GCIP water and energy budget synthesis (WEBS)

As part of the World Climate Research Program\u27s (WCRPs) Global Energy and Water-Cycle Experiment (GEWEX) Continental-scale International Project (GCIP), a preliminary water and energy budget synthesis (WEBS) was developed for the period 1996–1999 from the “best available” observations and models. Besides this summary paper, a companion CD-ROM with more extensive discussion, figures, tables, and raw data is available to the interested researcher from the GEWEX project office, the GAPP project office, or the first author. An updated online version of the CD-ROM is also available at http://ecpc.ucsd.edu/gcip/webs.htm/. Observations cannot adequately characterize or “close” budgets since too many fundamental processes are missing. Models that properly represent the many complicated atmospheric and near-surface interactions are also required. This preliminary synthesis therefore included a representative global general circulation model, regional climate model, and a macroscale hydrologic model as well as a global reanalysis and a regional analysis. By the qualitative agreement among the models and available observations, it did appear that we now qualitatively understand water and energy budgets of the Mississippi River Basin. However, there is still much quantitative uncertainty. In that regard, there did appear to be a clear advantage to using a regional analysis over a global analysis or a regional simulation over a global simulation to describe the Mississippi River Basin water and energy budgets. There also appeared to be some advantage to using a macroscale hydrologic model for at least the surface water budgets

Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours

Background: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitro-soureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloro-ethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therap

Sunscreens - Which and what for?

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome

The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users

ХИМИОПРОФИЛАКТИКА РАКА ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ У БОЛЬНЫХ ДОБРОКАЧЕСТВЕННОЙ ГИПЕРПЛАЗИЕЙ ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ С ПОВЫШЕННЫМ УРОВНЕМ ПРОСТАТСПЕЦИФИЧЕСКОГО АНТИГЕНА

The paper gives the comparative results of chemoprevention against prostate cancer (PC) in 189 patients with benign prostate hyperplasia with a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng/ml during 4‑year combined (avodart + omnic) or monotherapy with either drug. Biopsy revealed PC in 14.3 % of the patients treated with avodart and in 29.0 % of those who received omnic monotherapy (p < 0.05). In the avodart groups, the incidence rate of aggressive PC was almost twice the rate in the omnic monotherapy group. The long-term avodart therapy was safe with a stable reduction in the baseline levels of PCA and dihydrotestosterone, and conversely, any PSA rise and even an episodic fall in free PSA ratio are indications for transrectal multifocal prostate biopsy.В работе приведены сравнительные результаты химиопрофилактики рака предстательной железы (РПЖ), проведенной 189 больным доброкачественной гиперплазией предстательной железы с уровнем простатспецифического антигена (ПСА) от 2,5 до 10,0 нг/мл в процессе 4‑годичной комбинированной (аводарт + омник) и монотерапии аводартом или омником. РПЖ выявлен по результатам биопсии у 14,3 % больных, лечившихся аводартом, и у 29,0 % получавших монотерапию омником (р < 0,05). Частота агрессивного РПЖ в группах пациентов, принимавших аводарт, была почти в 2 раза меньшей, чем при монотерапии омником. Длительное лечение аводартом безопасно при стабильном снижении базового уровня ПСА и дигидротестостерона, и наоборот, любое повышение содержания ПСА и даже эпизодическое снижение коэффициента свободного ПСА являются показаниями для трансректальной мультифокальной биопсии предстательной железы