bluuebunny/crossref_metadata_2025 huggingface dataset:
Amniotic Fluid Transforming Growth Factor-β1 and the Risk for the Development of Neonatal Bronchopulmonary Dysplasia
Authors: Ichiba Hiroyuki , Saito Mika , Yamano Tsunekazu
Published: April 2009

Chorioamnionitis (CAM) can initiate fetal lung injury resulting in neonatal bronchopulmonary dysplasia (BPD). While neonates with BPD have higher amniotic fluid concentrations of proinflammatory cytokines, overexpression of transforming growth factor (TGF)-β1 also appears important in the pathogenesis of BPD. The aim of this study was to investigate the relationship between TGF-β1 and CAM-induced fetal lung injury. Forty-four amniotic fluid samples were obtained at delivery of preterm infants (median gestation, 28 weeks; birth weight, 908 g). TGF-β1 and interleukin (IL)-6 concentrations in the amniotic fluid were measured with ELISA. Both TGF-β1 and IL-6 concentrations in the amniotic fluid increased with increasing histological severity of CAM (each p < 0.0001). The presence of both BPD and histological CAM was associated with significantly higher amniotic fluid TGF-β1 and IL-6 concentrations than the presence of BPD without histological CAM, or the absence of both (each p < 0.0001). Both concentrations also correlated with the duration of oxygen administration in the neonates (each p < 0.0001). Amniotic fluid TGF-β1 seems to be important in CAM-induced fetal lung injury progressing to neonatal BPD.
Association of Interleukin-13/-4 and Toll-Like Receptor 10 with Preterm Births
Authors: Heinzmann Andrea , Mailaparambil Beena , Mingirulli Nadja , Krueger Marcus
Published: April 2009

Background: Preterm birth (PTB) is accompanied by an increased neonatal morbidity. The cause of PTB is multifactorial and the interplay between environmental and genetic factors – of mothers and newborns – determines the risk. Objectives: We were interested to identify fetal genes predisposing to PTB in the German population. Methods: We started our study by screening 31 polymorphisms within 15 genes of 121 preterm infants born below 32 gestational weeks and 270 healthy controls. Genotyping was performed by restriction fragment length polymorphism. Statistical analyses used Armitage’s trend test for single polymorphisms and FAMHAP for calculation of haplotypes. Results: No single polymorphism showed association with PTB; however, haplotypes of interleukin (IL)-13/IL-4 and Toll-like receptor (TLR)-10 were associated (p = 0.0001 and p = 0.0011, respectively). The association was further confirmed in an extended population of a total of 164 preterm infants. Furthermore, one polymorphism in IL-13 showed a weak association with PTB in this population (p = 0.031). Finally, we analyzed whether the cause of PTB, i.e. medically indicated cesarean section versus spontaneous PTB, affects association results and found evidence in favor of a separate analysis of both groups. Conclusions: IL-13/IL-4 and TLR-10 might be involved in the genetics of PTB. The dissection of the genetic background may provide a deeper understanding of the pathophysiology of PTB and help to identify new drug targets for its prevention.
Factors Influencing Long-Term Survival in Patients with T3 Gallbladder Adenocarcinoma
Authors: Chakravarty K. Dilip , Yeh Chun-Nan , Jan Yi-Yin , Chen Miin-Fu
Published: April 2009

Purpose: This study aimed to identify the factors influencing the surgical outcome in patients with T3 gallbladder adenocarcinoma (GBA). Methods: Between 1996 and 2006, 100 GBA patients who underwent surgical treatment in Chang Gung Memorial Hospital, Taiwan, were retrospectively reviewed. Among them, 39 patients with pathological stage T3 GBA were analyzed statistically in terms of demographic data and clinicopathological features. Results: The 1-, 3- and 5-year survival rates for patients with T3 GBA undergoing surgical treatment were 53.5, 37.0 and 32.9%, respectively. Univariate survival analysis revealed male gender, low serum carcinoembryonic antigen (CEA) level, and curative resection as factors which predicted favorable overall survival for T3 GBA patients. Multivariate survival analysis revealed low preoperative CEA levels and curative resections independently predicted favorable outcomes. Conclusions: Negative resection margin and serum CEA levels were found to be the independent prognostic factors in predicting long-term survival in patients with T3 GBA, and the serum CEA level was also found to be an independent prognostic factor in predicting the long-term prognosis of T0–T4 GBA; however, the result is preliminary due to the limited number of patients. Further studies with a large number of patients are necessary to confirm our result.
Role of TNF-α, sTNF-R55 and sTNF-R75 in Inflammation of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Zeng Mian , Wen Ying , Liu Ling-yun , Wang Hui , Guan Kai-pan , Huang Xiaomei
Published: April 2009

Backgrounds: Although some recent studies have demonstrated the important role of tumor necrosis factor-α (TNF-α) and soluble TNF receptors (sTNF-R) in inflammation of chronic obstructive pulmonary disease, the exact roles of TNF-α and sTNF-R as well as their interaction remained unclear. Objectives: To study changes in levels of systemic and airway local TNF-α and sTNF-R (sTNF-R55, sTNF-R75) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and clarify the relationship between these mediators and airflow limitation in AECOPD patients. Methods: TNF-α, sTNF-R55 and sTNF-R75 levels in induced sputum and plasma as well as lung functions were examined in 48 AECOPD patients before and after treatment. Samples from 28 healthy volunteers served as controls. Results: Compared to healthycontrols, both pre- and posttreatment levels of TNF-α, sTNF-R55 and sTNF-R75 in induced sputum and plasma of COPD patients were higher. In patients with AECOPD, posttreatment TNF-α levels significantly decreased compared to pretreatment levels (0.6 ± 0.46 vs. 0.82 ± 0.35 μg/l in plasma, p < 0.01; 0.48 ± 0.27 vs. 0.82 ± 0.34 μg/l in sputum, p < 0.001). While posttreatment sTNF-R55 and sTNF-R75 levels increased in both kinds of samples, mediator levels in plasma and lung functions were unrelated (p > 0.05). sTNF-R55 and sTNF-R75 levels in induced sputum were positively correlated with lung functions (p < 0.05), while TNF-α levels were negatively correlated with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to FEV1 predicted value. Conclusions: Inflammatory and anti-inflammatory mediators were imbalanced in the airways of AECOPD patients. It was local inflammation but not systemic inflammation that was closely related to airflow limitation.
Effects of Progesterone and Its Antagonist Mifepristone on Progesterone Receptor A Expression in Human Umbilical Vein Endothelial Cells
Authors: Toth Bettina , Scholz Christoph , Ochsenkühn Robert , Schulze Sandra , Kuhn Christina , Friese Klaus , Jeschke Udo
Published: April 2009

Effects of female steroid hormones on endothelial cells are gaining increased importance due to several studies on the effects of hormonal treatment on cardiovascular risk. Recent data argue for an improvement of endothelium-derived relaxation and impaired vascular contraction by estradiol, whereas progesterone and testosterone might entail contrary effects. So far, gestagenic influence on endothelial cell physiology is poorly understood. Human umbilical vein endothelial cells (HUVECs) exposed to the female sex hormones estradiol and progesterone show expression of estrogen receptor-β (ERβ) and progesterone receptor A (PR-A), and are negative for ERα and PR-B. The aim of this study was to analyze the expression and stimulation of PR-A and -B in HUVECs after stimulation with progesterone and PR antagonists that are commercially available. PR-B expression or upregulation was abrogated after application of progesterone or antagonists to HUVECs. Expression of PR-A could be significantly upregulated with progesterone and mifepristone. Unexpectedly, stimulation with the progesterone antagonist RU486 (mifepristone) was accomplished by an upregulation of PR-A expression in our study. We conclude that gestagenic effects on HUVECs independent of modulators are mediated via the PR-A.
Homocysteine Levels and Echocardiographic Findings in Obstructive Sleep Apnea Syndrome
Authors: Sarıman Nesrin , Levent Ender , Aksungar Fehime Benli , Soylu Akın Cem , Bektaş Osman
Published: April 2009

Background: The obstructive sleep apnea syndrome (OSAS) is characterized by repeated upper airway obstruction during sleep together with decreases in oxygen saturation leading to a series of pathological events, primarily in the cardiovascular system. Elevated plasma homocysteine levels have recently been considered as an independent risk factor for vascular disease, and increased levels are attributed to cardiovascular diseases. Objectives: We aimed to investigate the possible relationship between homocysteine levels and echocardiographic findings in OSAS patients at different stages of disease. Methods: Thirty-eight patients (23 males and 15 females) with polysomnographically verified OSAS (mean age, 49 ± 12 years, range 27–74) and a mean body mass index of 31.27 ± 5.24 kg/m2 (range 22.60–47.90) were prospectively studied. Plasma levels of homocysteine, cholesterols, triglycerides, vitamin B12 and high-sensitive C-reactive protein (hsCRP), as well as echocardiographic and lung function parameters were assessed. Results: Homocysteine levels were elevated in all OSAS groups and were statistically significantly different between the mild and moderate/severe groups. Significant differences were present between the variables nocturnal oxygen desaturation (NOD), respiratory arousal and light sleep among the mild and moderate/severe groups. We found a significant positive correlation between homocysteine levels and NOD duration, and hsCRP levels were positively correlated with the apnea-hypopnea index and NOD duration. Conclusions: In all OSAS groups, homocysteine levels were elevated regardless of the presence of cardiac dysfunction. Echocardiographic abnormalities were primarily left-ventricular (LV) hypertrophy and LV diastolic dysfunction and could be observed in all OSAS severity groups.
Classification of Stroke Subtypes
Authors: Amarenco P. , Bogousslavsky J. , Caplan L.R. , Donnan G.A. , Hennerici M.G.
Published: April 2009

This article reviews published stroke subtype classification systems and offers rules and a basis for a new way to subtype stroke patients. Stroke subtyping can have different purposes, e.g. describing patients’ characteristics in a clinical trial, grouping patients in an epidemiological study, careful phenotyping of patients in a genetic study, and classifying patients for therapeutic decision-making in daily practice. The classification should distinguish between ischemic and hemorrhagic stroke, subarachnoid hemorrhage, cerebral venous thrombosis, and spinal cord stroke. Regarding the 4 main categories of etiologies of ischemic stroke (i.e. atherothrombotic, small vessel disease, cardioembolic, and other causes), the classification should reflect the most likely etiology without neglecting the vascular conditions that are also found (e.g. evidence of small vessel disease in the presence of severe large vessel obstructions). Phenotypes of large cohorts can also be characterized by surrogate markers or intermediate phenotypes (e.g. presence of internal carotid artery plaque, intima-media thickness of the common carotid artery, leukoaraiosis, microbleeds, or multiple lacunae). Parallel classifications (i.e. surrogate markers) may serve as within-study abnormalities to support research findings.
Evaluation of Potential Power Gain with Imputed Genotypes in Genome-Wide Association Studies
Authors: Becker Tim , Flaquer Antonia , Brockschmidt Felix F. , Herold Christine , Steffens Michael
Published: April 2009

Background: With the beginning of the era of genome-wide association studies methods to obtain ‘in silico’ genotypes have gained importance. In this context, an evaluation of genome-wide power levels of current marker panels and the power gain achievable with imputed genotypes are of high interest. Methods: Power for single-marker analysis of imputed genotypes is evaluated via a simulation study based on HapMap data. Power values for genome-wide significance of marker panels of 1,000,000 SNPs are considered for small effect sizes typical of common diseases and large case-control samples. In order to evaluate the performance of imputing, we consider a method that is conceptually related to previous approaches. We introduce various modifications which together lead to an alternative implementation of the imputation idea. In particular, a Monte-Carlo (MC) simulation method for association testing of imputed markers is introduced. Results: We show that the incorporation of imputed genotypes can lead to a substantial power gain for common disease variants if the training sample is large enough. In addition, we show that the MC approach is valuable to for validating association results obtained with imputed genotypes. Discussion: Our simulation study also shows that even denser marker panels than those currently available are needed when sample size is limited. We thus expect that full genome SNP panels will lead to the identification of additional disease variants in the future. Until then, it is desirable that large and ethnically matched training samples genotyped on dense marker panels are available in each country.
Local Population Structure in Arabian Peninsula Revealed by Y-STR Diversity
Authors: Alshamali Farida , Pereira Luísa , Budowle Bruce , Poloni Estella S. , Currat Mathias
Published: April 2009

Genetic studies have been underway on Arabian Peninsula populations because of their pivotal geographic location for population migration and times of occurrence. To assist in better understanding population dynamics in this region, evidence is presented herein on local population structure in the Arabian Peninsula, based on Y-STR characterisation in four Arabian samples and its comparison in a broad geographical scale. Our results demonstrate that geography played an important role in shaping the genetic structure of the region around the Near-East. Populations are grouped regionally but none of these groups is significantly differentiated from others and all groups merge in the Near-East, in keeping with this important migration corridor for the human species. Focusing on the Arabian Peninsula, we show that Dubai and Oman share genetic affinities with other Near-Eastern populations, while Saudi Arabia and Yemen show a relative distinctive isolated background. Those two populations may have been kept relatively separated from migration routes, maybe due to their location in a desert area.
Expression of Two Inflammation-Related Genes (RIPK3 and RNF216) in Mononuclear Cells Is Associated with Weight-Loss Regain in Obese Subjects
Authors: Goyenechea Estibaliz , Crujeiras Ana B. , Abete Itziar , Martínez J. Alfredo
Published: April 2009

Background/Aims: Nutrigenomics is providing molecular biomarkers concerning the assessment of diet-related diseases. We analyzed the expression of two interacting genes (RIPK3 and RNF216) in obese subjects receiving a low-calorie diet (LCD) and during the subsequent weight changes. Methods: Two groups of obese subjects (BMI 32.3 ± 5.5kg/m2; age 37.7 ± 7.1 years) were selected according to the 6-month weight-regain outcome after the weight-loss induced by an 8-week LCD (n = 12). Body composition and mRNA levels of RIPK3 and RNF216 in peripheral blood mononuclear cells (PBMC) were evaluated by qRT-PCR at three time-points (week 0, week 8 and week 32). Results: All subjects lost weight significantly (–5.8 ± 2.3%, p < 0.001) and were grouped depending on the successful weight-loss maintenance (weight-loss regain ≤10% or >10%). At baseline (week 0), no differences were observed in the mRNA levels between groups (p > 0.05). However, at the end of the LCD (week 8), association analysis revealed that higher mRNA levels in PBMC of RIPK3 and RNF216 were able to detect those individuals who are more prone to regain weight 6-month after the nutritional intervention (p < 0.05). Conclusions: Gene expression of RIPK3 and RNF216 in PBMC could identify those obese subjects, who will regain more weight after a successful initial weight loss. The mRNA levels of these genes could be suggested as nutrigenomic biomarkers for predicting the obesity treatment outcome.
Hexadecane-induced Skin Hyperplasia in the Hairless Rat: Time Course of Histological and Biochemical Events Related to the Synthesis of Polyamines and DNA
Authors: Bouclier M. , Shroot B. , Milano G. , Ferracin J. , Chatelus A. , Hensby C.N.
Published: April 2009

Several biochemical parameters including ornithine decarboxylase activity (ODC) and tissue polyamine levels were measured during the hexadecane-induced epidermal hyperplasia of hairless rat skin. Animals received three applications of 200 µ1 pure n-hexadecane on day 1. ODC activity and polyamine levels (putrescine, spermidine and spermine) in the epidermis were significantly increased and reached maximum elevations at 12 h after the start of n-hexadecane treatment with DNA synthesis peaking at 24 h. Histological studies confirmed a significant cellular edema at 24 h after the beginning of the treatment followed at 48 h by an epidermal hyperplasia which was maximum at 72 h. These data support the view that ODC activation, increased biosynthesis of polyamines and DNA are early events in epidermal cell hyperproliferation.
Measurement of Epidermal Thickness in Normal Skin and Psoriasis with High-Frequency Ultrasound
Authors: Hermann Richard C. , Ellis Charles N. , Fitting Dale W. , Ho Vincent C. , Voorhees John J.
Published: April 2009

In this study, we employed a high-frequency ultrasound system to measure the epidermal thicknesses of psoriasis plaques and normal skin in vivo. Eighty-four percent of the ultrasound measurements fell within the range of epidermal thickness determined by histology. The average thickness of untreated psoriasis measured by ultrasound was significantly greater than that of either treated psoriasis or normal skin. Ultrasound measurement of thickness was consistent with clinical assessment. Ultrasound measurements also demonstrated known variations in epidermal thickness by body site. Further development is needed to obtain measurements that are fully representative of the epidermis.
Nitroglycerin and Sucrose Permeability as Quality Markers for Reconstructed Human Epidermis
Authors: Ponec Maria , Wauben-Penris Paulette J.J. , Burger Anita , Kempenaar Johanna , Boddé Harry E.
Published: April 2009

In order to evaluate the epidermal permeability barrier of in vitro reconstructed epidermis, the penetration of nitroglycerin (NG) and sucrose were measured across human keratinocytes cultured at the air-liquid interface, using de-epidermized dermis (DED) as a substrate. In the presence of reconstructed epidermis on top of DED the penetration rate of sucrose is about 100 times and that of NG 2 times lower, as compared to DED only, indicating that the stratum corneum of the cultured epidermis exhibits considerable barrier capacity. The permeability of reconstructed epidermis was for both solutes higher (3- to 10-fold) than that of freshly excised human skin. Based on the impaired barrier function and distribution of various differentiation markers it can be concluded that the reconstructed human epidermis used in the present study shows a high extent of similarity with hyperproliferating epidermis.
Transepidermal Water Loss Modifications in Rats and Humans Treated with Ciclosporin
Authors: Doucet O. , Tidjani A. , Venencie P.Y. , Bismuth H. , Marty J.P.
Published: April 2009

Modifications of transepidermal water loss (TEWL) of rat and human skin induced by oral administration of ciclosporin (CS) were investigated. The integrity of the cutaneous barrier was evaluated using TEWL measurement which is a relatively simple and noninvasive means of assessing the functional state of the cutaneous barrier. After 12 weeks, the TEWL of treated rats decreased significantly and this difference was still present after the 16 weeks of treatment. In humans, there was a statistically significant decrease of TEWL on both forearm and thigh in CS-treated patients compared to non-CS-treated patients and controls (p < 0.05). These results suggest that CS causes skin modifications, particularly concerning its barrier status. The nature of these skin modifications still remains to be determined.
Citropten and Bergapten Suction Blister Fluid Concentrations after Solar Product Application in Man
Authors: Treffel P. , Makki S. , Faivre B. , Humbert P. , Blanc D. , Agache P.
Published: April 2009

Citropten (5,7-dimethoxycoumarin) and bergapten (5-methoxypsoralen) are present in bergamot oil which is used as a cosmetic tanning product. The aim of this study was to quantify, using HPLC, the amount of citropten and bergapten in the skin after the application of suntan products (emulsion and oil formulations). A suction blister technique, performed on the volar aspect of the forearm, permitted the collection of these two molecules. The blister fluid concentrations were 37 and 51 ng/ml (emulsion) and 26 and 23 ng/ml (oil), respectively, for citropten and bergapten. Our results show that the suction blister technique could be used for comparing transepidermal penetration of several compounds in vivo in man.
Topical Retinoid Treatment for Skin Cancer: A Review
Authors: Lever L. , Marks R.
Published: April 2009

There is laboratory and clinical evidence to suggest that retinoids have a potentially important place in the management of neoplastic and preneoplastic disorders of the epidermis. Topical administration avoids the side-effects of orally administered retinoids, but doubts remain over their efficacy. Evidence from clinical studies suggests that although topical retinoids have some effect in treating established skin cancers, alternative treatments are more effective. Topical retinoids appear more effective in the treatment of solar keratoses and epidermal dysplasia in photodamaged skin.
In vitro Methods for the Assessment of Primary Local Effects of Topically Applied Preparations
Authors: Pape Wolfgang J.W. , Hoppe Udo
Published: April 2009

Three ‘alternative’ methods for the screening of the primary irritation potentials of topically applied preparations and raw materials are presented as a test battery and their in vitro endpoints are compared with in vivo data. The first method is the intermediate test on the chorioallantoic membrane of hens’ fertilized eggs, which is generally proposed for the prediction of the irritation potential of chemicals. Relevant test parameters, such as the time-dependent appearance of hemorrhages, vascular lysis and coagulation, are used to classify the test substances. Secondly, cytotoxicity tests with Balb/c 3T3 fibroblasts are used to characterize the influence of test materials on cellular homeostasis and viability, which is quantified by the dose-dependent uptake of Neutral red. As a second parameter changes in the cellular protein level can be easily measured by subsequent staining with Kenacid blue. Finally, the third approach to in vitro evaluation is presented in the form of the red blood cell assay, a rapid photometric assay which permits distinguishing basically between damage to the membrane and to proteins as endpoints which correlate with lesions observed on the conjunctiva, iris and cornea in the eye and the acute inflammatory responses evoked during epicutaneous irritancy testing. Changes in the optical behavior of oxyhemoglobin are used as the inherent indicator for monitoring both endpoints and their interrelations. These methods are proposed and can be used advantageously for testing newly developed topical preparations and their ingredients in view of their local irritation potential without further use of animal testing. Moreover, they can also be used for screening chemicals.
Synthetic Retinoids Affect Differently the Epidermal Synthesis of 3,4-Didehydroretinol
Authors: Törmä Hans , Stenström Eva , Andersson Eva , Vahlquist Anders
Published: April 2009

For unknown reasons, the epidermal concentrations of retinol and its metabolite 3,4-didehydroretinol become characteristically changed during treatment with certain synthetic retinoids. In the present study we investigated [3H]retinol uptake and conversion to 3,4-[3H]didehydroretinol in cultured human skin exposed to six different retinoids. The tissue accumulation of [3H]retinol increased by 50–130% following addition of 1.3 µM of all-trans-retinoic acid, 13-cis-retinoic acid, or 3,4-didehydroretinoic acid (putative metabolites of retinol), and by 13–55% after addition of acitretin, arotenoid Ro 13-7410, or 4-(N-hydroxyphenyl)retinamide. The formation of 3,4-[3H]didehydroretinol was markedly inhibited (minus 80–90%) by the three putative retinol metabolites, moderately inhibited (minus 60–70%) by the aromatic retinoic acid analogues acitretin and arotinoid, and only slightly inhibited (minus 25%) by 4-(N-hydroxyphenyl)retinamide. Addition of citral and ketoconazole, substances known to interfere with the oxidative metabolism of vitamin A, diminished the formation of 3,4-didehydroretinol by 70 and 95%, respectively, but only marginally affected the retinol values. We conclude that the increase in retinol and marked reduction in 3,4-didehydroretinol concentrations in epidermis especially during treatment with 13-cis-retinoic acid are most likely due to diminished conversion of retinol to 3,4-didehydroretinol, but whether or not this reflects feedback inhibition of retinol metabolism or direct inhibition of a specific enzyme remains to be established. Nonetheless, in vitro analysis of 3,4-didehydroretinol biosynthesis appears to be a sensitive means for screening compounds for their ability to interfere with the cutaneous vitamin A metabolism.
Fibroblast-Dependent Differentiation/Proliferation of Mast Cells
Authors: Kitamura Yukihiko , Kasugai Tsutomu , Ebi Yoshitaka , Nomura Shintaro
Published: April 2009

Fibroblast-dependent differentiation and proliferation of mast cells were reviewed from the viewpoint of mast cell-deficient mutant animals. Mice of W/Wv, Sl/Sldor mi/mi genotype are deficient in mast cells. However, since T cell-dependent differentiation and proliferation of mast cells are intact in these mutant mice, mast cells do develop when bone marrow cells of these mutant mice were cultured in the presence of T cell-derived growth factors. Cultured mast cells (CMC) of W/Wvmice cannot receive the prohferative stimulus from fibroblasts whereas fibroblasts derived from Sl/Sldembryos cannot provide normal (+/+) CMC with the prohferative stimulus. The W locus encodes a tyrosine kinase receptor and the SI locus the ligand for the receptor. Although +/+ CMC acquire the phenotype resembling connective tissue-type mast cells when cocultured with fibroblasts in medium containing T cell-derived growth factors, mi/mi CMC do not. We recently found a mast cell-deficient mutant of rats. Biological features of the mast cell-deficient rats were very similar to those of W/Wvmice. The mast cell-deficient mutant animals are invaluable tools for investigations of differentiation/proliferation and functions of mast cells.
Effects of Cetirizine, Loratadine and Terfenadine on Histamine Weal and Flare Reactions
Authors: Lever L.R. , Hill S. , Marks R. , Rosenberg R. , Thompson D.
Published: April 2009

This randomised double-blind, placebo-controlled, cross-over study compared the effects of single oral doses of terfenadine 120 mg, cetirizine 10 mg, and loratadine 10 mg on experimentally induced weal and flare reactions. The areas of weal and flare induced by intracutaneous injections of histamine were measured using planimetry, weal thickness by A-scan pulsed ultrasound and erythema index by a device which measures the relative reflectance of red and green light. All three antihistamines suppressed the weal and flare area and weal thickness 3, 6, 12 and 24 h after dosing. At the usual currently recommended doses terfenadine and cetririzine were most effective after 6 h and were more potent than loratadine for the first 6 h of the study.
Effect of Occlusion on in vitro Percutaneous Absorption of Two Compounds with Different Physicochemical Properties
Authors: Treffel P. , Muret P. , Muret-D’Aniello P. , Coumes-Marquet S. , Agache P.
Published: April 2009

It is a general rule that percutaneous absorption is increased when the site of application is occluded. In this study we compared the in vitro permeation profiles of two molecules with different physicochemical properties under occluded versus unoccluded conditions. Human abdominal skin samples were mounted on Dianorm® Teflon® macro 1 cells and Franz diffusion cells which represented occluded or unoccluded conditions, respectively. Our data show that occlusion increased the permeation of citropten (lipophilic compound) 1.6 times whereas that of caffeine (amphiphilic compound) remained unchanged. This lack of penetration enhancement under occluded conditions has also been observed by other authors, especially concerning hydrophilic and slightly lipophilic molecules. Our results support the view that occlusion does not necessarily increase the percutaneous absorption of a chemical.
The Human Hair Follicle Engages in Glutaminolysis and Aerobic Glycolysis: Implications for Skin, Splanchnic and Neoplastic Metabolism
Authors: Kealey Terence , Williams Rebecca , Philpott Michael P.
Published: April 2009

On maintenance in supplemented Williams E medium, human hair follicles grow at the normal rate, and retain their normal anagen morphology, for up to 10 days. This permits us to study their metabolism under near-physiological conditions. The ATP content of freshly isolated follicles was 124.4 ± 10.6 pmol/follicle (mean ± SEM; n = 50). The energy charge was 0.81 ± 0.08 and the glycogen content 2.3 ± 0.3 nmol/follicle. These did not alter significantly during any metabolic studies, which were performed for up to 6 h in supplemented Williams E medium. We found that the major fuel was glucose, which at physiological concentrations yields 5.47 ± 0.77 nmol ATP/follicle/h, but 90% of the glucose was metabolised to lactate, and only 10% oxidised. Glutamine was also an important fuel, generating 2.16 ± 0.33 nmol ATP/follicle/h, but this too was largely metabolised to lactate rather than oxidised. Lipid fuels such as palmitate or β-hydroxybutyrate only yielded 0.72 ± 0.15 and 0.72 ± 0.14 nmol ATP/follicle/h, respectively, and their oxidation did not inhibit glucose utilisation. No glucose-fatty acid cycle operates in the hair follicle, therefore, but a glucose-glutamine cycle does, since the presence of glutamine will inhibit glucose utilisation.
Lipid Composition and Barrier Function of Human Skin after Grafting onto Athymic Nude Mice
Authors: Higounenc Isabelle , Spies Ferry , Boddé Harry , Schaefer Hans , Demarchez Michel , Shroot Braham , Ponec Maria
Published: April 2009

The barrier properties of human epidermis grafted for 1–3 months onto nude mice are compared with normal human skin. Beside penetration studies with tritiated water and measurements of transepidermal water loss (TEWL), we analyzed the epidermal lipids by high-performance thin layer chromatography and evaluated the ultrastructure of the intercorneocyte lipid arrangement by freeze fracture electron microscopy (FFEM). The permeability of human skin for tritiated water and the TEWL exhibit no significant changes after grafting onto nude mice. FFEM analysis showed that grafted epidermis has the same morphological pattern as normal human epidermis. Regular desmosomes and lamellar lipid structures are present. Grafting did not qualitatively affect the lipid composition of human epidermis. Ceramides which contribute largely to the barrier function, have the same distribution profile.
The Kidney from Prenatal to Adult Life: Perinatal Programming and Reduction of Number of Nephrons during Development
Authors: Puddu Melania , Fanos Vassilios , Podda Francesca , Zaffanello Marco
Published: April 2009

Modified embryonic-fetal development resulting in low birth weight may lead to a reduced nephron endowment, hypertension and renal diseases in adulthood. Regarding the involvement of genetic factors, several environmental conditions may also contribute towards reducing the number of nephrons in the fetus and infant, subsequently constituting a health burden in later life. To date no methods of investigation for the early detection of a reduced nephron reserve are available. However, more structured studies should be implemented to investigate the role of angiotensin-converting enzyme inhibitors in managing proteinurias and glomerulosclerosis in children with renal conditions characterized by reduce nephron number and glomerular hypertrophic changes. In view of the current lack of specific methods of investigation and management, close monitoring of children and young adults at risk of reduced renal reserve should be carried out to enhance the early detection of potential changes in renal function.
Distribution and Keratolytic Effect of Salicylic Acid and Urea in Human Skin
Authors: Lodén Marie , Boström Per , Kneczke Marianne
Published: April 2009

Salicylic acid (SA) and urea are widely used in topical preparations. Using a simple tape stripping technique the effect on the binding forces within the stratum corneum and the skin absorption of SA and urea were studied. The degree of stratum corneum removal was recorded by measuring the transmission through the tape with a digital light-measuring instrument. With successive stripping of the skin the amount of tissue adhering to the tape decreased. Exposure of the upper arm to 2% SA for 6 h increased the skin material on the tape strips significantly. No significant increase was recorded after 3-hour exposure, or after exposure to 0.5% SA. Neither did the exposure to 10% urea for 3 or 6 h influence the amount of skin adhering to the tape significantly. Radiochemical analyses showed that the amount of SA and urea in each of the first 6 tape strips was about 5-15 μg/cm2. This technique provides a useful tool to evaluate the binding forces within the stratum corneum in relation to absorption of topically applied substances.
Modification of Lipogenesis in the Isolated Hamster Flank Organ through Clofibric Acid
Authors: Venencie P.Y. , Vantrou-Delaunay M. , Bougaret S. , Chaumeil J.C.
Published: April 2009

The hamster flank organ model was used to measure the effects of clofibric acid on the in vitro uptake of sodium [1-14C] acetate into lipids. Clofibric acid produces a dose-dependent inhibition of lipogenesis in the hamster flank organ in vitro.
Cyclosporine A Inhibits tPA mRNA Transcription in A431 Cell Line
Authors: Teofoli P. , Mancini A. , Lotti T.
Published: April 2009

Cyclosporine A (CyA), a well established treatment of psoriasis, is a highly lipophilic cyclic undecapeptide mainly used for its immunosuppressive properties and exerting a wide spectrum of biological activities including fungicidal antiproliferative and anti-inflammatory effects. Plasminogen activators (PA), urokinase (UK, Mr 55,000) and tissue type plasminogen activators (tPA, Mr 74,000), physiologically catalyze the conversion of the plasminogen to the wide spectrum proteinase plasmin. UK and tPA are involved in cell growth, differentiation and migration. It has recently been shown that psoriatic epidermis is provided with abnormal tPA-dependent PA activity and that in lesional epidermis elevated tPA mRNA levels are present. It has been suggested that the tPA-dependent PA activity is a marker of disease activity and is reversible with different topical and systemic treatments. In this preliminary study we investigate the effect of CyA on the tPA mRNA transcription on A431 keratinocytes cell line. Sub-confluent A431 cell cultures have been treated with CyA at in vivo relevant concentrations (10, 7.5, 5 µg/ml) for 48 h. Northern blot analysis of total RNA extracted from cultured A431 cell line has been performed for detecting tPA mRNA. mRNA for tPA has been detected in the control samples whereas an evident decrease of tPA mRNA expression has been detected in the CyA-treated samples. These data suggest that CyA could have an effect in clearing psoriatic lesions also modulating the abnormal plasminogen activation i.e. tPA-dependent serinoproteinase activity.
A Minoxidil-Related Compound Lacking a C6 Substitution Still Exhibits Strong Anti-Lysyl Hydroxylase Activity in vitro
Authors: Mahé Yann F. , Buan Bruno , Bernard Bruno A.
Published: April 2009

It has been previously reported that minoxidil inhibits the activity of lysyl hydroxylase (LH), an enzyme which catalyzes the formation of hydroxylysine, which is necessary for proper maturation of collagen at the transcriptional and enzymatic levels. Using the reverse transcriptase-polymerase chain reaction, we confirmed that this inhibition occurred at least at the transcriptional level. Furthermore, we took advantage of this sensitive and rapid method to perform a quantitative structure activity relation study using several compounds structurally related to minoxidil. We found that when the C6 of the pyrimidinyl moiety was substituted, it had to be by a tertiary nitrogen, i.e. an N-piperidin ring for the inhibition of LH mRNA synthesis to be observed. Surprisingly, however, we found that 2,4-diamino-pyrimidin-3-oxide, a new compound lacking an organic moiety para to the nitroxide oxygen, also retained a high inhibitory effect on LH mRNA expression, comparable to that of minoxidil. We thus conclude that the presence of a substituent para to the nitroxide oxygen is dispensable for inhibition of LH mRNA to be observed in vitro. This brings new insights into the design of therapeutic agents useful in any condition where an overproduction of mature collagen is unwanted, i.e. accelerated wound healing, keloids and localized scleroderma.
Metabolism of Benzocaine during Percutaneous Absorption in the Hairless Guinea Pig: Acetylbenzocaine Formation and Activity
Authors: Kraeling Margaret E.K. , Lipicky Raymond J. , Bronaugh Robert L.
Published: April 2009

The effect of dose and enzymatic inhibition on the percutaneous absorption and metabolism of benzocaine was studied in vitro in the hairless guinea pig. At the dose level of 2 μg/cm2, benzocaine was rapidly absorbed and extensively metabolized (80%) by acetyltransferase. As the applied dose of benzocaine was increased to 40 and 200 μg/cm2, N-acetylation of benzocaine decreased to 44 and 34%, respectively, suggesting saturation of the acetyltransferase system. Total 14C absorption after benzocaine application was not significantly different between control and enzyme-inhibited skin and therefore does not appear to be affected by the extent of benzocaine metabolism during percutaneous penetration. Skin provides a significant first-pass metabolic effect for therapeutic doses of percutaneously absorbed benzocaine, and the primary metabolite formed, acetylbenzocaine, is biologically active.
Cytochrome P-450 and Drug Development for Skin Diseases
Authors: Ahmad Nihal , Agarwal Rajesh , Mukhtar Hasan
Published: April 2009

Cytochromes P-450 (CYPs) are the most versatile and important class of drug-metabolizing enzymes which are induced in mammalian skin in response to xenobiotic exposure. CYPs are the target of special interest in the development of pharmaceuticals for skin diseases because most, if not all, drugs available in the armamentarium of the dermatologist are substrates, inducers or inhibitors of this enzyme family. The functional significance of drug metabolism in the skin and the implication of CYP in skin pathology and therapy is an area for future investigation. A detailed insight into the mechanism of action of various cutaneous CYPs, being capable of modulating the drug bioavailability, will be helpful in the development of better strategies for novel therapy against constantly increasing skin disorders. This brief review puts some of these perspectives together and suggests additional research in the area of CYPs with regard to their expression and modulation in mammalian skin as well as their implication in dermatological disorders and the therapy of skin diseases.
Evaluation of Topical Antipsoriatic Treatment by Chromametry, Visiometry and 20-MHz Ultrasound in the Psoriasis Plaque Test
Authors: Bangha E. , Elsner P.
Published: April 2009

The antipsoriatic effects of two topical antipsoriatic agents, betamethasone valerate (Betnovate®) and calcipotriol (Dai-vonex®), and a pure nanocolloid gel were assessed in 10 patients with chronic plaque-type psoriasis in a modified psoriasis plaque test. Three noninvasive bioengineering methods were applied to measure antipsoriatic effects: chromametry for objective evaluation of erythema; visiometry, a method for profilometry, and 20-MHz skin ultrasound for the measurement of skin thickness as a parameter of inflammatory infiltration and psoriatic hyperproliferation of the epidermis. Regarding inflammation parameters such as skin thickness (infiltration) and erythema (dilatation of vessels and hyperperfusion), the steroid preparation Betnovate proved to be significantly most effective in our study. Daivonex showed significant decreases in the skin roughness parameters, underlining its antiproliferative effect. The nanocolloid carrier was significantly effective in thickness reduction, this effect being most probably due to occlusion. 20-MHz ultrasound, chromametry and visiometry proved to provide multiparameter assessment of treated and untreated psoriatic skin and can be recommended as objective and reproducible measurements for further studies.
Influence of Human Ageing on Aspects of the Cerebral Circulation
Authors: Lovett Doust J.W.
Published: April 2009

Cerebral impedance plethysmography (REG) is a non-traumatic, reproducible method of continuously monitoring aspects y of the cerebral circulation. Its use in more than 200 healthy subjects aged 6–70 years was investigated, measurements being applied to three characteristics of the standardized averaged REG wave form. It was found that inflow angle and percent rise time changed progressively and significantly as chronological age advanced but amplitude was not so affected. Menstrual status, sex and hemispheric sidedness were not significant variables. The role of REG as a monitor of the ageing process in man is discussed.
The Ageing Pattern of Human Intervertebral Disc
Authors: Bijlsma F. , Copius Peereboom J.W.
Published: April 2009

The problem of intervertebral disc pathology (herniation, prolapsus) especially in younger persons (30–50 years of age) remains as yet unsolved. Observations on 26 post mortem samplestaken from individuals aged 0–83 years suggest a pattern of normal ageing which has not been described before and which has, in the authors’ opinion, to be compared with pathologically-changed, surgically-removed intervertebral discs. Also the occurrence of a lipid containing age pigment is discussed. A hypothesis is forwarded aboutthe origin of disc pathology in younger persons.
The 5-Methylcytosine in DNA of Rats
Authors: Vanyushin B.F. , Nemirovsky L.E. , Klimenko V.V. , Vasiliev V.K. , Belozersky A.N.
Published: April 2009

The GC content and amount of 5-methylcytosine (5-MeCyt) have been determined in total DNA from certain organs of male albino rats 1, 12 and 28 months of age. A marked tissue specificity of DNA with respect to the 5-MeCyt content has been revealed. The 5-MeCyt content in DNA decreases with age in the brain, heart and spleen; it does not change in the liver and lungs and slightly increases in the kidneys. There are no other age differences in the DNA studied (GC content, Tm and other physico-chemical properties). Thus, age differences in the 5-MeCyt content are most probably due to the different level of DNA methylation. The 5-MeCyt content in liver DNA changes drastically under the influence of hydrocortisone and other gene inducers. These changes are tissue specific and positively correlate with the functional activity of cells. The changes in the DNA methylation under the action of hormones resemble those appearing with age. DNA methylation may be one of the regulatory mechanisms of gene activity and the changes in 5-MeCyt content observed may be somehow responsible for the process of ageing.
Long-Term Culture of Human Adult Liver Cells: Morphological Changes Related to in vitro Senescence and Effect of Donor’s Age on Growth Potential
Authors: Le Guilly Y. , Simon M. , Lenoir P. , Bourel M.
Published: April 2009

The morphological aspects of ageing and growth capacity were studied in 100 lines of human liver cells. Under the culture conditions employed, liver cells appear to have a limited replicative life span. The morphological effects of ageing were similar to those described in the tissue culture of other organs. Studies on growth potential showed that there was a negative correlation between age of the donor tissue and age of the culture at the last passage, maximum number of doublings, number of doublings in phase II, and age of the culture at the end of phase II. The growth indices were different for epithelial-like and fibroblast-like cells.
Aortic Lathyrism: Ultrastructural Study of Lesions in the Aortic Wall and the Protective Effect of Pyridinol Carbamate
Authors: Pieraggi M.T. , Julian M. , Bouissou H.
Published: April 2009

Electron-microscopic examination of aortas of rat treated orally and chronically with β-aminopropionitrile (BAPN) has shown progressive lesions in the elastic framework. This is associated with modifications of cells in the media which dedifferentiate into histiocytes and fibrocytes and also multiply. These changes begin in the 5th week of treatment, and are responsible for the hyperplasia of the intima as well as its thickening and collagenization. They support observations made in man during aortic aging, namely with regard to the intima and the intima-media junction. A high lipid diet given at various times during intoxication causes lipid deposition in the intima and a substantial penetration into the media when the lesions are developing. This also corroborates some hypotheses on the development of human atheroma. The addition of pyridinol carbamate (PDC) to BAPN prevents the formation of elastic tissue lesions. When given after the cessation of lathyrism treatment, PDC arrests and causes regression of lesions in the aortic media. It has no effects on lipid deposits, but the deposits are confined to the intima only.
Loss of Mitochondrial DNA with Aging in Drosophila melanogaster
Authors: Massie H.R. , Baird M.B. , McMahon M.M.
Published: April 2009

The buoyant densities of nuclear and mitochondrial DNA from Drosophila melanogaster lysates has been found to show no change with increasing age in both CsCl and Cs2SO4 equilibrium density gradients. Whole fly homogenates were used to demonstrate no change in nuclear DNA content during adult life. Mitochondrial DNA increased from 1.2 to 4.3% of the total DNA during the first week of adult life and then decreased during senescence to a minimum of 1.5% at 10 weeks of age which represented a 65% loss in mitochondrial DNA content with age. These data are interpreted to support the proposal that mitochondria destruction occurs during senescence.