bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Impact of Molecular Diagnostics in Endocrinology
Authors: Höppner Wolfgang
Published: April 2003

Genetic defects in genes encoding hormones, hormone receptors or polypeptides of the signaling pathways usually cause complex disease manifestations characterized by the involvement of several tissues and variable expression. Genetic aberrations, like chromosome aneuploidy, gene translocations or mutations in key regulatory proteins (even if not directly affecting genes of the endocrine system) often lead to clinical symptoms, including central endocrine functions like sexual differentiation or metabolic disturbances, like diabetes mellitus. But also minor genetic alterations like point mutations can affect the function of gene products to cause endocrine diseases. If the underlying molecular defects of endocrinopathies are known, direct molecular diagnosis can be performed. This is particularly useful if it helps to solve difficult differential diagnosis problems or if there exist effective preventive therapeutic options. The present paper presents examples for endocrine diseases in which molecular testing significantly increases the specificity and sensitivity of diagnostics and demonstrates the benefits for the patients and the healthcare system. In multiple endocrine neoplasia type 2, an unambiguous identification of gene carriers in affected families can be achieved by genetic testing. As a preventive measure to avoid medullary thyroid carcinoma, prophylactic thyroidectomy is recommended for individuals carrying the disease causing mutation. In adrenogenital syndrome, sequence analysis of the steroid 21-hydroxylase gene has become an important tool to confirm or exclude suspected late-onset forms of the disease, where hormone measurements are not informative. The major benefit, however, lies in identifying heterozygous carriers and providing a reliable prenatal test for couples carrying a defect in the 21-hydroxylase gene. Today, prenatal treatment with dexamethasone, which prevents the virilization in female fetuses, should always be based on results from molecular diagnosis performed from chorionic villus samples.
Fatal Outcome of Sleep Apnoea in PWS during the Initial Phase of Growth Hormone Treatment
Authors: Eiholzer Urs , Nordmann Yves , l’Allemand Dagmar
Published: April 2003

The case of a boy with Prader-Willi syndrome (PWS) who suffered from respiratory problems since birth and suddenly died at the age of 6.5 years, 4 months after initiation of GH therapy, is presented. This case indicates the possibility of fatal courses in infants and children with PWS as a consequence of respiratory problems and raises the question as to a causal connection between the initiation of GH therapy and the sudden death of this child.
Effects of Growth Hormone in Patients with Chronic Renal Failure: Experience in Children and Adults
Authors: Wühl Elke , Schaefer Franz
Published: April 2003

Recombinant human growth hormone (GH) has proven effective in promoting growth in short children with chronic renal failure before and after renal transplantation. The action of GH and its mediator insulin-like growth factor 1 on body composition, protein, glucose and bone metabolism offers additional therapeutic options. One might be the improvement of the catabolic state in adults with end-stage renal failure. In few pilot studies and two placebo-controlled studies of 6 months duration, GH treatment in adults on dialysis showed clear anabolic effects resulting in a significant increase in lean body mass.
Effects of Growth Hormone on Skeletal Muscle
Authors: Weber Matthias M.
Published: April 2003

Human growth hormone (GH) is widely abused as a performance-enhancing anabolic drug by athletes and bodybuilders. However, the effects of GH on skeletal muscle mass, strength and fibre composition remain unclear. We therefore summarize in the following the current knowledge on the physiological role of GH in the regulation of skeletal muscle growth and function and evaluate its potential therapeutic potency as a muscle anabolic hormone. In states of GH deficiency, reduced muscle mass and strength are characteristic findings which can be reversed successfully by the supplementation of GH. In contrast, the currently available data suggest that GH administration alone or in combination with strength exercise has little, if any, effect on muscle volume, strength and fibre composition in non-GH-deficient healthy young individuals. This assumption is supported by the lack of evidence for a significant performance-enhancing effect of GH in athletes. However, further studies will be necessary to define patient populations which might benefit from GH treatment like frail elderly individuals in whom a GH-induced change into a more youthful muscle fibre composition has been reported.
Auxological, Ophthalmological, Neurological and MRI Findings in 25 Austrian Patients with Septo-Optic Dysplasia (SOD)
Authors: Riedl S.W. , Müllner-Eidenböck A. , Prayer D. , Bernert G. , Frisch H.
Published: April 2003

Septo-optic dysplasia (SOD) comprises ophthalmological, endocrinological and neurological disorders resulting from varying degrees of midline malformation of the forebrain like visual impairment by optic nerve hypoplasia, endocrine deficits due to hypothalamic and/or pituitary anomalies, and psychomental retardation by associated cortical malformation. MRI shows aplasia/hypoplasia of the septum pellucidum and corpus callosum as a radiological hallmark. For etiology, genetic defects (Hesx1/HESX1 gene) as well as vascular disruption during embryonic brain development are discussed. Aim: To perform detailed analysis of morphological findings and clinical symptoms and to improve care of SOD patients by interdisciplinary management. Patients: We investigated 25 patients with a mean age of 5.1 years at diagnosis. Results: Pituitary insufficiency was present in 11/25 patients, multiple deficits in 6 of them. Bilateral optic nerve hypoplasia was found in 70% of patients, unilateral in 20%. Mild or moderate neurological disorders were observed in the majority of patients (14/20), EEG was usually normal (12/19). Analysis of MRI films revealed very heterogeneous morphological anomalies, ranging from isolated agenesis of the septum pellucidum to multiple malformations, involving the cortex. Malrotation of the hippocampal structures was a common finding. Conclusion: We conclude that only interdisciplinary management of SOD patients can ameliorate the exact diagnosis and outcome, depending on early visual or developmental support as well as early diagnosis and substitution of potentially life-threatening endocrine deficits.
Effect of Short-Chain Fructooligosaccharides and Cellulose on Cecal Enzyme Activities in Rats
Authors: Gudiel-Urbano Montserrat , Goñi Isabel
Published: April 2003

The effect of fructooligosaccharides (FOS) on cecal enzyme activity was studied. Adult male Wistar rats were fed a fiber-free diet supplemented with 5% cellulose, a 5% mixture (1:1) of cellulose and FOS or 5% FOS as a source of fiber for 4 weeks. The cecal content was used to measure azoreductase, β-glucuronidase, β-glucosidase, nitrate reductase and nitroreductase activities. Cellulose-fed diet increased significantly body weight gain, food intake and fecal stool weight compared to FOS-fed diet. No differences in food intake between FOS-containing diets were found. FOS-containing diets showed statistically higher weight of cecal content and weight of cecal wall compared with the cellulose group. There were significant differences in cecal enzyme activities between cellulose-fed rats and FOS-fed rats. Cellulose-FOS-fed diet decreased significantly nitroreductase, β-glucuronidase and β-glucosidase enzymes, but did not differ statistically in azoreductase and nitrate reductase compared with the control group. FOS-fed diet increased significantly reductive enzymes and decreased hydrolytic enzymes compared with the cellulose group. The incorporation of cellulose in diet seems to affect the prebiotic effect of FOS, since both cellulose and FOS are possible substrates for bifidobacteria proliferation. The results suggest that a mixture of cellulose and FOS as a source of dietary fiber could have a healthier effect on bacterial enzyme activities than each type of dietary fiber alone.
Antihypertensive Effects of Hydrolysates of Wakame (Undaria pinnatifida) and Their Angiotensin-I-Converting Enzyme Inhibitory Activity
Authors: Sato Minoru , Oba Takashi , Yamaguchi Toshiyasu , Nakano Toshiki , Kahara Takashi , Funayama Katsura , Kobayashi Akio , Nakano Takahisa
Published: April 2003

Aim: The angiotensin-I-converting enzyme (ACE) inhibitory and antihypertensive activities of wakame hydrolysates have been investigated in several studies. Methods: Wakame (Undaria pinnatifida) was hydrolyzed using 17 kinds of proteases and the inhibitory activity of the hydrolysates for ACE was measured. Of these hydrolysates 4 with potent ACE inhibitory activity were administered singly and orally to spontaneously hypertensive rats (SHR). Results: The systolic blood pressure of SHR decreased significantly after single oral administration of protease S ‘Amano’ and proleather FG-F hydrolysates (10 mg protein/kg body weight). In a long-term feeding experiment, 7-week-old SHR were fed standard chow supplemented with protease S ‘Amano’-derived wakame hydrolysates for 10 weeks. In SHR fed the 1 and 0.1% wakame hydrolysates, elevation of systolic blood pressure was still significantly suppressed for 7 weeks. Conclusions: The hydrolysates derived from wakame by protease S ‘Amano’ have a powerful ACE-inhibitory activity (IC50 = 86 µg protein/ml) and were effective in spite of their slight bitterness as ‘physiologically functional food’ with antihypertensive activity.
Effect of Ingestion of Thermally Oxidized Sunflower Oil on the Fatty Acid Composition and Antioxidant Enzymes of Rat Liver and Brain in Development
Authors: Ammouche A. , Rouaki F. , Bitam A. , Bellal M.M.
Published: April 2003

Background: The current study was undertaken to assess the effects of oxidized sunflower oil ingestion (obtained by heating at 98°C with air insufflation during 48 h and incorporated at 5% in a fat-free diet) on liver and brain fatty acid composition, and some serum parameters and protective enzymes against peroxidation (glutathione peroxidase, glutathione reductase, catalase and glucose-6-phosphate dehydrogenase). Results: The main results show that the oxidized oil contains 262 mmol/kg of hydroperoxides, 5.7% of the esters are oxidized and 50.4% are polymerized. In the liver, we noticed that oxidized oil exercises a toxic effect as confirmed by the increase in the thiobarbituric acid reactive substance (TBARS) concentration. In the same way, we noticed that vitamin E exercises a favorable effect in the preservation against free radicals and lipid peroxidation; however, it cannot ensure this protection alone. In the liver, only glutathione peroxidase and glutathione reductase activities were positively correlated with the TBARS concentration. In the treated groups, we also noted changes in the fatty acid profiles of liver and brain homogenates, essentially by the appearance of trans fatty acid (18:1 trans) and an increase in arachidonic acid content.
Feeding Patterns in Breast-Fed and Formula-Fed Infants
Authors: Sievers Erika , Oldigs Hans-Dieter , Santer René , Schaub Jürgen
Published: April 2003

Aim: The intention of this study performed in healthy breast- and formula-fed infants was to characterize physiological feeding patterns as a basis for counseling parents to feed their infants on demand. Methods:Ingested milk volumes of 10 breast-fed and 14 formula-fed infants were measured during five 72-hour investigation periods during the 3rd, 6th, 9th, 13th, and 17th weeks of life. Results: A comparable diurnal distribution of feeds was observed in both groups during the first 9 weeks of life, with a day-night asymmetry of feeding first observed at the age of 6 weeks. Thereafter, formula-fed infants showed a further decrease in their nightly milk intake. Within the investigation period, the milk volume per feed rose from 100 (range 40–200) g to 140 (range 30–300) g in the breast-fed group and from 100 (range 20–200) g to 200 (range 20–450) g in formula-fed infants. From the 6th week of life onwards, formula-fed infants had significantly higher feeding volumes. Conclusions: Parents should be informed about the variability of infant demands per feed and of feeding at night observed in breast-fed infants. The results suggest that feeding patterns similar to those of breast-fed infants are difficult to accomplish in formula-fed infants.
Aortic Valve Replacement in the Elderly: Frequently Indicated yet Frequently Denied
Authors: Bramstedt Katrina A.
Published: April 2003

Background: The prevalence of aortic stenosis is nearly 20% in octogenarians. Aortic valve replacement (AVR) is the optimal therapy choice, yet many symptomatic patients are denied this beneficent technology. Whether mechanical or bioprosthetic, aortic valves are not a scarce resource and their safety, effectiveness and longevity are proven. Objective: Because the geriatric population is soaring, clinicians will be encountering more cases of aortic stenosis and the decision-making that leads to surgical referral or non-referral warrants exploration. Methods: A literature review was conducted to explore the notion that physicians deny AVR to their patients based solely on their chronological age value. Results: Using age as the sole exclusion criterion, medical literature documents the fact that AVR is frequently denied to the elderly. Conclusion: It appears that AVR is another beneficent cardiac technology that has been added to the age discrimination list, even though the devices are not scarce, they are cost-effective, and they can improve the life of a symptomatic elderly patient. There is no ethical justification for denying AVR to clinically suitable elderly candidates who request such therapy.
Pharyngoglottal Closure Reflex: Characterization in Healthy Young, Elderly and Dysphagic Patients with Predeglutitive Aspiration
Authors: Shaker Reza , Ren Junlong , Bardan Eytan , Easterling Caryn , Dua Kulwinder , Xie Pengyan , Kern Mark
Published: April 2003

Background: Mechanism(s) of aspiration, a common complication of oropharyngeal dysphagia, is not completely elucidated. Since the pharyngoglottal closure reflex induces vocal cord adduction in healthy young humans, it may help prevent aspiration during premature spill of oral content. Objective: The objective of this study was to characterize this reflex in normal young and elderly humans and dysphagic patients with predeglutitive aspiration; a potential group for developing abnormalities of this reflex. Methods: We used a concurrent video endoscopic and manometric technique for recording of the vocal cords’ response to pharyngeal water stimulation. We first studied 9 young (26 ± 2 years) and 9 elderly (77 ± 14 years) healthy volunteers to characterize and determine the effect of aging on the pharyngoglottal closure reflex. Subsequently, we studied 8 patients (65 ± 16 years) with predeglutitive aspiration and 7 age-matched controls to characterize this reflex among patients with compromised airway safety during swallowing. Results: The threshold volume of water for triggering both glottal closure and reflexive pharyngeal swallow in the elderly volunteers for rapid pulse injection was significantly larger than that for the young (p < 0.05). Neither glottal closure reflex nor pharyngeal reflexive swallow could be induced in any of the dysphagic patients with volumes of injected water as large as 1 ml. In contrast, in all age-matched controls, both the pharyngoglottal reflex and reflexive pharyngeal swallow were stimulated with threshold volumes of 0.3 ± 0.07 and 0.6 ± 0.05 ml, respectively. Conclusions: Pharyngeal stimulation by water induces vocal cord adduction in humans; the pharyngoglottal closure reflex. Although preserved, a significantly larger volume of water is required to stimulate this reflex by rapid pulse injection in the elderly, suggesting some deterioration in this age group. The pharyngoglottal closure reflex induced by rapid pulse injection is absent in dysphagic patients with predeglutitive aspiration, suggesting its contribution to airway protection against aspiration.
Effect of Age in Rats following Middle Cerebral Artery Occlusion
Authors: Wang Ray-Yau , Wang Paulus Shyi-Gang , Yang Yea-Ru
Published: April 2003

Background: Despite the impressive increased understanding of the ischemic brain damage in general, the study of effects on different age groups, young versus old, using comparable ischemic insults is clearly lacking. Objectives: To investigate the mortality rate and neurological outcome among young and old rats, through a model of cerebral ischemia by middle cerebral artery occlusion (MCAO). Methods: Twenty-three old (22–24 months of age) and 16 young (3–4 months of age) male rats underwent a MCAO procedure for 60 min. Surviving rats were randomly assigned to the 24-hour or 28-day resting group. The mortality rate and neurological outcome in different recovery time periods were determined for comparison between the young and old rats. Results: The overall mortality rate in old rats (43.5%) was significantly higher than that of the young rats (6.3%) (p = 0.01). The infarct volume for the 24-hour post-MCAO was 181.86 ± 11.87 mm3 for the young rats, and 204.64 ± 27.18 mm3 for the old rats. For the 28-day post-MCAO, the value was 91.16 ± 3.59 mm3 for the young rats, and 103.38 ± 26.43 mm3 for the old rats. A significant reduction in infarct volume is noted in both young (p < 0.01) and old (p < 0.05) rats after 28 days of recovery compared to that after 24 h of recovery. There was no meaningful difference in infarct volume between the young and old rats measured at 24 h or 28 days after the ischemic procedure. The right volume was larger than the left volume at 24 h post-MCAO for both the young and the old rats, whereas the quotient approached unity for the young rats at 28 days post-MCAO. For the old rats, the quotient was negative at 28 days post-MCAO, representing the ipsilateral hemisphere was smaller than the contralateral hemisphere. Conclusion: The mortality risk to ischemic damage is greater for old rats. If an old rat survives the high-risk mortality in a short period after the MCAO procedure, the recovery would be of no difference to that of a young rat.
Clinical Application of Oligonucleotide Probe Array for Full-Length Gene Sequencing of TP53 in Colon Cancer
Authors: Takahashi Yasuo , Ishii Yukimoto , Nagata Toshihito , Ikarashi Masahito , Ishikawa Koichi , Asai Satoshi
Published: April 2003

Objective:TP53 mutations are the most frequent genetic alterations in colon cancer. We studied whether the recently developed oligonucleotide microarray technique, GeneChip p53 assay, can be applied to sensitive detection of TP53 gene mutations in surgical specimens from colon cancer patients. Methods:TP53 gene mutations in exons 2–11 in 20 colon cancers and the corresponding histopathologically normal mucosa at the surgical margins were assessed by GeneChip p53 assay, and the results were further evaluated by direct sequencing of the involved exon or by mutant-allele-specific amplification (MASA). The expression of TP53 protein was also evaluated immunohistochemically and the result was compared with the gene alteration. Results: The GeneChip p53 assay detected TP53 mutations in 65% of primary cancers; 61% of the mutations were within the evolutionarily conserved regions, and 46% of the mutations were within the zinc-binding domains (regions of loop 2 and loop 3). Direct sequencing confirmed these mutations. Immunohistochemical examination detected TP53 protein overexpression in 47% of primary cancers, but this protein did not accumulate with all types of TP53 mutations. In addition, the GeneChip assay detected a mutation identical to that in the primary tumor in 2 samples from the surgical margins, and MASA confirmed both mutations, implying the presence of occult cancer cells. Conclusion: The GeneChip p53 assay is sufficiently sensitive to detect TP53 mutations in surgical specimens from colon cancers and may be applicable to screening examination in clinical laboratories as a routine procedure.
Clinical Significance of Angiogenic Factor Expression at the Deepest Invasive Site of Advanced Colorectal Carcinoma
Authors: Kaio Eijiro , Tanaka Shinji , Kitadai Yasuhiko , Sumii Masaharu , Yoshihara Masaharu , Haruma Ken , Chayama Kazuaki
Published: April 2003

Tumor angiogenesis is a complicated process for which the mechanisms remain unclear. The aim of this study was to elucidate the clinical significance of several angiogenic factor expression as a predictor of the invasive/metastatic potential and of the prognosis of advanced colorectal carcinoma (CRC) in relation to their intratumoral histologic heterogeneity. One hundred fifty two patients who had undergone surgical resection for advanced CRC entered this study. PD-ECGF, VEGF, and VEGF-C were examined immunohistochemically with antibodies 1C6-203, A-20, and C-20, respectively. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD34 antibody. Expression of PD-ECGF, of VEGF, and of VEGF-C at the deepest invasive site were detected in 77 (50.7%), 62 (30.8%), and 71 (46.7%) of the 152 lesions, respectively. PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site in lesions with liver metastasis (77, 67, and 70%) was significantly higher than that in those without liver metastasis (44, 34, and 41%). In cases with curative surgery, patients with PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site had a significantly poorer prognosis than those without PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site. PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site correlated significantly with MVD. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF expression were significant risk factors. Expression of PD-ECGF, VEGF, and VEGF-C was correlated significantly with metastatic potential and prognosis in relation to MVD. Of the several angiogenic factors, VEGF expression at the deepest invasive site of tumor was the most statistically significant indicator of prognosis in advanced CRC.
Combined Intrapleural and Intravenous Chemotherapy, and Pulmonary Irradiation, for Treatment of Patients with Lung Cancer Presenting with Malignant Pleural Effusion
Authors: Su Wu-Chou , Lai Wu-Wei , Chen Helen H.W. , Hsiue Tzuen-Ren , Chen Cheng-Wen , Huang Wen-Tsung , Chen Tsai-Yun , Tsao Chao-Jung , Wang Nai-San
Published: April 2003

Objectives: Patients with non-small-cell lung cancer (NSCLC) and malignant pleural effusion (MPE) are difficult to manage clinically and have a short life expectancy. In this pilot study, we designed a protocol of combined intrapleural (i.p.) and intravenous (i.v.) chemotherapy and pulmonary irradiation to enhance local as well as systemic control of the disease. Methods: From April 1998 to April 2000, 27 patients with NSCLC and symptomatic MPE were eligible for the study. Patients received pre-radiation chemotherapy (cisplatin 60 mg/m2 i.p. on day 1; gemcitabine 1,000 mg/m2 i.v. on days 1, 8, and 15, q4week × 3) after surgical implantation of i.p. and i.v. port-A, followed by radiotherapy (7,020 cGy/39fr), and, finally, post-radiation chemotherapy (docetaxel 60 mg/m2 q3week × 3–6 i.v.). Results: Grade 1/2 nausea/vomiting and impaired renal function were more common from pre-radiation than post-radiation chemotherapy; however, grade 3/4 toxicities from pre-radiation chemotherapy were minimal. Conversely, grade 3/4 leukopenia and grade 1/2 alopecia, diarrhea, elevation of SGOT/SGPT, and sensory impairment were more common following post-radiation chemotherapy. Only two patients experienced recurrence of pleural effusion. The overall response rate was 55% with 7% complete remission, 48% partial remission, 22% stable disease, and 22% progressive disease. The median failure-free and overall survival was 8 and 16 months, respectively. The one-year survival rate was 63% (95% confidence interval, 45–80%). Conclusions: We conclude that the combination of i.p. and i.v. chemotherapy and pulmonary irradiation is feasible and should be tested in a larger clinical trial to determine whether survival can be improved for this cohort of patients.
A Phase II Study with 5-Fluorouracil, Folinic Acid and Oxaliplatin (FOLFOX-4 Regimen) in Patients with Metastatic Renal Cell Carcinoma
Authors: Bennouna J. , Delva R. , Gomez F. , Lesimple T. , Geoffrois L. , Linassier C. , Chevreau C. , Douillard J.Y. , Négrier S.
Published: April 2003

Purpose: To investigate the efficacy and safety of the FOLFOX-4 regimen for patients with metastatic renal cell carcinoma (MRCC). Patients and Methods: Fifty-nine patients (median age 59 years) pre-treated or not by cytokines (29 vs. 30) received the FOLFOX-4 regimen every 2 weeks. Results: Three minor responses, and no complete or partial responses were obtained. The median progression-free survival was 3 months (95% CI: 2.6–3.4), the median survival 10.6 months (95% CI: 8.7–12.4), with no difference between pre-treated patients and others. Treatment was well tolerated. Conclusion: The FOLFOX-4 regimen is ineffective in patients with MRCC. We believe that oxaliplatin should no longer be explored in renal carcinoma.
Association between Inducible Nitric Oxide Synthase Expression and p53 Status in Human Esophageal Squamous Cell Carcinoma
Authors: Matsumoto Manabu , Furihata Mutsuo , Kurabayashi Atsushi , Araki Keijiro , Sasaguri Shiro , Ohtsuki Yuji
Published: April 2003

Nitric oxide (NO) produced by the NO synthase (NOS), a family of enzymes such as inducible NOS (iNOS), has been suggested to play an important role in tumor bioloty. We immunohistochemically examined iNOS and p53 protein expression in 105 patients with esophageal squamous cell carcinoma (ESCC). Direct sequence analysis for the p53 gene was performed in 51 of 105 tumors. In total, 56 of 105 (53.3%) tumors exhibited intracytoplasmic staining for anti-iNOS antibody, including 17 (16.2%) cases of homogeneous and intense immunostaining (++) and 39 (37.1%) of heterogeneous staining (+). Of 62 p53 protein-positive tumors, 40 (63.5%) were positive for iNOS, and of 43 p53 protein-negative tumors, 27 (62.8%) were negative for iNOS. Of 34 iNOS-positive tumors, 23 (67.6%) carried a p53 gene mutation, and of 17 iNOS-negative tumors, 12 (70.6%) had wild-type p53 gene. There was a significant relationship between iNOS immunoreactivity and p53 protein overexpression (p = 0.0058) as well as p53 mutation frequency (p = 0.0163). No association was found between iNOS immunoreactivity and p53 mutation type, any clinicopathological factor and patient prognosis. Our in vivo findings suggest that iNOS activity might be associated with p53 alteration and contribute to tumorigenesis in ESCC.
Front-Line Paclitaxel/Cisplatin-Based Chemotherapy in Brain Metastases from Non-Small-Cell Lung Cancer
Authors: Cortes Javier , Rodriguez Javier , Aramendia Jose Manuel , Salgado Esteban , Gurpide Alfonso , Garcia-Foncillas Jesus , Aristu Jose Javier , Claver Angela , Bosch Ana , Lopez-Picazo Jose Maria , Martin-Algarra Salvador , Brugarolas Antonio , Calvo Emiliano
Published: April 2003

Objective: Paclitaxel-cisplatin is considered to be a standard therapy for metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the activity and toxicity of this combination with vinorelbine or gemcitabine as front-line therapy in brain metastases from NSCLC. Methods: Twenty-six chemotherapy-naive patients with an ECOG performance status of 0–2 were treated with paclitaxel (135 mg/m2) on day 1, cisplatin (120 mg/m2) on day 1, and either vinorelbine (30 mg/m2) on days 1 and 15 or gemcitabine (800 mg/m2) on days 1 and 8. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. Results: All patients were evaluated for toxicity and 25 for response. An intracranial response rate was observed in 38% of the patients (95% CI: 22–59%). WHO grade 3–4 neutropenia and thrombocytopenia occurred in 31 and 4% of the patients, respectively. There was one treatment-related death. Non-hematological toxicities were mild. After a median follow-up of 46 months, the median overall survival for all patients was 21.4 weeks and the median time to progression was 12.8 weeks. Conclusions: Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve responses similar to those for extracranial disease, suggesting a meaningful role in this setting.
Evaluation of the Cariogenic Potential of Cassava Flours from the Amazonian Region
Authors: Rebelo Vieira J.M. , Rebelo M.A.B. , Cury J.A.
Published: April 2003

Cassava flour is the main dietary carbohydrate source in the Amazonian region. The cariogenic potentials of the two main kinds of cassava flour – ‘seca’ and ‘d’água’ – were evaluated in vivo and in vitro. A sweet made from a regional fruit (cupuaçú) and a species of local fish (tambaqui) were used as positive and negative controls, respectively. For in vivo evaluation of dental plaque acidogenicity, the study had a crossover design, in four legs, with 19 volunteers in four treatment groups. Dental plaque pH was determined by the microtouch method before and for 60 min after food consumption. For in vitro evaluation, stimulated saliva of each volunteer was incubated with the food and pH variation was determined over 4 h. Carbohydrates were chemically determined in the flours and the majority was found to be water-insoluble. In vivo, plaque pH decreased significantly after the consumption of the sweet (p < 0.05), increased after the fish (p < 0.05), but did not change after intake of the flours (p > 0.05). In vitro, the flours were slowly fermented by bacteria present in saliva. The in vivo and in vitro findings suggest that, in the form that the main cassava flours from the Amazonian region of Brazil are customarily eaten, they may be considered to have no or very low cariogenicity.
Chromosomal localization and genomic organization of the human Linker for Activation of T cells (LAT) gene
Authors: Windpassinger C. , Kroisel P.M. , Wagner K. , Petek E.
Published: April 2003

We have mapped the LAT gene by radiation hybrid mapping and fluorescence in situ hybridization to chromosome 16p11.2. The complete cDNA sequence of LAT was generated using assembled sequences of cDNA fragments already available. BLAST analysis using the cDNA sequence led to the identification of BAC clone CTB-134H23 (GenBank Accession No. AC112166). The genomic structure of the human LAT gene consists of 11 exons, encompassing 5.7 kb. Alternative splicing variants were identified.
Profiles of in vivo Gamma-Aminobutyric Acid Release in the Medial Preoptic Area of Intact and Castrated Male Rats
Authors: Tin-Tin-Win-Shwe T , Mitsushima Dai , Kimura Fukuko
Published: April 2003

We have suggested that gamma-aminobutyric acid (GABA) in the hypothalamus plays a tonic inhibitory role in the control of the luteinizing hormone (LH) release in intact male rats. To assess whether feedback from the testis alters the inhibitory GABAergic tone in the medial preoptic area (MPO) of male rats, an in vivo microdialysis study was performed in gonadally intact (n = 10), castrated (n = 12) and castrated testosterone-primed (n = 10) male rats. The microdialysis samples were collected and sequential blood samples were also obtained at 1-hour intervals. GABA in the dialysate was determined by high-performance liquid chromatography system and serum LH concentration was determined by radioimmunoassay. Episodic GABA release in the MPO was observed in all three groups of male rats, although castrated male rats showed lower GABA release (2.3 ± 0.3 ng/h) than intact and castrated testosterone-primed male rats (4.0 ± 0.5 and 4.6 ± 1.0 ng/h, respectively). Conversely, castrated male rats showed higher serum LH concentration (7.31 ± 0.46 ng/ml) than intact and castrated testosterone-primed male rats (0.71 ± 0.04 and 0.53 ± 0.07 ng/ml, respectively). In addition, intravenous infusion of bicuculline significantly increased serum LH in intact male rats, whereas bicuculline did not alter serum LH concentrations in castrated male rats. These results are consistent with the hypothesis that the feedback of testosterone stimulates GABA release in the region of the GnRH cell bodies and dendrites in male rats.
The Renin-Angiotensin System and Progression of Renal Disease: From Hemodynamics to Cell Biology
Authors: Wolf Gunter , Butzmann Ulrike , Wenzel Ulrich O.
Published: April 2003

The renal community is faced with an ever increasing number of patients reaching end-stage renal failure. Clinical studies have provided clear evidence that angiotensin-converting enzyme (ACE) inhibitors, and probably also AT1 receptor antagonists, at least in patients suffering from type 2 diabetes, slow disease progression to end-stage renal failure. This protective effect of drugs interfering with the renin-angiotensin system (RAS) are in part independent of reduction in systemic blood pressure, but involve normalization of glomerular hyperperfusion and hyperfiltration, restoration of altered glomerular barrier function, and reduction of stimulated tubular fluid reabsorption. Angiotensin II (ANG II) has emerged in the last decade as a multifunctional cytokine exhibiting many non-hemodynamic properties such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. This review tries to bridge the classical hemodynamic actions of ANG II in the kidney with the more recently characterized effects of this vasopeptide. Finally, clinical implications are suggested based on data from clinical studies. A thorough understanding of the RAS is important to recognize the potential of nephroprotective strategies through inhibition of its components.
Reconstructed Skin Kits: Reproducibility of Cutaneous Irritancy Testing
Authors: Faller C. , Bracher M.
Published: April 2003

The aim of this study was to determine the reproducibility of data obtained from in vitro irritation testing using three industrial reconstructed human epidermis models, EpiDermTM, EpiskinTM and SkinEthicR, and one in-house model developed at Wella/Cosmital. A common protocol was established based on the measurement of cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and of extracellular release of proinflammatory mediators and cytosolic enzymes after a range of exposure times to sodium lauryl sulfate (SLS). This time course protocol was applied to 6 different batches of each skin model using triplicate tissue cultures per test condition. The parameters analyzed for intra- and inter-batch reproducibility were the cell viability determined as MTT reduction capacity and the ET-50 values in the 6 batches, as well as the release of the cytokine IL-1α and of the cellular enzymes LDH and GOT in 3 batches only. The MTT viability results showed that EpiDerm was the most resistant to the SLS treatment and at the same time the most reproducible model, SkinEthic was the most sensitive to SLS and the least reproducible, and Episkin and the Cosmital model were intermediate. Measurements of IL-1α release showed a relatively high intra- and inter-batch variability in all the skin models. It was not possible to detect the extracellular release of the enzymes LDH and GOT in the Episkin assay medium. With the 3 other models, the release of LDH and GOT varied in about the same range as that of IL-1α. For all the parameters in this study, the inter-batch variability was generally greater than the intra-batch variability. A possible reduction in the number of batches and replicates for future applications in routine irritancy testing is discussed on the basis of the results obtained using 6 batches in triplicate.
Improvement of the Experimental Setup to Assess Cutaneous Bioavailability on Human Skin Models: Dynamic Protocol
Authors: Dreher F. , Patouillet C. , Fouchard F. , Zanini M. , Messager A. , Roguet R. , Cottin M. , Leclaire J. , Benech-Kieffer F.
Published: April 2003

Human skin models, such as EpiDerm® and Episkin®, are not easily mounted into static or dynamic diffusion cells that are commonly used to perform bioavailability studies with human skin ex vivo. For various reasons, such as fragility, small sample size, and other morphological constraints, skin absorption studies with human skin models are often carried out on the delimited skin surface obtained by gluing a ring onto the reconstituted epidermis and manually exchanging the receptor solution. However, such an experimental setup is prone to artifacts. Discontinuous removal of the receptor fluid leads to alternating sink conditions, and an area of application smaller than the area in contact with the receptor fluid, as well as imperfect seal of the glued ring, may result in inaccurate penetration rates. Human skin models were shown to be relatively easily mounted into In-Line cells (PermeGear Inc.), vertical diffusion cells which appear to be appropriately designed for such a purpose. In-Line cells allowed accurate determination of solute penetration as well as automated sampling of receptor fluid. Excised human skin can be mounted into these cells as well, making it possible to compare penetration rates through different types of skin samples under identical conditions. Using mannitol as a reference compound, penetration profiles and epidermal distribution similar to those obtained with human skin ex vivo were obtained both with EpiDerm and Episkin. Under the present conditions, human skin models were more permeable to mannitol than excised human skin, which was only slightly permeable to mannitol. Due to these experimental innovations and to the good agreement with the absorption characteristics through human skin ex vivo, EpiDerm and Episkin seem to be promising human skin models for testing the cutaneous bioavailability of topical products in vitro.
Differential Localization of Metabotropic Glutamate Receptors during Postnatal Development
Authors: Defagot María Cristina , Villar Marcelo J. , Antonelli Marta C.
Published: April 2003

The localization of metabotropic glutamate receptors (mGluRs) during development has been associated with brain maturation and plasticity. The developmental immunohistochemical analysis of mGluR1α, mGluR2/3 and mGluR4a expression was performed in the cerebral cortex, hippocampus and basal ganglia at postnatal days (P) 4, 8, 12, 35 and 60. In early stages (P4 and P8) mGluR1α-like immunoreactivity (mGluR1α-LI) was detected in cell bodies and fibers of the frontal cortex, hippocampus and globus pallidus. At P35 and P60, the staining was observed in pyramidal cells and fibers in the deepest layers of the cortex and in stratum oriens of the hippocampus, while a lower labeling was observed in fibers of the globus pallidus. No immunostaining was observed in substantia nigra pars reticulata until P12, when a dense network of fiber staining was detected through the adult stages (P35, P60). mGluR2/3-LI was present from the second week of development in fibers and cell bodies of the stratum lacunosum moleculare of the CA1–CA3 and striatum; this staining pattern persisted until adult stages. mGluR4a-LI was observed at P12 in neuronal bodies of the cortex, in pyramidal cells of the hippocampus and in neuronal cells of the striatum. At P35 and P60, a strong signal was observed in a reduced number of labeled cells of the cerebral cortex, in fibers of the stratum oriens of CA1 and in long processes of substantia nigra pars reticulata. Our results indicate that there are significant changes in the protein expression of mGluR subunits through postnatal development. These differences may play a significant role in the establishment of proper synaptic circuitry in early postnatal life, as well as contributing to the maintenance, stabilization, and plasticity of the rat forebrain, particularly through the participation of mGluR1α and mGluR4a.
Esberitox® N as Supportive Therapy when Providing Standard Antibiotic Treatment in Subjects with a Severe Bacterial Infection (Acute Exacerbation of Chronic Bronchitis)
Authors: Hauke Wilfried , Köhler Gert , Henneicke-von Zepelin Hans-Heinrich , Freudenstein Johannes
Published: April 2003

53 patients with planned antibiotic therapy for the treatment of acute exacerbation of chronic bronchitis as an example of a severe bacterial infection requiring antibiotics were included in a prospective, multicentre, double-blind, placebo-controlled study. The chronic bronchitis was staged by forced expiratory volume of the 1st second (FEV1) measured in the infection-free interval prior to the current episode and had to be between 35 and 75% for the predicted value. Patients were randomly assigned to receive newer macrolide antibiotics plus either Esberitox® N or placebo. Antibiotic therapy was administered according to generally accepted guidelines and Esberitox N or placebo was given for 28 days. The baseline-adjusted means for FEV1 (%) on day 10 were 68.7 points for the Esberitox N group and 59.2 points for the placebo group (p = 0.0303). For FEV1 the difference between the two treatment groups was 267 ml (p = 0.0499). The time to half maximal improvement was 5.7 days in the Esberitox N group compared to 12.8 days in the placebo group. The treatment was well tolerated; no serious adverse events were documented. In conclusion, comedication of antibiotics with Esberitox N in subjects with acute exacerbation of chronic bronchitis seems to be of benefit for the patient. Apparently, therapy with Esberitox N leads to a faster recovery from this severe bacterial infection, possibly via preventing an impairment of the host’s immune system which might otherwise occur as a consequence of aggressive antimicrobial therapeutics.
Comparison of in vitro Antifungal Activities of Amphotericin B Lipid Complex with Itraconazole against 708 Clinical Yeast Isolates and Opportunistic Moulds Determined by National Committee for Clinical Laboratory Standards Methods M27-A and M38-P
Authors: Carrillo-Muñoz Alfonso Javier , Ruesga Maite , Brio Sonia , del Valle Oscar , Rodriguez Virginia , Santos Patricia , Hernández-Molina Juan Manuel , Cantón Emilia , Pemán Javier , Guarro Josep , Quindós Guillermo
Published: April 2003

We compared the in vitro antifungal activity of amphotericin B lipid complex (ABLC) with that of itraconazole (ITZ) against 535 yeast strains and 173 opportunistic filamentous fungi by using a microdilution method (National Committee for Clinical Laboratory Standards M27-A and M38-P). The overall geometric mean MIC was 0.13 µg/ml and 0.177 µg/ml for ITZ and ABLC, respectively, and the MIC50 was 0.125 µg/ml for both agents against yeast isolates. ITZ had a similar or slightly superior efficacy compared to ABLC when tested against Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida krusei, Candida glabrata and Candida tropicalis. Effectiveness against C. glabrata was lower for ITZ (MIC90 2 µg/ml, and for ABLC, 0.5 µg/ml). For Aspergillus fumigatus, activity of ITZ was superior in comparison with ABLC (MIC90 1 and 16 µg/ml, respectively); MIC90 for Aspergillus niger was 4 and 2 µg/ml for ABLC and ITZ, respectively. Scedosporium spp. showed a low susceptibility to both ABLC and ITZ. In conclusion, ABLC and ITZ are useful alternatives for the treatment of severe fungal infections. The selection of an antifungal agent should be made considering the toxicological and pharmacological properties and cost/benefit relationship and be supported by the susceptibility of the isolate.
Antiproliferative Properties of Toremifene on AIDS-Related Kaposi’s Sarcoma Cells
Authors: Hong Angela , Leigh Bryan R.
Published: April 2003

Background: Kaposi’s sarcoma (KS) is the most common neoplastic apoptosis manifestation of acquired immunodeficiency syndrome. Toremifene is known to upregulate transforming growth factor beta-1 (TGF-β1), which is a growth-inhibitory factor for KS. We investigated the in vitro effect of toremifene on KS cells. Methods: MTT assay was used to measure the growth of four KS cell lines and a human umbilical vein endothelial (HUVE) cell line after incubation with toremifene. Reverse transcription polymerase chain reaction and ELISA were used to measure the level of TGF-β1. Results: The IC50 for the KS cells ranged from 2.2 to 3.2 µM, and 80% of the growth inhibition occurred within 24 h. Toremifene enhanced TGF-β1 mRNA expression, and the level of TGF-β1 increased from 103 to 473 pg/ml after 48 h of incubation. Toremifene had no effect on the growth of HUVE cells. Conclusion: Toremifene has a specific antiproliferative effect on KS cells. The stimulation of TGF-β1 production may play a role in the antiproliferative process.
Carbohydrate Epitopes and Their Relevance for the Diagnosis and Treatment of Allergic Diseases
Authors: van Ree Ronald
Published: April 2003

Allergenicity of plant and invertebrate N-glycans has been shown to be caused by the presence of two typical nonmammalian substitutions: an α(1,3)-fucose linked to the proximal N-acetylglucosamine and a β(1,2)-xylose linked to the core mannose. IgE antibodies against these carbohydrate structures are induced upon exposure to pollen or after insect stings, and result in extensive cross-reactivity to plant and invertebrate foods. These cross-reactive IgE antibodies have been shown to possess variable degrees of biological activity, but have never been convincingly shown to induce clinical food allergy. The most likely explanation for this lack of clinical relevance has to be sought in a combination of epitope valency and antibody affinity. In diagnostic tests, these antibodies are at the basis of many false-positive test results for food allergy. Recombinant technologies offer the possibility to produce allergens that do not carry IgE-binding glycans. Whether their absence or presence is of importance for the application of recombinant allergens in immunotherapy is still largely unknown.
CpG Motifs as Possible Adjuvants for the Treatment of Allergic Diseases
Authors: Bohle Barbara
Published: April 2003

DNA containing unmethylated CpG motifs and synthetic oligodeoxynucleotides derived thereof (CpG ODN) have intensively been investigated for their immunostimulatory properties in the recent past. CpG ODN were shown to induce strong Th1 immune responses in mammals. The downregulation of the antigen-driven Th2 response of type I allergies represents one important therapeutic goal of specific immunotherapy (SIT). Hence, CpG ODN represent promising substances which support the modification of the pathogenic Th2 immune profile toward a Th1 profile when used as adjuvants for SIT. This article discusses how the use of CpG ODN in immunotherapeutics could improve the treatment of type I allergy.