐promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation. In a double‐blind study we examined its effects in 30 healthy, non sleep‐deprived students (19 men and 11 women, aged 19–23 years), who were randomly allocated to placebo, 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms, before and after an extensive battery of cognitive tests (pen and paper and CANTAB). There were no significant differences between the three treatment groups on any of the cognitive tests used in this study. There was a significant post‐treatment change in the factor measuring ‘somatic anxiety’ and in individual ratings of ‘shaking’, ‘palpitations’, ‘dizziness’, ‘restlessness’, ‘muscular tension’, ‘physical tiredness’ and ‘irritability’, which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups. Further changes in mood were revealed after the stress of cognitive testing, with the 100 mg group showing greater increases in the ‘psychological anxiety’ and the ‘aggressive mood’ factors (as measured from the Bond and Lader scales). Copyright © 2002 John Wiley & Sons, Ltd.
Differences in the behavioral and psychological symptoms between Alzheimer's disease and vascular dementia: are the different pharmacologic treatment strategies justifiable?
Authors: Kim Jae‐Min , Lyons Declan , Shin Il‐Seon , Yoon Jin‐Sang
Published: March 2003

Background

This study aimed (1) to compare the behavioral and psychological symptoms of dementia (BPSD) between patients with Alzheimer's disease (AD) and vascular dementia (VaD); (2) to investigate the differences in the correlates of BPSD between them; and (3) to suggest potential different pharmacological strategies in treating BPSD of either etiology.

Methods

In a study group of 135 patients with dementia (99 AD, 36 VaD), information on age, gender, education, age at onset and duration of dementia was collected. The severity of dementia was measured by the following assessment scales: Korean version of Mini‐Mental State Examination (MMSE‐K) for cognitive function; Blessed Dementia Scale (BDS) for functional activities of daily living (ADL); Barthel Index (BI) for physical ADL; and Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Scale (HAM‐D) and Hamilton Anxiety Scale (HAM‐A) for BPSD. The independent variables between the patients with AD and VaD were compared, and then the correlations of BPSD with other variables were estimated.

Results

HAM‐D and HAM‐A scores were higher in patients with VaD than in those with AD, while other variables demonstrated no statistical differences. BPRS score correlated with scores on MMSE‐K, BDS and BI in AD, but only with BDS in VaD. The HAM‐D score correlated with scores on BDS and BI in AD, but only with BDS in VaD. The HAM‐A score was correlated with score on BDS in AD not in VaD.

Conclusions

BPSD were more severe in the patients with VaD. However, BPSD correlated more prominently with cognitive or ADL impairments in patients with AD. Different treatment approaches to BPSD may be required according to the clinical differentiation of dementia type. Copyright © 2002 John Wiley & Sons, Ltd.
Mismatch negativity is not correlated with neuroendocrine indicators of catecholaminergic activity in healthy subjects
Authors: Hansenne M. , Pinto E. , Scantamburlo G. , Couvreur A. , Reggers J. , Fuchs S. , Pitchot W. , Ansseau M.
Published: March 2003

The identification of the brain structures and neurotransmitters responsible for the generation and/or modulation of the mismatch negativity (MMN) may contribute to a clearer understanding of its functional significance, and may have clinical implications. In this context, some findings suggest that the scalp‐recorded MMN reflects activity from multiple neuronal ensembles within or in the immediate vicinity of the primary auditory cortex and with possible contribution from the frontal cortex. However, few data are available concerning the influence of neurotransmitter systems on the MMN. In this study, the relationship between both noradrenergic and dopaminergic systems and the MMN were investigated in 34 healthy volunteers. Noradrenergic and dopaminergic activities were assessed with the apomorphine and clonidine challenge tests. The results showed no significant relationship between either growth hormone (GH) responses to apomorphine or clonidine and the MMN amplitude or latency. Therefore, this study does not demonstrate the implication of dopaminergic and noradrenergic activities as assessed by GH response to apomorphine and clonidine for the generation and/or the modulation of the MMN. However, given the complexity of the central neurotransmitter systems, these results cannot be considered as definitive evidence against a relationship between dopaminergic and noradrenergic activity and the MMN. Copyright © 2002 John Wiley & Sons, Ltd.
Drug therapy of frontotemporal dementia
Authors: Allain Hervé , Bentué‐Ferrer Danièle , Tribut Olivier , Mérienne Marc , Belliard Serge
Published: March 2003

Frontal lobe dementia, or more generally frontotemporal dementia (FTD), includes several clinical entities and, although highly prevalent, lacks any codified therapeutic strategy. The present review is an attempt to depict the main neurochemical correlates of FTD and, as a consequence, to propose the most sound targets for symptomatic drugs. Large scale double‐blind controlled clinical trials should be carried out to test any hypothesis: serotonergic agents, glutamate neurotransmission enhancers, monoamine oxidase inhibitors. The recent discovery of tau gene mutations in FTD with Parkinsonism linked to chromosome 17 has reinforced the direct role attributed to abnormal tau proteins (hyperphosphorylation) and thus raised the possibility to target specifically these processes by drugs (aetiopathogenic compounds). Copyright © 2003 John Wiley & Sons, Ltd.
Zotepine in Huntington's disease
Authors: Bonelli Raphael M. , Niederwieser Gerald , Lahousen Theresa , Hofmann Peter
Published: March 2003

The authors report a patient with Huntington's disease (HD) presenting with severe chorea. The motor scale of the unified HD rating scale (UHDRS‐I) revealed 81 points. Motor function clearly improved with zotepine, until she reached an UHDRS‐I of 34 points on day 7 of treatment. The patient was stable for at least 12 weeks. The improvement includes all seven categories of the UHDRS‐I, especially chorea, gait and oral function. This is the first description of zotepine in HD. Our findings suggest that zotepine is useful in the treatment of HD chorea. Controlled trials of its use in HD would be welcome. Copyright © 2003 John Wiley & Sons, Ltd.
Assessing subjective sleep reports in the first‐degree relatives of antidepressant‐treated depressed outpatients
Authors: Mayers Andrew G. , van Hooff Johanna C. , Baldwin David S.
Published: March 2003

This study sought to investigate whether first‐degree relatives of depressed patients report, and react to, sleep perceptions in the same way as the depressed group. Our previous research suggested that depressed individuals may experience greater sleep ‘distress’ than healthy individuals; we wished to explore whether this was also apparent in their nearest relatives. A sample was recruited of 18 antidepressant‐treated patients with a current DSM‐IV diagnosis of major depressive disorder, 18 healthy controls, and a group of 10 first‐degree relatives for each study group. In accordance with previous findings, poorer sleep perceptions corresponded with poorer life‐quality and mood perceptions, and depressed individuals reported poorer sleep perceptions and poorer life‐quality/mood perceptions than controls. Additionally, there was evidence of similar sleep reporting between depressed patients and their relatives, and for a difference between these relatives and other non‐depressed groups. There was a non‐significant trend for depressed patients, and their relatives, to report total sleep time in the same manner as each other, and differently to other non‐depressed groups. Reports of poor sleep may be associated with reports of poor mood in depression, but in non‐depressed individuals the association may be with a feeling of weariness. Copyright © 2003 John Wiley & Sons, Ltd.
Novel stimulatory role for insulin‐like growth factor binding protein‐2 in prostate cancer cells
Authors: Moore Michael G. , Wetterau Lawrence A. , Francis Malik J. , Peehl Donna M. , Cohen Pinchas
Published: March 2003

The insulin‐like growth factor (IGF) axis is a complex system composed of 2 mitogenic ligands, IGF‐I and ‐II, 2 receptors, IGF‐1R and IGF‐2R, and 6 binding proteins, IGFBP‐1 to ‐6. The IGFBPs exert their actions through their regulation of IGF bioavailability for IGF receptors. In addition, some IGFBPs have also been found to have direct cellular actions independent of IGFs. IGFBP‐2 is a major IGFBP in the prostate and in seminal fluid. IGFBP‐2 levels, which are elevated in many malignancies, are markedly increased in prostate cancer, and show a positive correlation with prostate specific antigen (PSA) and prostate tumor aggressiveness. We investigated the potential role of IGFBP‐2 in the pathogenesis of prostate cancer by evaluating its ability to stimulate growth and the expression and activity of the nuclear enzyme, telomerase. We found IGFBP‐2 to have a modest suppressive effect on the growth of primary cultures of normal prostate epithelial cells and a potent IGF‐antagonistic effect in these cells, similar to previous reports on the inhibitory nature of this molecule. Surprisingly, IGFBP‐2 had a potent stimulatory effect on growth of LAPC‐4 prostate cancer cells, an effect that was more pronounced in the absence of androgens. IGFBP‐2 growth stimulation of LAPC‐4 cells was completely blocked by MAP‐kinase inhibitors and partially blocked by PI3‐kinase inhibitors. IGFBP‐2 stimulation of LAPC‐4 cell growth seen in serum‐free conditions was lost in the presence of 10% FBS. IGFBP‐2 also had a growth stimulatory effect on DU 145 prostate cancer cells. IGFBP‐2 significantly stimulated telomerase activity in LAPC‐4 cells in the absence of androgens. In addition, IGFBP‐2 significantly stimulated hTERT expression and telomerase activity in DU 145 cells. Thus, we demonstrated an inhibitory effect of IGFBP‐2 on non‐malignant prostate cells, but showed it to be stimulatory for prostate cancer cells in a MAP‐kinase and androgen‐modulated process. In conclusion, IGFBP‐2 may play a role in the progression, but not in the initiation of the prostate cancer disease process, suggesting the existence of a molecular switch transitioning IGFBP‐2 from a growth inhibitor to a pro‐carcinogenic molecule. © 2003 Wiley‐Liss, Inc.
n‐3 polyunsaturated fatty acid intake and cancer risk in Italy and Switzerland
Authors: Tavani Alessandra , Pelucchi Claudio , Parpinel Maria , Negri Eva , Franceschi Silvia , Levi Fabio , La Vecchia Carlo
Published: March 2003

Data from a series of case‐control studies, conducted in Italy and Switzerland between 1991 and 2001, have been analyzed to evaluate the role of n‐3 polyunsaturated fatty acid (PUFA) intake in the etiology of cancer of oral cavity and pharynx (736 cases, 1,772 controls), esophagus (395 cases, 1,066 controls), large bowel (1,394 colon, 886 rectum, 4,765 controls), breast (2,900 cases, 3,122 controls) and ovary (1,031 cases, 2,411 controls). Controls were patients admitted to hospital for acute, non‐neoplastic conditions, unrelated to modifications in diet. The multivariate odds ratios (OR) for the highest quintile of n‐3 PUFAs compared to the lowest one were 0.5 for oral and pharyngeal cancer, 0.5 for oesophageal cancer, 0.7 for colon cancer, 0.8 for rectal and breast cancer and 0.6 for ovarian cancer; the estimates and the trends in risk were significant for all cancer sites, excluding rectal and breast cancer. The estimates for an increase in n‐3 PUFAs of 1 g/week were 0.70 for oral and pharyngeal cancer, 0.71 for oesophageal, 0.88 for colon, 0.91 for rectal, 0.90 for breast and 0.85 for ovarian cancer. All the estimates were statistically significant, excluding that for rectal cancer, and consistent across strata of age and gender. These results suggest that n‐3 PUFAs decrease the risk of several cancers. © 2003 Wiley‐Liss, Inc.
Lung cancer rates convergence in young men and women in the United States: Analysis by birth cohort and histologic type
Authors: Jemal Ahmedin , Travis William D. , Tarone Robert E. , Travis Lois , Devesa Susan S.
Published: March 2003

Age‐specific rates of lung cancer have been consistently higher for men than for women in the United States, due primarily to different patterns of cigarette smoking. Gender differences in cigarette smoking have diminished in recent birth cohorts, however, especially among whites. We used U.S. population‐based incidence and mortality data and examined trends in age‐specific rates of lung cancer by birth cohort according to gender, ethnic group, and histology to evaluate the generational changes in U.S. lung cancer risk for menvs. women. All tests of statistical significance are 2‐sided (95% confidence interval [CI]). Lung cancer mortality rates have converged between men and women born after 1960, especially in whites. The male‐to‐female (M:F) mortality rate ratio for ages 35–39 years decreased from 3.0 (95% CI = 2.7–3.4) around the 1915 birth cohort to 1.1 (95% CI = 1.0–1.1) around the 1960 birth cohort among whites and from 4.0 (95% CI = 3.2–5.0) around the 1925 birth cohort to 1.5 (95% CI = 1.3–1.7) around the 1960 birth cohort among blacks. Similarly, incidence rates for white men and women converged rapidly for adenocarcinoma, small cell carcinoma, and large cell carcinoma, but less so for squamous cell carcinoma. These findings reflect the smoking patterns among white and black men and women: cigarette smoking prevalence at age 24 was essentially equal among white men and women born after 1960 but continued to be higher in black men than women. The convergence of lung cancer death rates among men and women born after 1960s supports the idea that males and females maybe equally susceptible to develop lung cancer from a given amount of cigarette smoking, rather than the hypothesis that women are more susceptible. © 2003 Wiley‐Liss, Inc.
55 kDa nuclear matrix protein (nmt55) mRNA is expressed in human prostate cancer tissue and is associated with the androgen receptor
Authors: Ishiguro Hitoshi , Uemura Hiroji , Fujinami Kiyoshi , Ikeda Naoya , Ohta Shinsuke , Kubota Yoshinobu
Published: March 2003

Most prostate cancer grows in a hormone‐dependent manner. Most patients, however, show hormone‐independent growth after several years of hormone therapy. The mechanism of hormone‐refractory prostate cancer remains unknown. It is important, therefore, to identify gene(s) related to prostate cancer that are up‐ or downregulated. We studied differences in gene expression in pairs of prostate cancer and normal prostate tissue utilizing the differential display method. Expression of the identified gene was examined by RT‐PCR and real time quantitative PCR (TaqMan‐PCR) using 26 pairs of human prostate cancer and normal tissues. We identified a specific upregulated gene encoding a 55 kDa nuclear matrix protein (nmt55) in human prostate cancer. nmt55 gene expression in human prostate cancer tissue was higher (20/26 cases) than that in normal prostate tissue. Moreover, the relationship between nmt55 and androgen receptor (AR) expression showed a positive correlation. In another experiment, transcriptional activity of the prostate specific antigen (PSA) promoter was upregulated by nmt55 in 293 cells. nmt55 showed high expression in prostate cancer compared to normal tissue and its expression showed a positive correlation with AR expression. The PSA promoter was activated by nmt55 expression. These results suggest the possibility that nmt55 expression is related to hormone‐dependency or ‐independence associated with the AR. © 2003 Wiley‐Liss, Inc.
Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase
Authors: Koyanagi Satoru , Kuga Minoru , Soeda Shinji , Hosoda Yoshiko , Yokomatsu Tsutomu , Takechi Hiroaki , Akiyama Takeshi , Shibuya Shiroshi , Shimeno Hiroshi
Published: March 2003

Ceramide is formed through sphingomyelin hydrolysis or de novo synthesis and may play a key role in cell growth, differentiation and apoptosis. To clarify which pathway tumor cells use to form ceramide and how its formation is regulated, we determined the levels of dihydroceramide and ceramide in mice inoculated with Sarcoma 180, B16 melanoma or Lewis lung carcinoma cells. The levels in these tumor masses were very high compared to those in other healthy tissues. The high levels were significantly reduced by a single administration of the dihydroceramide synthase inhibitor fumonisin B1, but not by a sphingomyelinase inhibitor, sphingomyelin analog‐1 (SMA‐1), suggesting that the tumor cells have a very effective means of synthesizing dihydroceramide and ceramide. To investigate the characteristics of dihydroceramide synthase, we prepared microsomes from Sarcoma 180 tumor masses and healthy mouse liver cells, and compared their catalytic activities on dihydroceramide formation. A kinetic analysis using sphinganine and palmitoyl CoA as substrates revealed that the enzyme present in the tumor formed dihydroceramide 3 times more efficiently than that in healthy liver cells. Partial purification of dihydroceramide synthase from bovine liver microsomes revealed that the enzyme was present in healthy tissues as a 333 kDa form constructed of 47 kDa subunit proteins. However, gel filtration of the enzyme solubilized from the Sarcoma 180 tumor masses demonstrated that its molecular weight was 1,300 kDa. These results suggest that malignant transformation causes the cell to produce a form of dihydroceramide synthase with a larger than normal molecular mass; the increased molecular mass may account for the enzyme's increased catalytic efficiency. © 2003 Wiley‐Liss, Inc.
Quantitative detection of micrometastases in the lymph nodes of gastric cancer patients with real‐time RT‐PCR: A comparative study with immunohistochemistry
Authors: Kubota Keisuke , Nakanishi Hayao , Hiki Naoki , Shimizu Nobuyuki , Tsuji Eiichi , Yamaguchi Hirokazu , Mafune Ken‐ichi , Tange Tsuyoshi , Tatematsu Masae , Kaminishi Michio
Published: March 2003

Histologic examination lacks the sensitivity to detect micrometastases in gastric cancer lymph nodes. In the present study, we applied a real‐time RT‐PCR approach to the quantitative detection of micrometastases in gastric cancer lymph nodes and compared diagnostic power with routine histology and immunohistochemistry. We studied 392 lymph nodes from 21 gastric cancer patients who underwent curative surgery. Real‐time quantitative RT‐PCR was performed on a LightCycler instrument using a hybridization probe for carcinoembryonic antigen (CEA) and cytokeratin‐20 (CK20) as marker genes. Immunohistochemistry with antibodies to wide‐keratin was also performed in the lymph nodes to compare the sensitivity and specificity. Median (average) values of CEA mRNA in lymph nodes in patients with histology+, immunohistochemistry+/histology−, immunohistochemistry−/histology− and negative control results were 4,600 (16,000), 200 (400), 0 (9.8) and 0 (0.6), respectively. There were some false‐negative results with simple CEA and CK20 real‐time RT‐PCR due to the presence of low gene‐expressing gastric cancers as revealed by CEA and CK20 immunohistochemistry. CEA in combination with CK20 (duplex) real‐time RT‐PCR partially covered this weakness. Consequently, all 71 histology+ lymph nodes were positive for duplex real‐time RT‐PCR as well as wide‐keratin immunohistochemistry. Positivity rates by histology, wide‐keratin immunohistochemistry and duplex real‐time RT‐PCR were 18.0% (71/392), 20.9% (82/392) and 25.8% (101/392), respectively. In 2 of 8 patients with pT1N0, positive lymph nodes were observed by real‐time RT‐PCR but not by immunohistochemistry. These results indicate that duplex quantitative real‐time RT‐PCR is the most sensitive method for detecting micrometastases and useful for evaluating the prognostic significance of lymph node micrometastasis in gastric cancer patients. © 2003 Wiley‐Liss, Inc.
Human malignant glioma cell lines are sensitive to low radiation doses
Authors: Beauchesne Patrick D. , Bertrand Suzanne , Branche Robert , Linke Steven P. , Revel Roland , Dore Jean‐François , Pedeux Rémy M.
Published: March 2003

Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Some cell lines that are considered radioresistant respond to low radiation doses (<1 Gy) with increased cell killing (low‐dose hypersensitivity). In our study, 4 of 5 human glioma cell lines exhibited significant X‐ray sensitivity at doses below 1 Gy. The surviving fractions (SFs) obtained at 0.7 and/or 0.8 Gy were comparable to those at 1.5 Gy. Low‐dose hypersensitivity was evident when irradiation was combined with etoposide treatment. Repeated irradiation with low doses was markedly more effective than irradiation with single, biologically equivalent doses in decreasing SFs, inhibiting xenograft tumor growth in mice. All experiments were conducted with an accelerator used in clinics, establishing that low‐dose hypersensitivity was present following megavoltage X‐irradiation. Thus, repeated low‐dose irradiation (ultrafractionation) could greatly improve the effectiveness of radiotherapy of gliomas and could allow safe treatment of patients with cumulative doses greater than 60 Gy. © 2003 Wiley‐Liss, Inc.
Plasma sex steroid hormones and breast cancer risk in Chinese women
Authors: Yu Herbert , Shu Xiao‐Ou , Shi Runhua , Dai Qi , Jin Fan , Gao Yu‐Tang , Li Benjamin D.L. , Zheng Wei
Published: March 2003

Estrogens regulate the growth and differentiation of mammary cells and play an important role in the development of breast cancer. High circulating levels of estrogens are associated with increased risk of breast cancer in Caucasian women. Because Asian women have low estrogens in the circulation compared with their Caucasian counterparts, the effect of estrogens on breast cancer risk in populations with low circulating estrogens remains to be elucidated. We conducted a population‐based case‐control study in China to evaluate the association of sex steroid hormones with breast cancer risk in Chinese women. Our study included 300 incident cases with primary breast cancer and 300 age‐ and menopausal status‐matched healthy controls randomly selected from the general population in Shanghai. Fasting blood samples were collected from cases prior to any treatment and from their matched controls. Commercial immunoassays were used to measure plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, progesterone, dehydroepiandrosteindian sulfate (DHEA‐S) and steroid hormone‐binding globulin (SHBG). Conditional logistic regression analysis was performed to examine the association between steroid hormones and breast cancer risk. The results showed that breast cancer risk was elevated with increasing levels of estrone and testosterone (p for trend < 0.05) but not with DHEA‐S, estradiol, estrone sulfate, progesterone or SHBG. The estimated relative risks between upper and lower tertiles were 2.07 (95% confidence interval [CI] 0.97–4.41) for estrone in postmenopausal women, 2.01 (95% CI 0.96–4.21) for testosterone in premenopausal women, and 2.40 (95% CI 1.11–5.21) for testosterone in postmenopausal women, after adjusting for age at first live birth, waist‐to‐hip ratio, total calorie intake, a history of fibroadenoma, a family history of breast cancer and SHBG. These results, in general, are consistent with the findings in Caucasian women and indicate that high sex steroid hormones in the circulation, both androgen and estrogen, are associated with increased risk of breast cancer even in populations with relatively low sex hormones. © 2003 Wiley‐Liss, Inc.
Predictors of metachronous colorectal neoplasms in sporadic adenoma patients
Authors: Bertario Lucio , Russo Antonio , Sala Paola , Pizzetti Paolo , Ballardini Giovanni , Andreola Salvatore , Spinelli Pasquale
Published: March 2003

Our objective was to assess the overall risk of subsequent colorectal neoplasms (cancer or adenoma) in relation with the various characteristics of the index lesion in a cohort of patients who underwent endoscopic polypectomies of colorectal adenomas. A total of 1,086 patients with adenomas of the large bowel were reported between 1979 and 1999 at the National Cancer Institute of Milan during a screening program for colorectal carcinoma. Data on patients who had colonoscopic examinations and treatments were collected prospectively. The relation between colorectal cancer (CRC) and adenoma features was assessed by computing the hazard ratio (HR) values and corresponding confidence intervals (95% CI) according to Cox proportional hazard models. Of the 1,086 eligible patients (487 females, 579 males), 736 had single adenomas (67.7%) and 350 had multiple adenomas (32.3%). Histologic examination revealed 772 cases of tubular adenoma (73%), 205 cases of tubulovillous adenoma and 80 cases of villous adenoma (7.5%). Severe dysplasia was found in 3.3% of the cases. During the 11,393 person‐years of follow‐up, with an average time of surveillance of 10.5 years, colorectal carcinomas developed in 10 patients (0.8%) and a new adenoma in 323 patients (29%). Multivariate analysis showed that male gender (HR 1.6; 95% CI 1.3–2.0), multiple polyps (HR 1.6; 95% CI 1.3–2.0), polyps larger than 2 cm (HR 1.5; 95% CI 1.1–2.1), tubulovillous and villous histology (HR 1.3; 95% CI 1.0–1.6 and HR 1.8; 95% CI 1.2–2.6, respectively) at index polypectomy were statistically significant risk factors for developing metachronous adenomatous polyps. The standardized incidence rates (SIR) for CRC was 0.52 (95% CI 0.25–0.95). The SIR was increased in subjects with severe dysplasia (2.8; 95% CI 0.34–1.02). Some features of large bowel adenomas are strongly correlated with an increased risk of metachronous adenomas and colorectal cancer. However, the endoscopic polypectomy is able to reduce by 50% the incidence of CRC in patients with large bowel adenomas. © 2003 Wiley‐Liss, Inc.
Cancer risks in hairdressers: Assessment of carcinogenicity of hair dyes and gels
Authors: Czene Kamila , Tiikkaja Sanna , Hemminki Kari
Published: March 2003

More than a decade ago, an increased risk for bladder cancer among male hairdressers was established. Frequent changes of hair dye formulations together with their widespread use call for safety guarantees. We carried out a follow‐up study of a cohort of 38,866 female and 6,824 male hairdressers from Sweden and analyzed all of their malignancies over a period of 39 years. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for 28 cancer sites were calculated using the economically active population as a reference. During the years 1960–1998 a total of 1,043 cancer cases were recorded in male hairdressers. Excess risks for cancers of the upper aerodigestive tract and lung and colorectal adenocarcinoma were observed. Additionally, male hairdressers working in 1960 had an increased risk for urinary bladder cancer, which was highest in the 1960s with an SIR of 2.56 (95% CI 1.36–4.39) and decreased with the follow‐up time. A total of 2,858 cancers were recorded in female hairdressers. An increased risk was observed for cancers of the pancreas, lung and cervix and in situ cancer of the skin. The increased risk for in situ skin cancer specifically affected the scalp and neck, sites of contact for hair dyes, with an SIR of 2.43 (95% CI 1.14–4.44). The increase in lung cancer, the only site for which cancer was increased in either sex, may depend on confounding from smoking. Bladder cancer was not increased among hairdressers in the recent decades and is therefore not likely to be associated with modern hair dyes. © 2003 Wiley‐Liss, Inc.
Phenotypic reversion of rat neoplastic liver nodules is under genetic control
Authors: De Miglio Maria R. , Simile Maria M. , Muroni Maria R. , Calvisi Diego F. , Virdis Patrizia , Asara Giuseppina , Frau Maddalena , Bosinco Giovanni M. , Seddaiu Maria A. , Daino Lucia , Feo Francesco , Pascale Rosa M.
Published: March 2003

Low DNA synthesis and high redifferentiation (remodeling) characterize neoplastic nodules induced by chemical carcinogens in hybrid BFF1 rats, generated by crossing the susceptible F344 and resistant BN strains. We performed whole‐genome scanning of BFF2 rats to identify loci controlling remodeling of nodules induced, 32 weeks after initiation with diethylnitrosamine, by the RH protocol. Remodeling nodules were identified as areas lacking uniformity of GST‐P immunostaining and with irregular margins. Two loci in suggestive linkage with the percentage of remodeling nodules were identified on chromosomes 7 and 1 (LOD scores 3.85 and 2.9 at D7Rat25 and D1Mgh14). Significant dosage‐negative effect of the B allele on remodeling and additive interaction between these loci were found. Significant epistatic interactions, showing a recessive, remodeling‐enhancing effect of B alleles, occurred between D1Mit3 and D11Rat11 (corrected p = 0.0013) and between D6Rat14 and D8Rat46 (corrected p = 0.028). These data show that remodeling of neoplastic nodules during rat hepatocarcinogenesis is under genetic control. Loci affecting remodeling map to chromosomal regions syntenic to chromosomal segments of human HCC showing structural abnormalities. © 2003 Wiley‐Liss, Inc.
Organization and modifications of sperm acrosomal molecules during spermatogenesis and epididymal maturation
Authors: Yoshinaga Kazuya , Toshimori Kiyotaka
Published: March 2003

The mammalian acrosome is a highly specialized organelle overlying the anterior part of the sperm nucleus and contains a variety of proteins, including hydrolytic enzymes and matrix molecules. Functionally, the anterior acrosome is involved in the acrosome reaction or sperm–zona pellucida interaction, while the equatorial segment (posterior acrosome) is involved in sperm–egg fusion. The acrosome is formed during spermiogenesis, during which associated molecules are transported from the Golgi apparatus and organized. Many of the molecules thus arranged gradually become compartmentalized during sperm passage through the epididymis. Some of them are further modified during the fertilization process. The findings indicate that acrosomal molecules are not only restricted to a specific region (domain) of the acrosome but also undergo ongoing relocation in a stage‐specific manner during sperm maturation in the testis and epididymis. Such maturation‐associated modifications are considered essential for sperm molecules to reach the correct or final site before fertilization. This review focuses on the organization and modifications of the acrosomal molecules as well as their compartmentalization within the acrosome. Microsc. Res. Tech. 61:39–45, 2003. © 2003 Wiley‐Liss, Inc.
Expression of mammalian spermatozoal nucleoproteins
Authors: Dadoune Jean‐Pierre
Published: March 2003

A dramatic remodeling of sperm chromatin occurs during mammalian spermiogenesis. Nuclear elongation and chromatin condensation are concomitant with modifications in the basic protein complement associated with DNA. A number of biochemical events accompany the displacement of histones and the appearance of protamines in elongating spermatids. The mRNAs of transition proteins and protamines are transcribed and stored in the cytoplasm of spermatids until days later when they are translated. The intrinsic regulation of the expression of the transition protein and protamine genes occurs at three levels: transcription, translation, and posttranslation. The aim of this review is to cover most of the morphological, biochemical, and functional events which concern nuclear protein transitions during spermiogenesis and which are thereby involved in the nuclear status of ejaculated sperm cells. Microsc. Res. Tech. 61:56–75, 2003. © 2003 Wiley‐Liss, Inc.
Ca2+/calmodulin‐dependent protein kinases II and IV both promote survival but differ in their effects on axon growth in spiral ganglion neurons
Authors: Hansen Marlan R. , Bok Jinwoong , Devaiah Anand K. , Zha Xiang‐Ming , Green Steven H.
Published: March 2003

Spiral ganglion neuron (SGN) survival in vitro can be maintained by neurotrophins, permeant cAMP analogs, and depolarization in an additive manner, with depolarization being the most efficacious. Therefore, we used cultured SGNs to determine the mechanism by which depolarization promotes neuronal survival. Our data implicate Ca2+/calmodulin‐dependent protein kinase (CaMK) activity by showing that it is induced by depolarization, that CaMK activity is necessary for at least part of the survival‐promoting effect of depolarization, and that CaMKII or CamKIV activity suffices to support neuronal survival in the absence of other trophic stimuli. First, that depolarization of SGNs activates CaMKs is evidenced by observation of increased CaMKII phosphorylation and of CaMK‐dependent CREB phosphorylation. Second, the requirement for CaMKs is shown by a reduction of SGN survival under depolarizing conditions in the presence of CaMK inhibitors. Third, transfection of COOH‐terminal‐truncated (lacking regulatory domain), constitutively active CaMKII or CaMKIV, but not of normal, full‐length CAMKs, promotes SGN survival in the absence of other trophic stimuli, indicating that CaMK activity is sufficient to promote survival. The survival‐promoting effect of truncated CaMKs is additive with that of depolarization, neurotrophins, or cyclic AMP. Although both CaMKII and CaMKIV activities converge in promoting survival, their actions on axon growth are markedly different: Transfection of truncated CaMKII, but not of truncated CaMKIV, into SGNs prevents axon outgrowth. © 2003 Wiley‐Liss, Inc.
Axons of alpha ganglion cells regenerate faster than other types into a peripheral nerve graft in adult cats
Authors: Maki Hideki , Watanabe Masami , Tokita Yoshihito , Saito Kiyoshi , Yoshida Jun
Published: March 2003

We reported previously that alpha ganglion cells in the cat retina have the highest ability in axonal regeneration. To examine whether alpha cells regenerate axons faster, we estimated the rate of axonal regeneration of retinal ganglion cells (RGCs) with transplantation of a peripheral nerve (PN) segment. After 4, 6, and 8 weeks of survival, regenerated RGCs were double‐labeled with two fluorescent dyes injected separately at 10 mm and 20 mm from the connected site. From a scatter diagram of double‐labeling ratios, we estimated that axons reached 20 mm by 3.2 weeks. Immunostaining suggested that first axon sprouts entered a PN segment on Day 4. These values enabled us to estimate average rates of axonal regeneration as 1.1 mm/day for all the RGCs. Proportions of cell types of regenerated RGCs were obtained with Lucifer yellow injections, and those of alpha cells were higher than those in normal retinas in any periods. From analysis of scatter diagrams, we estimated axonal growth rate of alpha, beta, and non‐alpha/beta cells as 1.4, 1.1, 1.0 mm/day, respectively. The higher regeneration rate of alpha cells may reflect greater regenerative ability compared to other cell types. The present system also provides control values when a method to promote axonal regeneration is developed. © 2003 Wiley‐Liss, Inc.
Activation of protein kinase C inhibits retrograde transport of neurotrophins in mice
Authors: Ozsarac Nesrin , Weible Michael , Reynolds Anna J. , Hendry Ian A.
Published: March 2003

Retrograde axonal transport of neurotrophins from nerve terminal to cell body requires a number of key processes, including internalization of the receptor‐neurotrophin complex into vesicles and formation of multivesicular bodies and their transport along the axon. Previous studies have shown that each of these processes can be regulated by kinases. In this study, we looked at the role of protein kinase C (PKC) in retrograde transport by injecting labeled neurotrophins together with relevant pharmacological agents into the eye and measuring the accumulation of radioactivity in the trigeminal and superior cervical ganglia. Inhibitors of PKC, Ro‐31‐8220 and rottlerin, did not affect the retrograde transport of nerve growth factor (NGF); however, phorbol ester activation of classical and novel PKCs blocked retrograde transport. The effect of phorbol esters was partially reversed by rottlerin and Ro‐31‐8220. Activation of PKC has been shown to be involved in the disorganization of actin filaments. In this study, we show that Ro‐31‐8220 reverses growth cone collapse by phorbol 12‐myristate 13‐acetate and suggest that one of the effects of activating PKC on retrograde transport is to disrupt the actin filaments. © 2003 Wiley‐Liss, Inc.
Altered gene expression in frontal cortex and midbrain of 3,4‐methylenedioxymethamphetamine (MDMA) treated mice: Differential regulation of GABA transporter subtypes
Authors: Peng Weiping , Simantov Rabi
Published: March 2003

Changes in gene expression were examined in the brain of mice treated with a drug of abuse, 3,4‐methylenedioxymethamphetamine (MDMA, also called Ecstasy). Frontal cortex and midbrain mRNA, analyzed by differential display polymerase chain reaction (DD‐PCR) method, showed an altered expression of several cDNAs, 11 of which were isolated, cloned and sequenced. The sequence of one MDMA‐induced mRNA corresponds (99.3%) to the mouse γ‐amino butyric acid (GABA) transporter 1 (mGAT1). The established involvement of GABA neurotransmission in the activity of several abused drugs prompted us to focus herein on MDMA effect on the GABA transporter gene family. Semi‐quantitative PCR analysis with primers selective to the reported mGAT1 sequence confirmed that MDMA treatment increased mGAT1 expression. Time‐course study of the expression of the three GABA transporter subtypes showed that MDMA induced a differential temporal activation of mGAT1 and mGAT4, but had no effect on mGAT2. Quantitative real‐time PCR further proved the increased expression of mGAT1 and mGAT4 upon MDMA treatment. Western immunoblotting with anti‐GAT1 antibodies showed that MDMA also increased GAT1 protein levels, suggesting that neurotransmission of GABA was altered. MDMA effect was also verified in serotonin transporter knockout (−/−) mice that are insensitive behaviorally to MDMA; the drug did not increase GAT1 protein level in these mutants. In mice, tiagabine and NO‐711, inhibitors of GABA transporters, restrained MDMA‐induced acute toxicity and death. These results should facilitate novel approaches to prevent deleterious effects, including fatality, induced by MDMA and similar abused psychostimulants. © 2003 Wiley‐Liss, Inc.
Modulation of perch connexin35 hemi‐channels by cyclic AMP requires a protein kinase A phosphorylation site
Authors: Mitropoulou Georgia , Bruzzone Roberto
Published: March 2003

Retinal neurons are coupled via gap junctions, which function as electrical synapses that are gated by ambient light conditions. Gap junctions connecting either horizontal cells or AII amacrine cells are inhibited by the neurotransmitter dopamine, via the activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. Fish connexin35 (Cx35) and its mouse ortholog, Cx36, are good candidates to undergo dopaminergic modulation, because they have been detected in the inner plexiform layer of the retina, where Type II amacrine cells establish synaptic contacts. We have taken advantage of the ability of certain connexins to form functional connexons (hemi‐channels), when expressed in Xenopus oocytes, to investigate whether pharmacological elevation of cAMP modulates voltage‐activated hemi‐channel currents in single oocytes. Injection of perch Cx35 RNA into Xenopus oocytes induced outward voltage‐dependent currents that were recorded at positive membrane potentials. Incubation of oocytes with 8‐bromoadenosine 3′,5′‐cyclic monophosphate (8‐Br‐cAMP), a membrane permeable cAMP analog, resulted in a dose‐dependent and reversible inhibition of hemi‐channel currents at the more positive voltage steps. In contrast, treatment with 8‐Br‐cAMP did not have any effect on hemi‐channel currents induced by skate Cx35. Amino acid sequence comparison of the two fish connexins revealed, in the middle cytoplasmic loop of perch Cx35, the presence of a PKA consensus sequence that was absent in the skate connexin. The results obtained with two constructs in which the putative PKA phosphorylation site was either suppressed (perch Cx35R108Q) or introduced (skate Cx35Q108R) indicate that it is responsible for the inhibition of hemi‐channel currents. These studies demonstrate that perch Cx35 is a target of the cAMP/PKA signaling pathway and identify a consensus PKA phosphorylation site that is required for channel gating. © 2003 Wiley‐Liss, Inc.
Influence of the frequency parameter on extracellular glutamate and γ‐aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats
Authors: Windels François , Bruet Nicolas , Poupard Annie , Feuerstein Claude , Bertrand Anne , Savasta Marc
Published: March 2003

High‐frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas γ‐aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency‐dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep‐brain‐stimulation mechanisms. © 2003 Wiley‐Liss, Inc.
NFAT4 is expressed in primary astrocytes and activated by glutamate
Authors: Jones Elizabeth A. , Sun Doug , Kobierski Linda , Symes Aviva J.
Published: March 2003

Calcium signaling is a critical component of astrocyte activation but little information is available regarding the identity and function of transcriptional targets of calcium signaling in these cells. As a first step in elucidating the mechanisms that astrocytes use to regulate transcription in response to raised intracellular calcium concentrations, we have investigated expression and activation of the calcium activated transcription factors of the NFAT family. We report here that NFAT4 is expressed in U373 astrocytoma cells and in primary cultures of astrocytes. Treatment of U373 cells or primary astrocytes with the calcium ionophore A23187, or the neurotransmitter glutamate, leads to NFAT nuclear translocation and increased DNA binding to a NFAT consensus site through a cyclosporin A‐sensitive process. These data suggest that NFAT4 functions as a calcium‐responsive transcription factor in astrocytes. Published 2003 Wiley‐Liss, Inc.