bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical Large Well-Differentiated Hepatocellular Carcinoma with Benign Nature: A New Clinical Entity
Authors: Kudo Masatoshi
Published: September 2004

Based on intranodular hemodynamic studies of nodular lesions associated with liver cirrhosis using computed tomography (CT) during arteriography, CT during arterial portography (CTAP) and angiography under ultrasonography, relatively large hepatocellular nodules with portal perfusion have been depicted. We report 17 such nodules in a total of 663 patients who underwent CTAP. Large well-differentiated hepatocellular carcinomas (HCCs) are characterized by the presence of intranodular portal perfusion even if they measure more than 2.5 cm in diameter. Such nodules display a benign nature clinically as well as pathologically. These nodules, called ‘atypical large well-differentiated HCC or dysplastic nodules’, show extremely slow growth. Pathological study showed extremely peculiar findings; the nodules consisted of homogeneously hyperplastic or well-differentiated HCC without the component of moderately or poorly differentiated HCC, and without fibrous capsules, vessel invasion or intrahepatic metastasis, all of which are commonly found in typical overt HCC. The incidence of such nodules is not rare; it was 2.6% (17/663) in our HCC patients who underwent CTAP over a period of 7 years. During the 7-year observation period, none of 10 such nodules developed into arterial supply-dominant overt HCC. The recognition of these benign-nature nodules (or large low-grade malignant nodules) is extremely important for the following three reasons. First, the knowledge that such large atypical nodular lesions exist is important for clinicians. Second, regarding the treatment strategy for such nodular lesions, it should be kept in mind that these nodules show a benign nature, and rarely cause death. Finally, considering the etiology and clinical significance of such atypical large benign-nature nodules, the recognition of these nodules provides an important suggestion regarding the pathogenesis of progression from dysplastic nodule to early HCC and finally to overt HCC during multistep human hepatocarcinogenesis. These atypical large benign-nature nodules do not seem to be the nodules in a sequence of multistep progression. The early step of hepatocarcinogenesis includes mainly hyperplastic change, whereas the late step includes mainly an angiogenic process. Although the detailed molecular pathogenesis of both the early and late steps of hepatocarcinogenesis is not clear, it is speculated that these atypical benign-nature nodules do not undergo the phenotypic change of late-step hepatocarcinogenesis. In that sense, these atypical benign-nature nodules are suggestive for the clarification of the mechanism of multistep human hepatocarcinogenesis based on the intranodular vascular supply or hemodynamics. From the viewpoint of clinical practice as well as pathogenesis of human hepatocarcinogenesis, these nodular lesions should be managed as a different disease from overt HCCs; atypical large HCCs or dysplastic nodules with benign nature should be regarded as a new clinical entity.
MRI in the Evaluation of Hepatocellular Nodules: Role of Pulse Sequences and Contrast Agents
Authors: Ichikawa Tomoaki
Published: September 2004

Magnetic resonance (MR) imaging is more useful than computed tomography (CT) in the evaluation of hepatocellular nodules based on the excellent soft-tissue image contrast of MR imaging. In addition, recent MR units have allowed various fast MR imaging techniques (i.e., parallel imaging or echo-planar imaging) to dramatically improve image quality and image contrast. A variety of liver-specific MR contrast agents are also currently available or have been evaluated in clinical trials to improve the contrast between the liver parenchyma and hepatocellular nodules.
Expression of S100A4 and Met: Potential Predictors for Metastasis and Survival in Early-Stage Breast Cancer
Authors: Lee Wen-Ying , Su Wu-Chou , Lin Pin-Wen , Guo How-Ran , Chang Tsai-Wang , Chen Helen H.W.
Published: September 2004

Background: To formulate individually tailored therapy for patients with early-stage breast cancer, it is necessary to identify biomarkers for predicting metastasis and survival. Methods: A homogeneous cohort of 92 T1-2N0M0 breast carcinoma patients with a long-term follow-up were divided into two groups: the metastasis group (n = 41) and the disease-free group (n = 51). We evaluated the ability of risk discrimination of six biomarkers, including S100A4, Met, bcl-2, p53, survivin, and HER-2/neu, in early-stage breast cancer. Results: In multiple logistic regression analysis, only S100A4 expression (odds ratio = 5.37, p = 0.008) and Met expression (odds ratio = 6.91, p = 0.002) were independent predictors of distant relapse. Multivariate Cox models showed S100A4 and Met expressions were associated with 10-year disease-free survival (DFS) (risk ratio 3.2 and 4.0, respectively); however, tumor size and histological grade were not significant predictors. The 10-year DFS of T1-2N0M0 patients was 55.4%. T1-2N0M0 patients with S100A4-positive tumors had a significantly worse 10-year DFS than those with S100A4-negative tumors (29.0 vs. 68.9 %, p = 0.001). The 10-year DFS in T1-2N0M0 patients with Met-negative tumors was 82.4 vs. 39.7% if Met expression was positive (p = 0.0002). S100A4, but not Met, was still a significant predictor of 10-year DFS in T1N0M0 breast carcinoma patients (p = 0.02). For the T2N0M0 subgroup, both S100A4 and Met were significantly correlated with survival. The 10-year DFS of T2N0M0 patients with S100A4-negative and Met-negative tumors was 92.3%; in those with S100A4-positive and Met-positive tumors, however, it was only 11.8%. Conclusions: S100A4 expression is an indicator of a poor prognosis for T1N0M0 breast cancer. In addition, the combination of S100A4 and Met expression gives the best risk group discrimination in the T2N0M0 subgroup. S100A4 expression appears to be an earlier step in the metastatic progression compared to Met expression in early-stage breast carcinoma.
Development of a Cancer Pain Assessment Tool in Korea: A Validation Study of a Korean Version of the Brief Pain Inventory
Authors: Yun Young Ho , R. Mendoza Tito , Heo Dae Seog , Yoo Taiwoo , Heo Bong Yul , Park Hyeoun-Ae , Shin Ho Cheol , Wang Xin Shelley , Cleeland Charles S.
Published: September 2004

Objective: The aim of this study was to validate the Korean version of the Brief Pain Inventory (BPI-K), a pain assessment tool that has been validated in several languages. Methods: The sample consisted of 132 patients in Seoul who had recurrent or metastatic cancer and who expressed pain. The Korean version of the Beck Depression Inventory (BDI-K), the Eastern Cooperative Oncology Group (ECOG) performance status score, the Pain Management Index (PMI), and the PMI-Revised (PMI-R) were used to further validate the BPI-K. Results: Cronbach alphas, computed for the pain interference and pain severity item, were 0.93 and 0.85, respectively. Confirmatory factor analysis of the BPI-K items showed a two-common-factor solution for the BPI-K, consistently demonstrated in other language versions of the BPI. The mean pain interference score was more correlated with the BDI-K scale (r = 0.44) and ECOG (r = 0.39) than the mean pain severity score. Seventy-four percent of the patients in the Seoul sample had inadequate analgesia using the PMI. Conclusion: The BPI-K is a valid and useful instrument for assessing cancer pain and pain impact in Korea.
Establishment and Characterization of a Novel Human Pancreatic Cancer Cell Line (SUIT-4) Metastasizing to Lymph Nodes and Lungs in Nude Mice
Authors: Kawano Kikuo , Iwamura Takeshi , Yamanari Hideo , Seo Yasuhisa , Suganuma Tatsuo , Chijiiwa Kazuo
Published: September 2004

A new tumor cell line (SUIT-4) derived from ascites of a patient with carcinoma of the pancreas has been established in tissue culture and in nude mice, and maintained for over 7 years. In tissue culture, the cells grew as a confluent monolayer with piling up of cells in some areas. The population doubling time during the exponential phase of the cell growth was 43.9 h in vitro. Chromosome count ranged from 63 to 68 with a modal number of 67. Subcutaneous injection of cultured cells into the flanks of nude mice resulted in tumor formation with a doubling time of 88.8 h. Histopathologically, xenografts in nude mice were moderately differentiated tubular adenocarcinoma, and the tumor cells showed spontaneous metastasis to the regional lymph nodes in 6 of 21 nude mice and to the lung in 4 of 21. Transmission electron microphotographs confirmed the ductal cell origin of the carcinoma and revealed that the cells had abundant mitochondria and lysosomes. SUIT-4 cells released carcinoembryonic antigen (3.08 × 102 ng/1 × 106 cells/24 h) and carbohydrate antigen 19-9 (4.75 × 104 U/1 × 106 cells/24 h) during exponential cell growth in vitro. Reverse transcriptase-polymerase chain reaction studies revealed that SUIT-4 cells expressed matrix metalloproteinases 1, 3, 7, 10 and 14.
Attachment of Human Colon Cancer Cells to Vascular Endothelium Is Enhanced by N-Acetylglucosaminyltransferase V
Authors: Murata Kohei , Miyoshi Eiji , Ihara Shinji , Noura Shingo , Kameyama Masao , Ishikawa Osamu , Doki Yuichiro , Yamada Terumasa , Ohigashi Hiroaki , Sasaki Yo , Higashiyama Masahiko , Tarui Takehiko , Takada Yoshikazu , Kannagi Reiji , Taniguchi Naoyuki , Imaoka Shingi
Published: September 2004

Expression of N-acetylglucosaminyltransferase V (GnT-V) in colon cancer has been shown to be related to hematogenous metastasis and poor prognosis. To investigate the mechanism by which cancer cells expressing GnT-V metastasize to distant organs, we established GnT-V-overexpressing DLD-1 and WiDr cells (human colon cancer cell lines) by transfecting them with a GnT-V expression vector. Attachment to endothelial cells expressing E-selectin was studied, and expression of the E-selectin ligand, sialyl Lewis x, in colon cancer cells was investigated. Both of the cell lines showed reduced adhesion to fibronectin as compared with mock transfectants. In contrast, attachment to human umbilical vein endothelial cells expressing E-selectin was significantly enhanced by GnT-V expression (p < 0.01). Sialyl Lewis x is a ligand for E-selectin and a marker for poor prognosis of colon cancer. Its synthesis in cells has been shown to involve GnT-V. We demonstrated that expression of sialyl Lewis x in colon cancer cells was induced by GnT-V expression. These results suggest that GnT-V induces sialyl Lewis x expression and leads colon cancer cells to metastasize by enhancing their ability to attach to vascular endothelium in distant organs, such as liver or lung. Inhibition of GnT-V activity may prevent metastasis in colon cancer patients with high sialyl Lewis x expression.
Clear Cell Renal Cell Carcinoma Associated with Bilateral Atypical Acute Posterior Multifocal Placoid Pigment Epitheliopathy
Authors: Parmeggiani Francesco , Costagliola Ciro , D’Angelo Sergio , Incorvaia Carlo , Perri Paolo , Sebastiani Adolfo
Published: September 2004

Background/Objective: Clear cell renal cell carcinoma (CCRCC) is a malignant neoplasm frequently associated with an increase in circulating immune complexes (CIC). Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a disease involving the chorioretinal structures of the eye, and it is commonly observed in association with several immunogenic disorders. We report here the clinical association between humoral immunologic modifications during tumoral diseases (long-standing CIC increase) and chorioretinal changes resembling atypical APMPPE. Case Report: A 52-year-old white male affected by metastatic CCRCC is described. Histopathologic review of his surgically removed organs (kidney and lung), periodical laboratory immunologic tests and ophthalmologic examinations, including fluorescein and indocyanine green angiographies, were performed. Results: The patient underwent total left nephrectomy (May 1997) and total left pneumonectomy (March 2001) for the presence of stage III CCRCC and CCRCC lung metastasis, respectively. On both occasions, postoperative immunotherapy was started. From June 1997 to February 2003, laboratory analyses demonstrated the presence of marked CIC peaks. During the follow-up period, an atypical APMPPE pattern, complicated by asynchronous choroidal neovascularization, occurred in both eyes. Conclusions: Long-standing tumorous disease, through a pathogenic mechanism triggered by CIC spreading, can be responsible, over time, for a progressive choroidal occlusive microangiopathy (atypical APMPPE pattern), associated with a high risk of poor visual outcome. Therefore, bilateral APMPPE could be related to a systemic disease able to increase CIC levels.
F4 Fimbriae Expressed by Porcine Enterotoxigenic Escherichia coli, an Example of an Eccentric Fimbrial System?
Authors: Verdonck F. , Cox E. , Goddeeris B.M.
Published: September 2004

An overwhelming number of infectious diseases in both humans and animals are initiated by bacterial adhesion to carbohydrate structures on a mucosal surface. Most bacterial pathogens mediate this adhesion by fimbriae or pili which contain an adhesive lectin subunit. The importance of fimbriae as virulence factors led to research elucidating the regulation of fimbrial expression and their molecular assembly process. This review provides an overview of the current knowledge of induction, expression and assembly of F4 (K88) fimbriae and discusses its unique as well as its identical characteristics compared to other intensively studied fimbriae or pili expressed by Escherichia coli.
Glycerol Metabolism of Lactobacillus rhamnosus ATCC 7469: Cloning and Expression of Two Glycerol Kinase Genes
Authors: de Fátima Alvarez María , Medina Roxana , Pasteris Sergio E. , Strasser de Saad Ana M. , Sesma Fernando
Published: September 2004

Lactobacillus rhamnosus ATCC 7469 was able to grow in glycerol as the sole source of energy in aerobic conditions, producing lactate, acetate, and diacetyl. A biphasic growth was observed in the presence of glucose. In this condition, glycerol consumption began after glucose was exhausted from the culture medium. Glycerol kinase activity was detected in L. rhamnosus ATCC 7469, a characteristic of microorganisms which catabolize glycerol in aerobic conditions. Genetic analysis revealed that this strain possesses two glycerol kinase genes: gykA and glpK, that encode for two different glycerol kinases GykA and GlpK, respectively. The glpK geneis associated in an operon with α-glycerophosphate oxidase (glpO) and glycerol facilitator (glpF) genes. Transcriptional analysis revealed that only glpK is expressed when L. rhamnosus was grown on glycerol.
Metabolic Analysis of Corynebacterium glutamicum during Lactate and Succinate Productions under Oxygen Deprivation Conditions
Authors: Inui Masayuki , Murakami Shikiko , Okino Shohei , Kawaguchi Hideo , Vertès Alain A. , Yukawa Hideaki
Published: September 2004

Lactate and succinate were produced from glucose by Corynebacterium glutamicum under oxygen deprivation conditions without growth. Addition of bicarbonate to the reaction mixture led not only to a 3.6-fold increase in succinate production rate, but also to a 2.3- and 2.5-fold increase, respectively, of the rates of lactate production and glucose consumption, compared to the control. Furthermore, when small amounts of pyruvate were added to the reaction mixture, acid production rates and the glucose consumption rate were multiplied by a factor ranging from 2 to 3. These phenomena were paralleled by an increase in the NAD+/NADH ratio, thus corroborating the view that the efficient regeneration of NAD+ could be triggered by the addition of either bicarbonate or pyruvate. To investigate the global metabolism of corynebacteria under oxygen deprivation conditions, we engineered several strains where the genes coding for key metabolic enzymes had been inactivated by gene disruption and replacement. A lactate dehydrogenase (LDH)-deficient mutant was not able to produce lactate, suggesting this enzyme has no other isozyme. Although a pyruvate carboxylase (pyc) mutant exhibited similar behavior to that of the wild type, phosphoenolpyruvate carboxylase (ppc) mutants were characterized by a dramatic decrease in succinate production, which was concomitant to decreased lactate production and glucose consumption rates. This set of observations corroborates the view that in coryneform bacteria under oxygen deprivation conditions the major anaplerotic reaction is driven by the ppc gene product rather than by the pyc gene product. Moreover, intracellular NADH concentrations in C. glutamicum were observed to correlate to oxygen-deprived metabolic flows.
Cloning, Expression, and Characterization of a Lipolytic Enzyme Gene (lip8) from Pseudomonas aeruginosa LST-03
Authors: Ogino Hiroyasu , Mimitsuka Takashi , Muto Toshiaki , Matsumura Miharu , Yasuda Masahiro , Ishimi Kosaku , Ishikawa Haruo
Published: September 2004

A lipolytic enzyme gene (lip8) was cloned from organic solvent-tolerant Pseudomonas aeruginosa LST-03 and sequenced. In the sequenced nucleotides, an open reading frame consisting of 1,173 nucleotides and encoding 391 amino acids was found. Lip8 is considered to belong to the family VIII of lipolytic enzymes whose serine in the consensus sequence of -Ser-Xaa-Xaa-Lys- acts as catalytic nucleophile. The gene was expressed in Escherichia coli and purified by a combination of ammonium sulfate fractionation and hydrophobic interaction and ion-exchange chromatographies to homogeneity on SDS-PAGE analysis. The optimum temperature and heat stability of Lip8 were not as high as those of Lip3 and LST-03 lipase, two other lipolytic enzymes from the same strain. Addition of glycerol to a solution containing Lip8 stabilized this enzyme. By measuring the activities against various triacylglycerols and fatty acid methyl esters having carbon chains of different lengths, Lip8 was categorized as an esterase which has higher activities against fatty acid methyl esters with short-chain fatty acids.
Revisiting the Gender-Linked Melanoma Burden
Authors: Quatresooz Pascale , Uhoda Isabelle , Fumal Isabelle , Piérard-Franchimont Claudine , Piérard Gérald E.
Published: September 2004

Background: Much is known about the worldwide rising incidence of skin cancers in the white populations. However, contradictory reports have been presented about a gender-linked risk for malignant melanoma (MM). Objective: To review the recent epidemiological information about primary and metastatic MM in south-east Belgium. Methods: Laboratory records of primary MM according to age and gender were compared per 3-year periods from 1988 to 2002. The numbers of MM per decade of patient age were corrected with regard to the number of citizens in the defined periods of age. This led to the calculation of the rate of estimated prevalence (REP). The same assessments were performed on 187 sentinel lymph node biopsies collected during the last 3-year period. Results: A total of 1,051 primary MM in women and 594 primary MM in men were diagnosed over the 15-year period. The female-to-male ratio rose by 24% over time, with a mean value of 1.77. The most recent years showed a marked increase both in the numbers and REP of primary MM. This situation was present in both genders, although it was most prominent in women of the reproductive age. MM metastases were found in 38/187 sentinel lymph nodes with a female-to-male ratio of 2.17. The age distribution for all sentinel lymph node biopsies copied that of primary MM, but the vast majority of the nodal metastatic MM was found in patients older than 50 years. The ratio between MM metastases and primary MM reached 6.1% (12/198) in men and 6.9% (26/378) in women. Conclusion: A recent increase in primary MM incidence was observed in our laboratory. The most likely cause is ascribed to more sensitive MM detection using the combination of clinical dermoscopy and laboratory immunohistochemistry. During the past 15 years, women were more affected than men by both primary and metastatic MM. The gender difference in incidence of primary MM has progressively widened due to an increased incidence in young and middle-aged women. By contrast, nodal metastatic MM mostly affected postmenopausal women.
Finasteride Treatment of Patterned Hair Loss in Normoandrogenic Postmenopausal Women
Authors: Trüeb Ralph M.
Published: September 2004

Background: Finasteride, an inhibitor of type 2 5α-reductase, inhibits conversion of testosterone to dihydrotestosterone, resulting in a decrease in serum and scalp dihydrotestosterone levels believed to be pathogenic in androgenetic alopecia. Oral finasteride has been shown to be effective in the treatment of hair loss in men, while its efficacy in women has remained controversial. Methods: 5 postmenopausal women without clinical or laboratory signs of hyperandrogenism were given 2.5 or 5 mg/day oral finasteride for the treatment of pattern hair loss. Efficacy was evaluated by patient and investigator assessments, and review of photographs taken at baseline and at months 6, 12 and 18 by an expert panel. Results: Finasteride treatment improved scalp hair by all evaluation techniques. The patients’ self-assessment demonstrated that finasteride treatment decreased hair loss, increased hair growth and improved appearance of hair. These improvements were confirmed by investigator assessment and assessments of photographs. No adverse effects were noted. Conclusions: Oral finasteride in a dosage of 2.5 mg/day or more may be effective for the treatment of pattern hair loss in postmenopausal women in the absence of clinical or laboratory signs of hyperandrogenism.
Cutaneous Angiosarcoma Arising in an Irradiated Breast
Authors: Tomasini Carlo , Grassi Marcella , Pippione Mario
Published: September 2004

Angiosarcoma (AS) is a rare, aggressive tumour of endothelial origin occurring in various clinical settings, including idiopathic AS on the head and neck in elderly people, lymphoedema-associated AS, post-irradiation AS, soft-tissue AS, and various others. Despite the widespread use of radiation therapy in the treatment of breast carcinoma, AS developing in the wake of a radiation therapy is extremely infrequent. Although there is little doubt that radiation in therapeutic doses can induce sarcomas, quantification of that risk is complicated by many variables, among them chronic lymphoedema. We describe a 70-year-old woman in generally good health who presented with a 2-year history of a maculo-papular eruption on the skin of her right breast. There was no lymphoedema of the thoracic area. The lesions developed 3 years after she had undergone ipsilateral quadrantectomy for an invasive ductal carcinoma followed by 25 tangent field radiotherapy sessions on the breast. The oncological follow-up did not disclose local recurrence of the tumour or metastases of breast carcinoma. Histopathologic examination of a papule was diagnostic for AS. In addition, signs of chronic radiation dermatitis were found in the biopsy specimens. The patient underwent monthly cycles of chemotherapy with intravenous doxorubicin with partial remission of the affected area after 24 months, followed by the occurrence of liver metastases and exitus 30 months after diagnosis. From the review of the literature, it appears that post-irradiation mammary AS mainly affects women over 60 who have undergone breast-sparing surgery and that it is usually associated with axillary lymphadenectomy. Whereas the role of lymphoedema does not seem relevant to the pathogenesis of this malignancy, the association with chronic radiation dermatitis in our case reinforces the supposed role of radiation in the development of this tumour. Onset of AS should be taken into consideration when treating patients who develop multiple lesions on the skin above the irradiated area, even many years after the therapy.
Speckled Lentiginous Nevus Syndrome: Report of a Further Case
Authors: Vente Claudia , Neumann Christine , Bertsch Hans , Rupprecht Rainer , Happle Rudolf
Published: September 2004

A 42-year-old man had a large speckled lentiginous nevus on the left side of his trunk. The involved area was painful when touched and paresthetic. Moreover, the ipsilateral half of his body showed a pronounced hyperhidrosis. This case can be categorized as a typical example of speckled lentiginous nevus syndrome, a recently recognized phenotype characterized by a speckled lentiginous nevus of the papular type and ipsilateral neurological abnormalities in the form of dysesthesia, muscular weakness or hyperhidrosis. Speckled lentiginous nevus syndrome represents a mosaic phenotype. Most likely it originates from loss of heterozygosity occurring in a heterozygous embryo at an early developmental stage.
Lymphogranuloma venereum – A Rare Cause of Genital Ulcers in Central Europe
Authors: Rampf J. , Essig A. , Hinrichs R. , Merkel M. , Scharffetter-Kochanek K. , Sunderkötter C.
Published: September 2004

Lymphogranuloma inguinale, caused by Chlamydia trachomatis serovar L1–L3 is rare in patients from western countries but needs yet to be considered in the differential diagnosis of genital ulcers. We report a case of a young male patient without any eventful travel history who presented with a genital ulcer at the sulcus coronarius and painfully enlarged lymph nodes in the right inguinal area. The typical clinical picture and serum IgM and IgG antibody titers of 1:16 and 1:512, respectively, against C. trachomatis were suggestive of infection with C. trachomatis serovar L1–L3. The diagnosis was confirmed by isolation of the organisms from the ulcer ground and subsequent sequence analysis of the omp1 gene which led to identification of C. trachomatis genotype L2 with 99% homology to a reference strain of C. trachomatis serovar L2. The lesion healed rapidly under treatment with doxycycline for 3 weeks, and the lymph nodes did not ulcerate. Thus, clinical suspicion was confirmed by genotyping of the isolated strain allowing timely diagnosis and treatment of lymphogranuloma inguinale.
Treatment of Pyoderma gangrenosum with Low-Dose Colchicine
Authors: Kontochristopoulos George J. , Stavropoulos Panagiotis G. , Gregoriou Stamatis , Zakopoulou Nikoleta
Published: September 2004

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis of unknown origin. Systemic agents occasionally administered provide either incomplete long-term control of the disease or have been associated with serious adverse side effects after chronic administration. We present two patients with PG successfully treated with low-dose colchicine. Antimitotic, anti-inflammatory and immunomodulating properties of colchicine might account for its beneficial effects in PG patients. Colchicine is effective and well tolerated in low doses by most patients. In addition, it is inexpensive and safer for long-term treatment than corticosteroids and other immunosuppressive agents. Colchicine may be proposed either as a single agent or as a corticosteroid-sparing agent for early treatment of PG.
Correlates of Varying Vocal Fold Adduction Deficiencies in Perception and Production: Methodological and Practical Considerations
Authors: Koreman Jacques , Pützer Manfred , Just Manfred
Published: September 2004

In this study the voice characteristics of normal male and female speakers are compared to those of two groups of patients with unilateral vocal fold paralysis. In order to enhance phonation, the patients in the first group compensate for the adduction deficiency which results from paralysis. The patients in the second group do not use compensatory strategies. Sustained vowels [i:, a:, u:] were produced by the speakers and scored for roughness, breathiness and hoarseness (RBH) by 8 raters. Although interrater agreement for RBH scores is only moderate on average, these percepts make consistent distinctions between the three speaker groups. Consistent but different distinctions are made between the three speaker groups for male and female speakers. The results show that male and female speakers should not be pooled in experimental studies of the pathological voice. Our results also indicate that female patients with a compensated unilateral vocal fold paralysis cannot be clinically evaluated solely on the basis of perception, because their voices cannot be distinguished from normal, healthy female speakers, despite their physiological impairment. The group distinctions made on the basis of RBH scores are supported by differences in the acoustic parameters which are derived by automatic analysis of the sustained vowels. Despite identical group distinctions for RBH scores and acoustic parameters, the acoustic basis of the percepts is not straightforward. Different acoustic predictors of the percepts were found for male compared to female speakers. Additionally, interrater differences point towards the presence of perceptual trading relations.
Phonétogramme par registre laryngé
Authors: Roubeau Bernard , Castellengo Michèle , Bodin Patricia , Ragot Maryse
Published: September 2004

Le phonétogramme par registre (ou mécanisme vibratoire laryngé) résulte de la superposition de deux phonétogrammes élaborés séparément pour chacun des deux principaux registres vocaux. Il permet d’évaluer l’ensemble des possibilités de la voix suivant les deux axes amplitude et fréquence, en rendant compte des possibilités inhérentes à chaque mécanisme. Cette technique permet de mieux comprendre l’influence des zones de passage sur l’aspect général du tracé. Le calcul de l’aire des phonétogrammes par registre laryngé, appliqué à une population de 42 sujets issus de trois catégories: non-chanteurs, chanteurs amateurs et chanteurs confirmés des deux sexes, met en évidence le rôle de la technique vocale sur les potentialités acoustiques du vibrateur laryngé. Enfin, cette approche fournit des informations complémentaires précieuses pour la connaissance des registres vocaux.
Hyaluronic Acid in the Treatment and Prevention of Skin Diseases: Molecular Biological, Pharmaceutical and Clinical Aspects
Authors: Weindl G. , Schaller M. , Schäfer-Korting M. , Korting H.C.
Published: September 2004

The glycosaminoglycan hyaluronic acid (HA), or hyaluronan, is a major component of the extracellular matrix of skin, joints, eye and many other tissues and organs. In spite of its simple structure, HA demonstrates remarkable rheological, viscoelastic and hygroscopic properties which are relevant for dermal tissue function. Biological activities in skin, however, are also due to its interaction with various binding proteins (hyaladherins). Due to an influence on signaling pathways, HA is involved in the wound-healing process and scarless fetal healing. Increased HA concentrations have been associated with inflammatory skin diseases. In clinical trials, topical application of HA improved wound healing; in particular, acute radioepithelitis, venous leg ulcers or diabetic foot lesions responded to HA treatment. Moreover, as a topical drug delivery system for diclofenac, an HA gel has recently been approved for the treatment of actinic keratoses. Finally, chemical modifications led to new HA derivates and biomaterials, which may be introduced into therapy in the future. Therefore, ongoing research offers new horizons for the therapeutic use of this glycosaminoglycan which has been regarded as an inert structural component until recently.
Penciclovir Cream – Improved Topical Treatment for Herpes simplex Infections
Authors: Schmid-Wendtner M.-H. , Korting H.C.
Published: September 2004

Human herpesviruses can be found worldwide and cause many viral infections in immunocompetent as well as in immunocompromised patients. Herpes simplex virus (HSV) diseases can be the cause of life-threatening disease, especially in neonates. After initial infection, HSV persists latently in host neurons with the risk of periodical reactivation over a lifetime. The development of acyclovir, a potent and specific nucleoside inhibitor of the herpes DNA polymerase, was a milestone in the history of antiviral drugs in the late 1970s. During the last decades a better understanding of the replication and disease-causing state of HSV types 1 and 2 has been achieved enabling the development of new and potent antiviral compounds. In the mid-1990s, for example, valacyclovir and famciclovir were launched as prodrugs of acyclovir with improved bioavailability. Despite the numerous drugs available for the systemic treatment of HSV infections, the topical application of a cream containing an antiviral agent is still the most convenient method of treating herpes simplex labialis/facialis in the general population. For some time, the topical standard treatment for recurrent HSV infections has been acyclovir cream, despite the fact that the evidence for efficacy in recurrent episodes has been equivocal. Penciclovir, a novel acyclic nucleoside analogue, has demonstrated efficacy against HSV types 1 and 2 and seems to have a pharmacological advantage due to a prolonged half-life of its active form in HSV-infected cells. This review discusses and compares the topical treatment modalities available for HSV infections. As a conclusion, different studies are available that have shown that it is possible to reduce viral replication and hasten lesion resolution with 1% penciclovir treatment beyond the prodromal phase of the HSV infection. Comparing data of topical treatment with acyclovir and penciclovir revealed a superiority for penciclovir cream showing a significant decrease in time to lesion healing, lesion area and pain. While systemic acyclovir or valacyclovir may be valid drugs especially for HSV prophylaxis, 1% penciclovir cream should be preferred as topical treatment since there are good therapeutic results independent of the phase of development of herpetic eruptions.
The Combined Effects of Extracts Containing Carotenoids and Vitamins E and C on Growth and Pigmentation of Cultured Human Melanocytes
Authors: Smit N. , Vicanova J. , Cramers P. , Vrolijk H. , Pavel S.
Published: September 2004

In the present study, we investigated the effects of tomato extract (TE) containing lycopene and palm fruit extract (PE) rich in carotenoids on the growth and pigmentation of melanocyte cultures of Caucasian origin. The extracts were tested at different concentrations and in combination with vitamins E and C. Melanocytes with basic and increased (tyrosine-induced) pigmentation were treated in short-term and long-term experiments. Prevention of UVA-induced DNA damage was studied by using the comet assay. Melanocytes with stimulated melanin production showed reduced growth. Incubation of the cells with TE/PE (20/4 µg/ml) in combination with 35 µM vitamin E and 100 µM vitamin C (COMB 20/4) reduced this growth inhibition, especially in the long-term cultures. Increased production of melanin pigment was obtained when the cells were treated with 2.5 × and 10 × higher concentrations of the TE/PE and the same concentration of vitamins E and C (COMB 50/10 and 200/40). Reduced DNA damage was found after UVA irradiation in cells preincubated with COMB 50/10. The results indicate that the presence of carotenoids from TE and PE in combination with vitamins E and C may influence growth and pigmentation in melanocyte monocultures. Depending on the concentration of the carotenoid mixtures, their presence may provide some protection against the melanogenic intermediates and/or exogenous DNA damage.
Dead but Highly Dynamic – The Stratum corneum Is Divided into Three Hydration Zones
Authors: Richter T. , Peuckert C. , Sattler M. , Koenig K. , Riemann I. , Hintze U. , Wittern K.-P. , Wiesendanger R. , Wepf R.
Published: September 2004

Topically applied water exerts mechanical stress on individual corneocytes as well as on the whole stratum corneum (SC), resulting in an alteration of barrier function. In this study we used complete skin biopsies and showed that the SC reacts to water stress as a highly optimized and well-regulated structure against osmotic changes. Following a relatively new cryo-processing protocol for cryo-SEM, it is possible to reliably maintain and investigate the hydrated state of the SC and individual corneocytes after treatment with solutions of different ionic strength. Treatment with distilled water results in swelling of SC cells together with formation of massive water inclusions between adjacent cell layers. Treatment with 5–20% NaCl reveals three different hydration zones within the SC: Corneocytes near the live-dead transition zone can swell to nearly double their thickness. The second zone is the most compact, as the corneocytes here show the smallest thickness variation with all treatments. Within the outermost zone, again a massive swelling and loosening of intracellular filament packing can be observed. We therefore conclude that the SC itself is subdivided into three functional zones with individual water penetration and binding potentials. Since the second zone remains nearly unaffected by water stress, we propose that this zone hosts the functional SC barrier.
Molecular Analysis of the Effect of Topical Imiquimod Treatment of HPV 2/27/57-Induced Common Warts
Authors: Jacobs S. , Grußendorf-Conen E.-I. , Rösener I. , Rübben A.
Published: September 2004

Imiquimod is effective in the treatment of genital warts and clinical studies suggest activity against common warts as well. We have analyzed the effect of topical imiquimod on gene expression and virus load in human papilloma virus (HPV) 2/27/57-induced common warts. mRNA was extracted from keratinocyte culture, from normal skin, from three untreated common warts and from three common warts treated topically with 5% imiquimod cream twice daily. Differential gene expression was demonstrated by RT-PCR and by cDNA microarray hybridization. We further analyzed viral DNA content in scales from three superficially pared imiquimod-treated warts by real-time PCR. Comparison of normal skin with wart tissue revealed that HPV 2/27/57 infection led to an induction of IL-6, IL-10 and interferon-γ inducible protein (IP10) and to an up-regulation of TGF-β. We could further detect expression of PCTAIRE-3, WNT2B, frizzled-3, notch-2, notch-4 and BRCA2 in normal skin and common warts. Analysis of imiquimod-treated warts demonstrated that imiquimod enhanced IL-6 expression and induced IL-8, GM-CSF, MRP-8 and MRP-14. It could also be shown that imiquimod led to an infiltration of wart tissue with macrophages and to a strong decrease of viral copy number in warts within 3 months of treatment. Our data thus provide molecular proof of principle for imiquimod treatment of cutaneous common warts.
Extra-Esophageal Disorders in Gastroesophageal Reflux Disease
Authors: Jaspersen Daniel
Published: September 2004

Gastroesophageal reflux disease (GERD) is a common condition that effects about 10% of the adult population comprising a broad spectrum of symptoms and varying degrees of severity and frequency. Extra-esophageal manifestations are increasingly being recognized. Up to 50% of patients with an endoscopically proven or negative esophagitis suffer from symptoms other than heartburn or acid regurgitation such as laryngitis, hoarseness, chronic cough, asthma, or non-cardiac chest pain. The therapy of choice is proton pump inhibitors.
Acid Suppression and Chemoprevention in Barrett’s Oesophagus
Authors: Raj Anita , Jankowski Janusz
Published: September 2004

Barrett’s oesophagus is a pre-malignant condition affecting 1% of the population in the West. Even though most patients with Barrett’s will not develop oesophageal cancer, the incidence of adenocarcinoma is 0.45–1%, conferring a 40-fold increased risk compared with the general population. The risk rises to 40–50% within 5 years for those with high grade dysplasia. Currently, the only strategies available to diminish adenocarcinoma rates are surveillance endoscopy, endoscopic thermal or photodynamic ablation or tissue resection. The latter options are reserved for those who already have dysplasia. 10–50% of patients undergoing oesophagectomy for high grade dysplasia have been shown to have adenocarcinoma. Therefore approaches are needed to be that either remove or prevent stimuli propelling patients down the dysplasia-adenocarcinoma pathway. Both gastric acid and bile acids have been reported as potential insults involved in the pathogenesis of Barrett’s oesophagus. This is thought to be mediated by a range of molecules including cyclo-oxygenase-2, c-myc and mitogen-activated protein kinase signalling. Proton pump inhibitors not only suppress acid but also bile reflux, although symptom control is a poor guide as to adequacy of acid suppression. There is some evidence that proton pump inhibitors cause partial regression in Barrett’s oesophagus length, although the data is contradictory. Proton pump inhibitors have also been shown to increase cell differentiation and apoptosis, reduce proliferation and COX-2 levels, with the supposition that this may diminish cancer risk. However this role in decreasing cancer risk has not yet been evaluated. The use of NSAIDS and aspirin, most likely via inhibition of COX-2 and other inflammatory pathways, is associated with a reduction of adenocarcinoma rates. Both PPIs and NSAIDs/Aspirin may therefore be potential chemopreventative agents but further studies are required to appraise their use.
Oesophageal Histology in Gastro-Oesophageal Reflux Disease Is of Minor Pre- and Postoperative Diagnostic Value
Authors: Rantanen Tuomo K. , Mäkinen Judith E. , Sipponen Pentti I. , Sihvo Eero I.T. , Leppäniemi Ari , Salo Jarmo A.
Published: September 2004

Background and Aim: The clinical value of oesophageal histology in non-complicated gastro-oesophageal reflux disease (GORD) is controversial. Our aim was to explore the role of histology in preoperative diagnosis and postoperative follow-up in GORD. Methods: From 40 patients 2 histopathologists graded and scored 191 oesophageal biopsies in a blinded manner to evaluate inter- and intraobserver variation pre- and postoperatively. Correlation between preoperative histology and objective clinical findings (endoscopy, esophageal 24-hour pH monitoring, and manometry) was calculated as well. Results: Pathologist I interpreted 16 (50%) preoperative biopsies as normal, 5 (16%) with mild, 4 (12.5%) moderate, and 7 (21.9%) severe reflux changes. Pathologist II interpreted 11 (35.5%) preoperative biopsies as normal, 11 (35.5%) with mild, 6 (19.4%) moderate, and 3 (9.7%) severe reflux changes. In preoperative biopsies, interobserver variation was 33.8% and intraobserver variation 9.7%. A positive correlation was detectable between preoperative endoscopic and morphologic findings; no correlation existed between either acid reflux or LES pressure and oesophageal morphology. Normal pH monitoring and fundic wrap were noted postoperatively in all cases. In postoperative histology no significant differences according to pathologist I existed when compared with preoperative changes: 22 normal (69%), 7 mild (22%), 1 moderate (3.1%), and 2 severe (6.3%). Compared to preoperative analysis, pathologist II interpreted 24 (77%, p = 0.001) of the postoperative findings as normal, 1 (3%, p = 0.003) as mild, 4 (12.9%, n.s.) as moderate, and 2 (6.5% n.s.) as severe reflux changes. In postoperative biopsies interobserver variation was 21.1% and intraobserver variation 5.6%. Conclusion: The role of oesophageal histology in preoperative diagnosis and postoperative follow-up of GORD may be considered limited.
Radial Distribution of Dilated Intercellular Spaces of the Esophageal Squamous Epithelium in Patients with Reflux Disease Exhibiting Discrete Endoscopic Lesions
Authors: Vieth M. , Fiocca R. , Haringsma J. , Delarive J. , Wiesel P.H. , Tam W. , Tytgat G.N.J. , Dent J. , Edebo A. , Lundell L. , Stolte M.
Published: September 2004

Introduction: Dilatation of intercellular spaces of the esophageal squamous epithelium has been suggested as a marker of early acid reflux-induced damage. This change is a potentially useful addition to histomorphological changes that represent so called minimal endoscopic lesions. We have assessed dilatation of intercellular spaces with regard to: (1) interobserver variability, and (2) whether the incidence of this varies between ‘red streaks’ and the adjacent normal looking squamous epithelium. Methods: Esophageal biopsies from 44 patients with chronic gastro-esophageal reflux (GERD) were evaluated. At endoscopy, these patients had one or more red streaks on the tops of the mucosal folds in the distal esophagus. Biopsies were taken from the red streaks and from the normal-appearing mucosa 1 cm lateral to the red streaks. Biopsies were assessed in a blinded fashion by two independent pathologists (MV & RF). Criteria for assessing intercellular space dilatation were evaluated and agreed on prior to the study. Results: Good interobserver agreement was recorded (kappa = 0.82 at the streaks and 0.77 for the control tissues) for absence/presence of intercellular space dilatation. Red streak and control biopsies differed significantly (p = 0.0001), with respect to presence of dilated intercellular spaces, with 90.5 % of the former demonstrating this as present compared to 56.1% in the controls. Conclusion: This study supports the concept that esophageal mucosal minimal changes due to reflux is localised and that dilatation of intercellular spaces is an early sign of reflux-induced epithelial damage. The low interobserver variability in the assessment of intercellular space dilatation suggests that this may be a useful variable for assessment of early signs of acid-reflux induced damage to the squamous epithelium of the esophagus by use of light microscopy.
Minimal Change Esophagitis: Prospective Comparison of Endoscopic and Histological Markers between Patients with Non-Erosive Reflux Disease and Normal Controls Using Magnifying Endoscopy
Authors: Kiesslich R. , Kanzler S. , Vieth M. , Moehler M. , Neidig J. , Thanka Nadar B.J. , Schilling D. , Burg J. , Nafe B. , Neurath M.F. , Galle P.R.
Published: September 2004

Introduction: More than half the patients with gastroesophageal reflux disease (GERD) show no endoscopic abnormality or minimal change esophagitis (non-erosive reflux disease, NERD). We investigated the value of endoscopic and histological markers for the prediction of NERD before and after treatment with 20 mg esomeprazole. Methods: Between July and October 2002, consecutive patients presenting for upper endoscopy were stratified into GERD and non-reflux patients (control group) with the help of a questionnaire. The endoscopist was blind to the presence of reflux symptoms. Using magnifying endoscopes minimal change esophagitis was defined by the presence of vascular injection or vascular spots above the Z-line, villous mucosal surface and islands of squamous cell epithelium below the Z-line. Targeted and random biopsies were taken below and above the Z-line. Patients with endoscopically visible classical signs of esophagitis (Los Angeles A–D) or histologically proven Barrett’s esophagus were not further investigated in the study (drop out). The esophageal specimens were histologically evaluated for erosions, infiltration with leukocytes, hyperplasia of basal cells and length of papillae. Patients with NERD were treated with 20 mg esomeprazole/day for 4 weeks and reevaluated by endoscopy as described before. Results: 39 patients with heartburn and 39 patients without reflux symptoms (controls) were finally included in the analysis (per protocol). Patients with NERD significantly (p = 0.005) more often showed endoscopic signs of minimal change esophagitis (27/39) than the control group (8/39). An increased length of papillae (14/39 versus 2/39; p = 0.005) and basal cell hyperplasia (17/39 versus 4/39; p = 0.009) were significantly more common in the heartburn group. After treatment with esomeprazole, no significant endoscopic or histological differences between the NERD and control group could be observed. Conclusions: Minimal change esophagitis can be seen with high resolution magnifying endoscopy. By combining endoscopic and histological markers NERD can be predicted with a sensitivity of 62% and a specificity of 74%. Treatment with esomeprazole for 4 weeks reverses the slight alterations to normal.