bluuebunny/crossref_metadata_2025 huggingface dataset:
Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated–p53 activation
Authors: Kaur Manjinder , Agarwal Rajesh , Agarwal Chapla
Published: May 2006

Prostate cancer is the second leading cancer diagnosed in elderly males in the Western world. Epidemiologic studies suggest that dietary modifications could be an effective approach in reducing various cancers, including prostate cancer, and accordingly cancer-preventive efficacy of dietary nutrients has gained increased attention in recent years. We have recently shown that grape seed extract (GSE) inhibits growth and induces apoptotic death of advanced human prostate cancer DU145 cells in culture and xenograft. Because prostate cancer is initially an androgen-dependent malignancy, here we used LNCaP human prostate cancer cells as a model to assess GSE efficacy and associated mechanisms. GSE treatment of cells led to their detachment within 12 hours, as occurs in anoikis, and caused a significant decrease in live cells mostly due to their apoptotic death. GSE-induced anoikis and apoptosis were accompanied by a strong decrease in focal adhesion kinase levels, but an increase in caspase-3, caspase-9, and poly(ADP-ribose) polymerase cleavage; however, GSE caused both caspase-dependent and caspase-independent apoptosis as evidenced by cytochrome c and apoptosis-inducing factor release into cytosol. Additional studies revealed that GSE causes DNA damage–induced activation of ataxia telangiectasia mutated kinase and Chk2, as well as p53 Ser15 phosphorylation and its translocation to mitochondria, suggesting this to be an additional mechanism for apoptosis induction. GSE-induced apoptosis, cell growth inhibition, and cell death were attenuated by pretreatment with N-acetylcysteine and involved reactive oxygen species generation. Together, these results show GSE effects in LNCaP cells and suggest additional in vivo efficacy studies in prostate cancer animal models. [Mol Cancer Ther 2006;5(5):1265–74]
Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics
Authors: Gerweck Leo E. , Vijayappa Shashirekha , Kozin Sergey
Published: May 2006

The extracellular pH of tumor tissue is significantly lower than the extracellular pH of normal tissue, whereas the intracellular pH of both tissues is similar. In principle, extracellular acidity may be expected to enhance the intracellular uptake and cytotoxicity of weak acid chemotherapeutics that are membrane permeable in their uncharged state and inhibit the efficacy of weak bases. However, procedures for assessing the role of the gradient as a determinant of drug efficacy in vivo by altering the pH gradient may also alter drug availability and thus mask or exaggerate the effect of the gradient change. In the present study, we have altered the extracellular pH of tumors and compared the effect of the resultant pH gradient change on the efficacy of a weak acid versus a weak base. This experimental design gives rise to a change in the ratio of chlorambucil- to doxorubicin-induced tumor growth delay, independent of possible changes in drug availability. The extracellular pH of the 54A human tumor in NCr/Sed/nu/nu mice was altered by administration of 5 mg/g i.v. glucose. The resultant 0.2 pH unit increase in the tumor cell pH gradient gives rise to a predicted 2.3-fold increase in the ratio of chlorambucil to doxorubicin growth delay. The experimentally measured change in the growth delay ratio was 2.1. The results provide compelling evidence that the pH gradient in a determinant of the efficacy of weak electrolytes in the complex in vivo environment and may be exploited for the treatment of cancer. [Mol Cancer Ther 2006;5(5):1275–9]
Drugs Affecting Visceral Sensitivity: Ready for the Prime Time?
Authors: Delvaux Michel M. , Gay Gérard
Published: May 2006

Visceral sensitivity has been recognized over the last decade as a frequent pathophysiological component of functional bowel disorders. Studies in animals and humans have identified numerous neurotransmitters involved in the processing of sensations from the gut to the brain. However, up to now none of them has actually been proven to have a marked clinical efficacy and the benefit comes rather from their action of bowel disturbances. Reproducible tests are lacking to detect visceral hypersensitivity in humans and distension tests are difficult to undertake in a clinical setting. Therefore, abnormal visceral sensitivity may not be regarded as a tool to select IBS patients as candidates for a given treatment.
Opioid-Induced Gastrointestinal Dysfunction
Authors: Mehendale Sangeeta R. , Yuan Chun-Su
Published: May 2006

Use of opioid analgesics is associated with a number of side effects, especially opioid-induced gastrointestinal dysfunction. The extensive use of these compounds and the significant negative impact of the resulting gastrointestinal dysfunction on patients’ quality of life make it an important clinical issue. In recent years our understanding of the mechanisms of opioid-induced gastrointestinal dysfunction has advanced greatly. This article reviews the underlying pathophysiological mechanisms of specific gastrointestinal adverse effects of opioids. The role of endogenous opioid peptides in certain gastrointestinal diseases is also discussed. A better understanding of the pathophysiological mechanisms of opioid-induced bowel dysfunction should lead to the development of newer opioid analgesics and improved regimens resulting in reduced gastrointestinal adverse effects.
‘Rescue’ Therapies for the Management of Helicobacter pylori Infection
Authors: Di Mario Francesco , Cavallaro Lucas G. , Scarpignato Carmelo
Published: May 2006

Helicobacter pylori infection is the main cause of gastritis, gastroduodenal ulcer and gastric cancer and should be considered as a major public health issue. According to several international guidelines, first-line therapy for treating H. pylori infection consists of proton pump inhibitor (PPI) or ranitidine bismuth citrate (RBC) with any two antibiotics of amoxicillin, clarithromycin or metronidazole given for 7–14 days. However, even with the recommended treatment regimens, approximately 20% of patients will fail to obtain H. pylori eradication. The proportion of patients with first-line H. pylori therapy failure may be higher in clinical practice and it may increase thanks to diffusion of H. pylori treatment. The recommended second-line therapy is the quadruple regimen composed by tetracycline, metronidazole, bismuth salts and a PPI. However, the efficacy of this regimen is limited by poor patient’s compliance due to its side effects, number of tablets per day, and long duration. Moreover, bismuth and metronidazole are not available in all countries. Alternatively, a longer-lasting (i.e. 10–14 days) PPI or RBC triple therapy with two antibiotics has generally been used. In an empirical strategy, the choice of second line depends on the treatment initially used. If a clarithromycin-based regimen was administered in first line, a quadruple regimen or PPI (or RBC) triple therapy with metronidazole and amoxicillin (or tetracycline) should be suggested as a second line. In case of second-line treatment failure, the patient should be evaluated by a case-by-case approach. A susceptibility-guided strategy, if available, is recommended in order to choose the best third-line treatment. Culture can reveal the presence of H. pylori-sensitive strains to clarithromycin (the best effective) or other antimicrobials (such as amoxicillin, metronidazole and tetracycline). Conversely, in an empirical strategy, a third-line not yet used therapy, can reach a high success rate. PPI or RBC, amoxicillin and a new antimicrobial (e.g. rifabutin, levofloxacin or furazolidone) could be used. Several studies have obtained relatively good results with triple therapy combining PPI, rifabutin, and amoxicillin, although a reversible myelotoxicity as leukopenia and thrombocytopenia has been described. Preliminary good results were also achieved with triples PPI regimens combining levofloxacin and amoxicillin without important adverse effects. Furazolidone has also shown efficacy for H. pylori eradication, although untoward reactions could limit its use, especially when high doses are employed. Finally, in more than one H. pylori treatment failure, non-antimicrobial add-on medications (such as lactoferrin, probiotics and others) could be used with the aim either to improve the eradication rate or to minimize side effects.
Treatment of Gastrointestinal Stromal Tumor with Imatinib Mesylate: A Retrospective Single-Center Experience in Heidelberg
Authors: Kasper Bernd , Kallinowski Birgit , Herrmann Thomas , Lehnert Thomas , Mechtersheimer Gunhild , Geer Thomas , Ho Anthony D. , Egerer Gerlinde
Published: May 2006

Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Surgery has been the only effective therapy. However, many patients still eventually die of disease recurrence. Chemotherapy and radiation therapy have been of limited value. Imatinib mesylate (Glivec®) is an orally administered competitive inhibitor of tyrosine kinases associated with the KIT, ABL protein, licensed for the treatment of metastatic GIST since 2002 in Germany. Methods: We summarized the data of 16 patients with advanced or metastatic GIST treated with imatinib mesylate in palliative and neoadjuvant settings. Results: Overall response was 81%, with no evidence of disease (NED) in 3/16 (19%), partial response (PR) in 9/16 (56%) and stable disease (SD) in 1/16 (6%), whereas 3/16 patients (19%) suffered from progressive disease (PD). Mean follow-up was 18.6 months [range: 4–30]. Mean progression-free survival (PFS) was 17.6 months [range: 0–30], mean overall survival (OS) from initial diagnosis was 32.3 months [range: 5–122]. Most common side effects were periorbital edema and skin rash. Conclusion: Imatinib mesylate is well tolerated in a dose of up to 800 mg/day and has significant activity during long- term treatment of patients with advanced or metastatic GIST.
Gastroesophageal Reflux in Healthy Subjects Induced by Two Different Species of Chilli (Capsicum annum)
Authors: Milke Pilar , Diaz Angelica , Valdovinos Miguel Angel , Moran Segundo
Published: May 2006

Background: Although the ingestion of chilli has been associated with gastroesophageal reflux (GER) symptoms, there are no studies that have explored the effect of a chronic ingestion of different kinds of chilli with a variable content of capsaicin as a cause of GER. Methods: The effect of chilli on esophageal 24-hour pH monitoring was studied in 12 healthy subjects without GER symptoms before and after of ingestion one of two kinds of chilli. Patients were randomized to ingest 3 g daily of cascabel chilli (Capsicum annum coraciforme containing 880 ppmof capsaicin) or ancho chilli (Capsicum annum grossum containing 488 ppm of capsaicin). Results: After chilli ingestion, the Johnson De Meester Index (JDI) increased significantly [basal: 7 (1–14), after chilli: 13 (2–69), p = 0.0047]. When considering both kinds of chilli separately, the JDI varied, although nonsignificantly, with the ancho chilli [basal: 3 (1–8), after chilli: 10 (2–69), p = 0.11], and significantly with the cascabel chilli [basal: 10 (5–14), after chilli: 18 (2–44), p = 0.028]. Conclusion: Our results suggest that the chronic ingestion of chilli induces GER, and that the magnitude of the induced reflux seems to be related to the kind of chilli.
Diarrea persistente en países en vías de desarrollo
Authors: Bhutta Zulfiqar A.
Published: May 2006

Globalmente, las enfermedades diarreicas representan casi 1/5 de todas las muertes de niños menores de 5 años, con una estimación de 2,2 millones de fallecimientos anuales. De estas muertes, una proporción significativa guarda relación con episodios de diarrea persistente (DP; definida como una diarrea que persiste más de 14 días con crecimiento vacilante). Se ha demostrado que la DP identifica a niños con una carga diarreica considerablemente mayor. Estos representan del 36 al 54% de todas las muertes relacionadas con diarrea. Aunque la patogénesis exacta de la DP sigue sin conocerse a ciencia cierta, la mayoría de los episodios está relacionada con una diarrea infecciosa aguda previa en la que se prolonga el episodio más reciente. Esto puede guardar relación con varios factores del hospedante, como subnutrición preexistente, deficiencia de micronutrientes, inmunodeficiencia y tratamiento inapropiado del episodio diarreico agudo más reciente. El acontecimiento final común parece una lesión prolongada de la mucosa intestinal y una reparación ineficaz. En contraste con la DP postinfecciosa, algunos lactantes pueden presentar diarrea intratable grave debido a diversos trastornos, muchos de los cuales comparten una base hereditaria. Ésta constituye actualmente el tipo dominante de diarrea prolongada en los países desarrollados. El tratamiento de la DP depende de una minuciosa atención a la rehabilitación nutricional y a la identificación precoz de las complicaciones. Aunque se han asociado la DP con diversos patógenos, el papel del tratamiento antimicrobiano por vía oral en la terapéutica sistemática de la DP es exiguo. No obstante, la atención a la rehidratación, la detección y el tratamiento apropiados de las infecciones sistémicas y la rehabilitación nutricional enteral con dietas fácilmente digeribles son elementos cruciales en el tratamiento de estos niños, frecuentemente en entornos ambulatorios. La administración de cinc y vitamina A puede acortar la duración de la DP y contribuir también a reducir las recidivas. No obstante, las estrategias preventivas más importantes para la DP son la lactancia materna exclusiva durante los 6 primeros meses de vida, el mantenimiento de dicha lactancia durante 2 años con nutrición complementaria apropiada y el tratamiento óptimo de los episodios diarreicos agudos.
Dearomatizing Benzene Ring Reductases
Authors: Boll Matthias
Published: May 2006

The high resonance energy of the benzene ring is responsible for the relative resistance of aromatic compounds to biodegradation. Nevertheless, bacteria from nearly all physiological groups have been isolated which utilize aromatic growth substrates as the sole source of cell carbon and energy. The enzymatic dearomatization of the benzene nucleus by microorganisms is accomplished in two different manners. In aerobic bacteria the aromatic ring is dearomatized by oxidation, catalyzed by oxygenases. In contrast, anaerobic bacteria attack the aromatic ring by reductive steps. Key intermediates in the anaerobic aromatic metabolism are benzoyl-CoA and compounds with at least two meta-positioned hydroxyl groups (resorcinol, phloroglucinol and hydroxyhydroquinone). In facultative anaerobes, the reductive dearomatization of the key intermediate benzoyl-CoA requires a stoichiometric coupling to ATP hydrolysis, whereas reduction of the other intermediates is readily achieved with suitable electron donors. Obligately anaerobic bacteria appear to use a totally different enzymology for the reductive dearomatization of benzoyl-CoA including selenocysteine- and molybdenum- containing enzymes.
[NiFe]-Hydrogenases of Ralstonia eutropha H16: Modular Enzymes for Oxygen-Tolerant Biological Hydrogen Oxidation
Authors: Burgdorf Tanja , Lenz Oliver , Buhrke Thorsten , van der Linden Eddy , Jones Anne K. , Albracht Simon P.J. , Friedrich Bärbel
Published: May 2006

Recent research on hydrogenases has been notably motivated by a desire to utilize these remarkable hydrogen oxidation catalysts in biotechnological applications. Progress in the development of such applications is substantially hindered by the oxygen sensitivity of the majority of hydrogenases. This problem tends to inspire the study of organisms such as Ralstonia eutropha H16 that produce oxygen-tolerant [NiFe]-hydrogenases. R. eutropha H16 serves as an excellent model system in that it produces three distinct [NiFe]-hydrogenases that each serve unique physiological roles: a membrane-bound hydrogenase (MBH) coupled to the respiratory chain, a cytoplasmic, soluble hydrogenase (SH) able to generate reducing equivalents by reducing NAD+ at the expense of hydrogen, and a regulatory hydrogenase (RH) which acts in a signal transduction cascade to control hydrogenase gene transcription. This review will present recent results regarding the biosynthesis, regulation, structure, activity, and spectroscopy of these enzymes. This information will be discussed in light of the question how do organisms adapt the prototypical [NiFe]-hydrogenase system to function in the presence of oxygen.
Targets of Cytoprotection in Acute Ischemic Stroke: Present and Future
Authors: Lizasoain I. , Cárdenas A. , Hurtado O. , Romera C. , Mallolas J. , Lorenzo P. , Castillo J. , Moro M.A.
Published: May 2006

Although the management of stroke has improved remarkably over the last decade due mainly to the advent of thrombolysis, most neuroprotective agents, although successful in animal studies, have failed in humans. Our increasing knowledge concerning the ischemic cascade is leading to a considerable development of pharmacological tools suggesting that each step of this cascade might be a target for cytoprotection. Glutamate has long been recognized to play key roles in the pathophysiology of ischemia. However, although some trials are still ongoing, the results from several completed trials with drugs interfering with the glutamatergic pathway have been disappointing. Regarding the inhibition of glutamate release as a possible target for cytoprotection, it might be afforded either by decreasing glutamate efflux or by increasing glutamate uptake. In this context, it has been shown that glutamate transport is the primary and only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels. This transport is executed by the five high-affinity, sodium-dependent plasma membrane glutamate transporters. Among them, the transporter EAAT2 is responsible for up to 90% of all glutamate transport. We will discuss the effect of different neuroprotective tools (membrane stabilizers or endogenous neuroprotection) affecting glutamate efflux and/or expression of EAAT2. We will also describe the finding of a novel polymorphism in the EAAT2 promoter region which could be responsible for differences in both gene function and regulation under pathological conditions such as cerebral ischemia, and which might well account for the failure of glutamate antagonists in the clinical practice. These results may possess important therapeutic implications in the management of patients at risk of ischemic events, since it has been demonstrated that those patients with progressing stroke have higher plasma concentrations of glutamate which remain elevated up to 24 h when compared to the levels in patients without neurological deterioration.
Gene Expression in Cerebral Ischemia: A New Approach for Neuroprotection
Authors: Millán Mónica , Arenillas Juan
Published: May 2006

Cerebral ischemia is one of the strongest stimuli for gene induction in the brain. Hundreds of genes have been found to be induced by brain ischemia. Many genes are involved in neurodestructive functions such as excitotoxicity, inflammatory response and neuronal apoptosis. However, cerebral ischemia is also a powerful reformatting and reprogramming stimulus for the brain through neuroprotective gene expression. Several genes may participate in both cellular responses. Thus, isolation of candidate genes for neuroprotection strategies and interpretation of expression changes have been proven difficult. Nevertheless, many studies are being carried out to improve the knowledge of the gene activation and protein expression following ischemic stroke, as well as in the development of new therapies that modify biochemical, molecular and genetic changes underlying cerebral ischemia. Owing to the complexity of the process involving numerous critical genes expressed differentially in time, space and concentration, ongoing therapeutic efforts should be based on multiple interventions at different levels. By modification of the acute gene expression induced by ischemia or the apoptotic gene program, gene therapy is a promising treatment but is still in a very experimental phase. Some hurdles will have to be overcome before these therapies can be introduced into human clinical stroke trials.
Estrogens as Neuroprotectants against Ischemic Stroke
Authors: Alonso de Leciñana María , Egido Jose Antonio
Published: May 2006

Estrogens have proven vasoprotective properties against atherosclerosis that depend on the direct effect on vascular smooth muscle and endothelium and on systemic actions that imply serum lipids, coagulation and fibrinolytic cascades, vasoactive proteins and antioxidant systems. They also have neuroprotective effects against cerebral ischemia that include antioxidant and anti-inflammatory effects, modulation of protein synthesis, inhibition of apoptosis and trophic effects and preservation of microvascular blood flow in the ischemic area. Estrogenic actions depend on activation of specific estrogen receptors that modulate gene expression and produce long-term effects on vascular endothelial and smooth muscle cells, neurons and glia, on interaction with plasma membrane sites that produce rapid non-genomic actions and also on receptor-independent mechanisms. This paper reviews what it is known about the mechanisms underlying the vaso- and neuroprotective effects of estrogens. Experimental and clinical evidences of such protective effects are also discussed. Therapeutical implications for stroke prevention and treatment derived from the available evidence are considered.
Thrombolysis and Neuroprotection in Cerebral Ischemia
Authors: Gutiérrez M. , Díez Tejedor E. , Alonso de Leciñana M. , Fuentes B. , Carceller F. , Roda J.M.
Published: May 2006

Stroke is a major cause of death and disability worldwide. The resulting burden on society grows with the increase in the incidence of stroke. The term brain attack was introduced to describe the acute presentation of stroke and emphasize the need for urgent action to remedy the situation. Though a large number of therapeutic agents, like thrombolytics, NMDA receptor antagonists, calcium channel blockers and antioxidants, have been used or are being evaluated, there is still a large gap between the benefits of these agents and the properties of an ideal drug for stroke. So far, only thrombolysis with rtPA within a 3-hour time window has been shown to improve the outcome of patients with ischemic stroke. Understanding the mechanisms of injury and neuroprotection in these diseases is important to target news sites for treating ischemia. Better evaluation of the drugs and increased similarity between the results of animal experimentation and in the clinical setting requires critical assessment of the selection of animal models and the parameters to be evaluated. Our laboratory has employed a rat embolic stroke model to investigate the combination of rtPA with citicoline as compared to monotherapy alone and investigated whether neuroprotection should be provided before or after thrombolysis in order to achieve a greater reduction of ischemic brain damage.
Measuring Bone Mass in Children: Can We Really Do It?
Authors: Bachrach Laura K.
Published: May 2006

Bone densitometry is used to assess skeletal health in clinical and research settings, with the goal of achieving reproducible measurements of bone mass that help to identify individuals predisposed to fracture. The search is now on for better methods of capturing additional factors that contribute to bone strength, including bone size, geometry, microarchitecture, and turnover rates. This has proved particularly challenging in growing children, whose bones continually change in size, shape, and mass. Dual energy X-ray absorptiometry is the preferred method for measuring bone mass in children, but the technique has several limitations, and interpreting the findings can be problematic. Peripheral quantitative computed tomography is a promising method for assessing bone mass and other indices correlating with bone strength, but a lack of precision and paediatric norms currently restricts its clinical utility. Although bone mineral density is predictive of future fracture risk in adults, the evidence in children is less conclusive, and a diagnosis of osteoporosis in a child should not be made on densitometric findings alone. Developing a clearer understanding of how measures of bone mass and strength correlate with bone fracture in children will help target preventive strategies for those in greatest need.
Adolescents with Childhood-Onset GHD: How Do We Get Them to Peak Bone Mass?
Authors: Shalet Stephen
Published: May 2006

The development of osteoporosis, with its attendant risk of fragility fracture, is in part related to the peak bone mass (PBM) achieved in early adulthood. Adolescence is a critical time for the acquisition of bone mass, with around 40% of skeletal mass being accrued during pubertal maturation. Growth hormone (GH) plays an integral role in the achievement of PBM after completion of linear growth, and several recent studies have suggested that GH replacement should continue in individuals with childhood-onset GHD until PBM has been attained – irrespective of the height achieved. In those with severe GHD after growth and pubertal development are complete, a seamless transition of GH therapy into adult life may be preferable to allowing a gap in GH treatment. The ‘window of opportunity’ concept for achieving PBM will, nevertheless, continue to be challenged by GHD teenagers who may resent the seamless continuation of GH replacement beyond adolescence. Preparation for this possibility should therefore begin during childhood, with all GHD teenagers being encouraged to remain on GH therapy until at least their mid-20s.
An Instrument to Measure Engagement in Life: Factor Analysis and Associations with Sociodemographic, Health and Cognition Measures
Authors: Parslow Ruth A. , Jorm Anthony F. , Christensen Helen , Mackinnon Andrew
Published: May 2006

Background: It has been proposed that active engagement with life may protect against cognitive decline. However, existing instruments for measuring life engagement have covered limited domains. Objective: To present a new instrument to measure engagement with life; the RIASEC Activities List draws on activities categorised according to interest categories previously developed by Holland: Realistic, Investigative, Artistic, Social, Enterprising and Conventional (RIASEC). Methods: Participants in a longitudinal, community-based survey were drawn from 3 age groups: 2,404 participants aged 20–24; 2,530 aged 40–44, and 2,551 aged 60–64 years. They provided information on which of 54 selected activities they had performed in the 6 months prior to their survey interview. Other information obtained from participants included measures of sociodemographic characteristics, personality attributes and mental and physical health. Two measures of cognition were also examined. Analyses were conducted separately for men and women in each of the 3 age groups. Results: Confirmatory factor analyses identified six scales of activity types corresponding to Holland’s six interest categories. The number of activities of any type undertaken in the past 6 months was significantly associated with cognitive measures, better physical health, and better mental health although these findings varied for men and women across the 3 age groups. Further, for both men and women in all age groups, performing activities of any type was associated with having higher extraversion and mastery scores, and lower levels of neuroticism. Associations were also found between performing specific types of activities and cognitive measures. Conclusions: This instrument has the potential to identify more clearly types of activities that may offer cognitive benefits and warrants further testing in longitudinal studies.
Increased Soluble E-Cadherin in Melanoma Patients
Authors: Billion K. , Ibrahim H. , Mauch C. , Niessen C.M.
Published: May 2006

Cadherin switching is thought to contribute to melanoma progression. E-cadherin expression is downregulated, facilitating the release of contacts with keratinocytes, while N-cadherin expression is increased, potentially contributing to more migration. Proteolytic cleavage of the cadherin extracellular domain, a process called ectodomain shedding, is one way to decrease cadherin cell surface expression. In addition, the released ectodomain could actively contribute to a more invasive phenotype. To examine if melanoma progression correlates with increased cadherin ectodomain shedding, we tested the presence of N- and E-cadherin extracellular domains in different melanoma cell lines and the presence of E-cadherin in sera of patients. Shedding occurs and is regulated in several melanoma cell lines expressing these cadherins. No correlation could be found between cadherin shedding and invasive capacity of the cell lines. However, we did find a significant increase in serum E-cadherin levels of melanoma patients with advanced disease correlating with increased S100 tumor marker values, suggesting that increased cadherin shedding may contribute to melanoma progression.
Tight Junction Proteins in the Skin
Authors: Brandner J.M. , Kief S. , Wladykowski E. , Houdek P. , Moll I.
Published: May 2006

It has long been accepted that tight junctions (TJ) are crucial for the formation and maintenance of the paracellular barrier and for cell polarity in simple epithelia and endothelia. Moreover, it is long known that they play a role in barrier function of amphibian skin. However, only in recent years were TJ and TJ proteins identified in the epidermis of men and mice. Their involvement in the barrier function of mammalian skin has been shown. This review summarizes our current knowledge about TJ and TJ proteins in mammalian skin.
Differential Protein Expression in the Epidermis of Wild-Type and COX-2 Transgenic Mice
Authors: Müller-Decker K. , Fürstenberger G. , Neumann M. , Schnölzer M.
Published: May 2006

Cyclooxygenases (COX) 1 and 2 are the key enzymes of prostaglandin biosynthesis. Like in many tissues, in adult skin COX-1 is a constitutive ‘housekeeping’ enzyme, while COX-2 is induced transiently in stress situations such as tissue damage and regeneration. In human skin carcinomas and corresponding early-stage cancer lesions, permanent COX-2 expression and activation is a consistent feature. Knockout and various transgenic approaches and pharmacologic studies show strong evidence for a cause-and-effect relationship between the aberrant COX-2 activation and tumor formation. In skin epidermis, keratin 5 promoter-driven overexpression of COX-2 caused hyperplasia and dysplasia, and sensitized skin for carcinogenesis. Therefore, this model offers the unique possibility of identifying COX-2-dependent and prostaglandin-mediated molecular pathways leading to the formation and malignant progression of early-stage cancer lesions.
Skin Ultrastructure in Senile Lentigo
Authors: Noblesse E. , Nizard C. , Cario-André M. , Lepreux S. , Pain C. , Schnebert S. , Taïeb A. , Kurfurst R.
Published: May 2006

Senile lentigo is a common component of photoaged skin. It is characterized by hyperpigmented macules which affect chronically irradiated skin mostly after the age of 50. This study was undertaken to assess the morphology of senile lentigo on the dorsum of the hands. A systematic comparison between lesional and perilesional skin using histology and transmission electron microscopy was done to determine whether melanocytes or keratinocytes are affected in the evolution of lesions and which tissue structure is modified. The histology study showed that lesional skin is characterized by a hyperpigmented basal layer and an elongation of the rete ridges, which seem to drive deeply into the dermis. The epidermis contained clusters of keratinocytes, which retained and accumulated the melanin pigment. Electron microscopy studies showed important modifications in the lesional skin ultrastructure in comparison with perilesional skin. In melanocytes from perilesional and lesional skin, we observed normal size melanosomes at all stages of maturation in the cytoplasm and in migration within dendrites. No pigment accumulation was observed. However, the morphology of melanocytes in lesional skin revealed an activated status with numerous mitochondria and a well-developed endoplasmic reticulum, which could reflect intense protein synthesis. In basal keratinocytes from lesional skin, we observed numerous melanosome complexes called polymelanosomes, which formed massive caps on the nuclei. Observations in colored semi-thin sections also revealed perturbed structures in the basal layer region, which could explain the skin perturbation. Indeed, we observed keratinocytes that presented important microinvaginations and pendulum melanocytes, which sank into the dermis, beneath the basal layer of keratinocytes. These cell modifications seemed to be due to a perturbation of the dermal-epidermal junction, which appeared disorganized and disrupted and could directly disturb the basal support of the cells.
The Physiological Function of the Urothelium – More than a Simple Barrier
Authors: Lazzeri Massimo
Published: May 2006

The urothelium, the epithelium lining the surface of the urinary bladder, is a unique cell type with high plasticity and a variety of cellular functions. The urothelium represents the first line of bladder defense and an interface between pathogens and defense mechanisms. Functions of the urothelium include control of permeability, immune responses and cell-cell communication, which seems to play a pivotal role in responding to injuries and infections. The urothelium responds to stretch, during the filling phase of micturition reflex, by increasing the size of apical umbrella cells and by releasing mediators which activate the sensory fibers. For this reason the concept of ‘neuron-like properties’ was suggested. Finally, despite the fact that the urothelium is a frequent site of cancer formation, few experimental model systems are currently available or well characterized for studying urothelial cancer in the era of genomics and proteomics. The purpose of this review is to give emphasis to urothelial physiology and pathophysiology in different bladder disorders and to offer an up-to-date contribution to the field of urothelial research.
Discontinuation of Tamsulosin Treatment in Men with Lower Urinary Tract Symptoms: A Pilot Study
Authors: Kobayashi Minoru , Tokue Akihiko , Morita Tatsuo
Published: May 2006

Objectives: Since little investigation has been undertaken to determine if α1-blockers should be given continuously to sustain their efficacy, we conducted a pilot study to determine symptom change following discontinuation of tamsulosin after an initial improvement in symptoms in men with lower urinary tract symptoms (LUTS). Patients and Methods: Thirty-three of 78 patients with mild-to-moderate prostate hyperplasia, who had symptom improvement according to the International Prostate Symptom Score (IPSS) to <10 or the quality of life (QOL) index to ≤3 after initial treatment with tamsulosin, were enrolled in this study. Subjective parameters (IPSS and QOL index) and objective parameters (maximum and mean urinary flow rates) were evaluated at baseline and after initial treatment, and 4, 8, 12 and 24 weeks after discontinuing tamsulosin. Results: The rates of successful discontinuation of tamsulosin were high throughout the follow-up period, i.e., 80.6% at 4 weeks, 80.6% at 8 weeks, 80.0% at 12 weeks, and 68.9% at 24 weeks. Temporary worsening in both subjective and objective parameters was observed only at 4 weeks; however, these parameters recovered to almost post-treatment levels at 24 weeks. Conclusion: The present study suggests that continuous treatment is not always needed to maintain urinary symptom relief in a specific subset of patients who felt symptom improvement after initial treatment with tamsulosin.
Comparative Study of International Prostate Symptom Scores and Urodynamic Parameters in Men and Women with Lower Urinary Tract Symptoms
Authors: On Seung-June , Ku Ja Hyeon
Published: May 2006

Background: We compared urinary symptoms and urodynamic parameters in men and women with lower urinary tract symptoms. Methods: A total of 164 individuals (76 men and 88 women) were rated according to the International Prostate Symptom Score and underwent a detailed urodynamic investigation. Patients were stratified by age into 2 groups, namely, those <50 years (the younger group) and those >50 years (the elderly group). Results: In the elderly group, scores of voiding symptoms for men were higher than those for women (p = 0.012). Maximum flow rates (Qmax) for women were higher than those for men (p = 0.025 for the younger groups, and p < 0.001 for the elderly groups). Detrusor pressure at Qmax (p < 0.001), opening pressure (p < 0.001) and closing pressure (p = 0.023) were elevated in elderly men vs. in elderly women. A multiple linear regression analysis identified straining (β = 0.479, p < 0.05) and incomplete emptying (β = 0.487, p < 0.05) as the only variables influencing quality of life (QOL) in younger men and women, respectively. In elderly men, nocturia (β = 0.352, p < 0.05) and frequency (β = 0.287, p < 0.05) were significantly associated with QOL. Frequency (β = 0.452, p < 0.05) possibly explained a QOL reduction in elderly women. Conclusions: Our findings suggest that in the elderly patients, storage symptoms are more associated with QOL than voiding symptoms. However, storage symptoms were not associated with QOL in younger men.
Sacral Colpopexy with Concurrent Burch Colposuspension in Patients with Vaginal Vault Prolapse
Authors: Wille S. , Braun M. , Heidenreich A. , Hofmann R. , Engelmann U.
Published: May 2006

Introduction: Abdominal sacral colpopexy (SC) is one option in the management of vaginal vault prolapse. In patients who are additionally incontinent an anti-incontinence procedure such as a Burch colposuspension or pubovaginal sling is usually performed at the same time. For those patients undergoing SC who are continent there are no clear guidelines for the use of a ‘prophylactic’ anti-incontinence procedure. We describe our experience with SC and concurrent Burch colposuspension. Patients and Methods: 47 patients (mean age 65 years) underwent SC and concurrent Burch colposuspension. The preoperative diagnostic check-up included a validated questionnaire, clinical examination, urodynamic tests, ultrasound and colpocystorectography. Patients were also evaluated using Stress, Emptying, Anatomic, Protection and Instability (SEAPI) scores. All patients had a uterine or vaginal vault prolapse in combination with a cystocele, enterocele or rectocele. Thirty-three of 47 (70%) patients were continent and 14 (30%) incontinent. Nineteen (40%) of the 33 ‘continent’ patients were found to have occult incontinence. Clinical examination according to the Halfway system showed 9 of 47 (19%), 21 of 47 (45%) and 17 of 47 (36%) patients with grade 2, 3 and 4 vaginal vault prolapse, respectively. Thirty-five of 47 (74%) patients demonstrated a grade-4 cystocele and 12 of 47 (26%) a grade-3 cystocele. The mean follow-up was 34 months and included a questionnaire (SEAPI), clinical examination and ultrasound. Results: Postoperative SEAPI scores showed a statistically significant improvement in all SEAPI domains (p < 0.001). Ninety-four percent of the patients were satisfied, continent and would undergo the surgery again. Three patients were incontinent. No continent patient who underwent concurrent Burch colposuspension had obstructive symptoms or residual urine. Five patients (11%) who had dyspareunia preoperatively were free of this symptom postoperatively. Complications were: dilatation of the upper urinary tract in 2 patients (4%) secondary to distal ureteric deviation by suturing the posterior peritoneum. One patient underwent psoas hitch neoureterocystostomy and 1 patient was successfully treated by insertion of a ureteric stent for 6 weeks. One patient (2%) had a mesh infection necessitating removal of the Gore-Tex mesh. Conclusions: Sacral colpopexy provides good patient satisfaction, durable pelvic support and restores vaginal function. Due to excellent continence rates concurrent Burch colposuspension should be considered as a joint procedure even in continent patients.
Lack of Local Anesthetic Properties of Lidocaine Gel in an Experimental Model
Authors: Drewa T. , Wolski Z. , Galazka P. , Olszewska-Slonina D. , Musialkiewicz D. , Czajkowski R.
Published: May 2006

Introduction: Many reports negate the anesthetic properties of lidocaine gel placed in the urethra during catheterization. The anesthetic action of lidocaine is inseparably associated with the toxic action of this compound on cells. Materials and Methods: A primary rabbit urothelial cell culture (PRUCC) was previously established as a monolayer. The effect of 2% lidocaine gel on the viability of the PRUCC was assessed and compared with the cytotoxic effect of decreasing concentrations of lidocaine solution. . Cell viability was evaluated after 1-hour exposure using the trypan blue exclusion test. Results: The 2% lidocaine gel did not show cytotoxic properties after 1 h of incubation on a PRUCC. The 2 and 1% lidocaine solutions induced statistically significant decreases in the viability of the PRUCC after 1 h of incubation. Conclusions: Experimental tests evaluating the cytotoxicity of local anesthetics may prove to be an objective measure of the accessibility of these substances to cells and their anesthetic action.
Ectopic Insertion of a Single Ureter into the Bladder Adjacent to the Contralateral Ureter
Authors: Kilciler Mete , Bedir Selahattin , Erdemir Fikret , Avci Ali , Ozgok Yasar
Published: May 2006

We report a 30-year-old female with a single ectopic ureter that opens into the bladder adjacent to the right ureter.
Ih Is Maturing: Implications for Neuronal Development
Authors: Rocha Nino , Rolfs Arndt , Strauss Ulf
Published: May 2006

Vast electrophysiological activity near resting potential, including rhythmic oscillatory activity, is a hallmark of many brain regions and a motor of the developing CNS. This activity is mediated and influenced by diverse receptor-operated and voltage-gated ion channels. In turn, these channels are modulated during the course of development by altering their density, distribution and properties. The hyperpolarization-activated and cyclic nucleotide-gated cation current, Ih, impacts on the resting membrane potential and is involved in the generation and modulation of neuronal oscillatory activity. Therefore, it is conceivable that Ih is well suited to govern the specific processes involved in activity-dependent neuronal development. Here, we review the evidence that maturation of Ih accounts, at least in part, for the control of membrane properties during neuronal development of various parts of the brain. The temporal and regional variations in Ih development might underlie the normal maturation of neuronal circuits and, consequently, the perturbations of this might account for some of the neuropathology of the brain. This review summarizes the evidence for the stage and localization dependence of Ih in CNS development with a focus on arborized cells with high dendritic Ih. Further, it outlines hypotheses on the contribution of Ih to neuronal and network maturation.
Erythropoietin and Normal Brain Development: Receptor Expression Determines Multi-Tissue Response
Authors: Chen Zhi-Yong , Warin Renaud , Noguchi Constance Tom
Published: May 2006

Erythropoietin (EPO) is a hypoxia-inducible hormone required for erythroid differentiation. Expression of the EPO receptor is not restricted to hematopoietic cells and exhibits a multi-tissue distribution that includes neural cells, vascular endothelium and muscle progenitor cells. The ability for EPO to stimulate progenitor cell proliferation and prevent apoptosis is critical for maintenance of the erythroid lineage, but is also observed in neural and muscle progenitor cells. Mice lacking the EPO receptor die in utero due to severe anemia. However, even prior to lack of erythroid cell production in the embryo proper, these mice exhibit increased apoptosis in the brain as early as E10.5 and a reduction in the number of neural progenitor cells. Corresponding cultures of primary neural cells exhibit decreased neuron generation and increased sensitivity to reduced oxygen tension, and neurons do not survive after 24 h at low oxygen tension. In contrast, hypoxia induces EPO and EPO receptor in wild-type neuronal cells, and EPO enhances neuron survival at low oxygen tension. In vivo EPO is neuroprotective in adult animal models for brain ischemia. Induction of EPO and its receptor by hypoxia likely contributes to its neuroprotective activity and selective cell survival in the brain during hypoxic stress.
Smoking Prevalence and Its Effect on Dental Health Attitudes and Behavior among Dental Students
Authors: Alomari Qasem , Barrieshi-Nusair Kefah , Said Khalid
Published: May 2006

Objective: To determine smoking prevalence and its effect on dental health attitudes and behavior among dental students in Jordan. Subjects and Methods: A cross-sectional study of 314 dental students was conducted at Jordan University of Science and Technology. Subjects were surveyed using a modified version of the Hiroshima University Dental Behavior Inventory (HU-DBI) questionnaire. Multivariate logistic regression analyses were performed to study differences between male smokers and nonsmokers only. Results: The response rate was 83.7%, with 48% males and 52% females. The prevalence of smoking was 17.2%. Smoking was more prevalent among male students (31%) than female (4.3%). For male students, the multivariate logistic regression analysis showed 6 items that were different between smokers and nonsmokers. Nonsmokers tended to brush their teeth more often than smokers (OR 8.67, 95% CI 1.66–45.25); claimed that they had never been professionally taught how to brush their teeth (OR 11.15, 95% CI 1.89–65.67); believed that they spend too much time brushing their teeth (OR 12.24, 95% CI 2.0–75.05); were more concerned about having bad breath (OR 41.86, 95% CI 3.44–58.75) and were more concerned about the color of their gums (OR 8.04, 95% CI 1.55–41.84). Conclusions: Smoking prevalence among male dental students in Jordan was high, 7 times greater than for females. Male smokers and nonsmokers had different attitudes and oral health behaviors as indicated by the study survey.
Persistence, Recurrence, and Progression Rates of Superficial Bladder Tumours after Resection Using the Differentiated Technique
Authors: Langbein S. , Badawi K. , Haecker A. , Weiss C. , Hatzinger M. , Alken P. , Siegsmund M.
Published: May 2006

Objective: To investigate whether the differentiated resection technique for excising superficial bladder cancer leads to higher recurrence and progression rates as compared with regular resection. Subjects and Methods: We evaluated 163 patients, 66 undergoing a differentiated and 97 a regular resection. All patients underwent a routine second resection within 6–10 weeks. Recurrence and progression rates as well as tumour persistence on second resection were analyzed. Results: Patients with differentiated resections of bladder tumours did not have higher tumour recurrence and progression rates. Also, these patients had a significantly higher percentage of tumour-free second resections (p = 0.03). Conclusion: The differentiated resection technique for excising superficial bladder cancer has no negative influence on recurrence and progression rates, but it leads to a reduced tumour persistence.