bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics in Rats of N-Dimethylaminoacetyl-Partricin A 2-Dimethylaminoethylamide Diascorbate (SPK-843)
Authors: Bruzzese T. , Galmozzi M.R. , Buffa G. , Sala P. , Bonabello A.
Published: April 2003

Single- and multiple-administration trials in rats were performed in this study to assess the serum and tissue concentrations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure. A dose of 1.25 mg/kg (roughly 1 mg/kg of free base) by intravenous route was used both for the single- and multiple-administration trials. The single-administration trial was carried out in comparison with amphotericin B (AmB) at intravenous doses of 1 mg/kg. Plasma samples were drawn at intervals from 15 min to 96 h after injection. The elimination half-lives were 22.15 and 18.15 h, and the area under the curve to infinity (AUC0–∞) values were 35.52 and 10.33 µg·h·ml–1, respectively, for SPK-843 and AmB. Both drugs showed an extensive tissue distribution, with higher uptake by the kidneys, followed by the liver, spleen and lungs for SPK-843, and higher uptake by the spleen, followed by the lungs, liver and kidneys for AmB. The multiple-administration trial (1.25 mg/kg/day for 7 days) led to sustained serum and tissue concentrations. On the seventh day, the rats were bled at intervals from 5 min to 96 h after dosing. The serum elimination half-life and AUC0–∞ values were roughly twice those of the single-dose study (41.4 h and 72.1 µg·h·ml–1, respectively). Also, the half-lifes and AUCs from 0 to ∞ of tissues were greater than those in the single-dose trial.
In vitro Activity of Gemifloxacin against Streptococcus pneumoniae Isolates in Germany
Authors: Lemmen Sebastian , Al-Lahham Adnan , Lütticken Rudolf , Reinert Ralf René
Published: April 2003

The MICs (minimal inhibitory concentrations) of gemifloxacin, moxifloxacin, ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, penicillin G, tetracycline and erythromycin were determined for 200 clinical pneumococcal isolates using the microbroth dilution method. MIC50 and MIC90 values were as follows (mg/l): 0.016 and 0.016 (gemifloxacin, penicillin-intermediate strains), 0.03 and 0.06 (gemifloxacin, penicillin-susceptible strains); 0.125–0.5 and 0.25 (moxifloxcacin); 1–2 and 4 (ciprofloxacin and ofloxacin); 1 and 2 (levofloxacin), and 0.25–0.5 and 0.5 (sparfloxacin). MIC50 and MIC90 values for the fluoroquinolones were nearly identical for individual antimicrobial agents in the penicillin-susceptible and penicillin-intermediate groups of strains. Erythromycin and tetracycline were less active against penicillin-intermediate pneumococci isolates (erythromycin: MIC90 8 mg/l; MIC range 0.06–≧64 mg/l; tetracycline: MIC90 ≧64 mg/l, MIC range 0.25– ≧64 mg/l) as compared to penicillin-susceptible isolates (erythromycin: MIC90 0.5 mg/l, MIC range 0.06–≧64 mg/l; tetracycline: MIC90 8 mg/l, MIC range 0.06–≧64 mg/l).
Cisplatin Pharmacokinetics and Its Nephrotoxicity in Diabetic Rabbits
Authors: Najjar Tawfeeg A.O. , Saad Sherif Y.
Published: April 2003

Background: This study was designed to investigate the relationship between the attenuation of cisplatin (CDDP)-induced nephrotoxicity in experimental diabetic rabbits and the plasma pharmacokinetics of the free ultrafilterable and total plasma platinum (Pt) levels. Methods: Two groups of age-matched male New Zealand white rabbits were used; the first group consisted of rabbits with streptozotocin-induced diabetes (single i.v. bolus dose of streptozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of nondiabetic rabbits treated with the same volume of citrate buffer. Both groups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after induction of the diabetic state in the first group. The plasma Pt levels were followed for 4 h after CDDP administration, in which the free ultrafilterable and total plasma Pt concentrations were determined by atomic absorption spectrometry. The pharmacokinetic parameters of free ultrafilterable plasma Pt were determined using a noncompartment pharmacokinetic model of analysis. Results: The total plasma Pt levels declined in a biphasic manner and were adequately described by a two-compartment model. No significant change was observed in the pharmacokinetics of either the free ultrafilterable or total plasma Pt levels in the diabetic group in comparison with the control nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher than that of the diabetic rabbits (p < 0.001). Indices of nephrotoxicity were determined 7 days after CDDP administration. The results revealed that the diabetic state protected against CDDP-induced nephrotoxicity. The nondiabetic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in comparison with the diabetic group. Conclusions: These findings might suggest that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug follow-up period. It could be anticipated that the rapid decline in the total plasma Pt level after CDDP administration to diabetic rabbits, as well as the reduction in the terminal elimination half-life of the total plasma Pt level might be responsible for the reduction in CDDP-induced nephrotoxicity. Also, alterations in the how kidneys of diabetics deal with the renal excretion of Pt and reduction of its accumulation in kidney tissue are not excluded.
Antituberculous Activity of Norfloxacin Mannich Bases with Isatin Derivatives
Authors: Pandeya S.N. , Sriram D. , Yogeeswari P. , Ananthan S.
Published: April 2003

Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. The compounds were evaluated in vitro against Mycobacterium tuberculosis H37Rv at 12.5 µg/ml in BACTEC 12B medium using the BACTEC radiometric system. Among the compounds tested, S-10 showed promising activity, with 100% inhibition at a concentration lower than 6.25 µg/ml.
Increased Sensitivity to Cisplatin in Gastric Cancer by Antisense Inhibition of the HER-2/neu (c-erbB-2) Gene
Authors: Funato Tadao , Kozawa Kanoko , Fujimaki Shinichi , Miura Toshihiko , Kaku Mitsuo
Published: April 2003

Background: The c-erbB-2 oncogene encodes a transmembrane tyrosine kinase receptor and its abnormal expression may be related to the prognosis of gastric cancer. Gastric cancer is relatively resistant to various drugs, including cisplatin. Cisplatin is widely used in cancer chemotherapy, but the mechanisms of drug resistance are not yet known. Methods: We used the human gastric cancer cell lines MKN-7 and KATO-III, which express the c-erbB-2 oncogene, as a model for relative resistance to cisplatin. We investigated whether inhibition with antisense oligonucleotides against c-erbB-2 increased the sensitivity of MKN-7 and KATO-III cells to cisplatin. Results: Antisense oligonucleotides for c-erbB-2 inhibited the expression of c-erbB-2 mRNA and protein and increased sensitivity to cisplatin, but not to other drugs, in MKN-7 and KATO-III cells. Cell growth was also inhibited by c-erbB-2 antisense oligonucleotides but not sense oligonucleotides. Conclusions: These findings indicate that c-erbB-2 expression in gastric cancer is one of the factors related to cisplatin sensitivity, and that anti-c-erbB-2 antisense oligonucleotides induced increased sensitivity to cisplatin.
Comparative Activity of Cefditoren and Other Oral β-Lactams against Nonpneumococcal Streptococci
Authors: Thornsberry C. , Karlowsky J.A. , Kelly L.J. , Draghi D.C. , Critchley I.A. , Jones M.E. , Sahm D.F.
Published: April 2003

Background: In vitro studies of cefditoren activity have focused primarily on Streptococcus pneumoniae and other bacterial species isolated from patients with respiratory infections, but relatively few reports have been published describing the activity of cefditoren against clinical isolates of nonpneumococcal streptococci. Methods: Cefditoren activity was determined by broth microdilution (M7-A5, NCCLS, 2000) for 450 viridans group streptococci, 917 Streptococcus pyogenes and 800 other β-hemolytic streptococci collected throughout the US during 1999–2000. Results: Against viridans group streptococci, cefditoren (MIC90, 0.5 µg/ml) was 4- to 32-fold more active than the other β-lactams tested (penicillin ampicillin, amoxicillin-clavulanate, cefprozil and cefuroxime). The difference in activity between cefditoren and the other β-lactams was greater for penicillin-nonsusceptible isolates (MIC90s, 1 µg/ml versus 8–32 µg/ml) than among penicillin-susceptible isolates (MIC90s, 0.12 versus 0.25– 1 µg/ml). Cefditoren also demonstrated potent activity against S. pyogenes (MIC90, 0.015 µg/ml) and other β-hemolytic streptococci (MIC90, 0.06 µg/ml), comparable to that of the other β-lactams. Conclusions: The activity demonstrated by cefditoren against nonpneumococcal streptococci, including β-lactam- and macrolide-resistant isolates, suggests that this agent holds promise as therapy for infections caused by all clinically significant species of streptococci.
In vitro Activity of Novel Fluoroquinolones against Streptococcus pneumoniae Isolated from Children with Acute Otitis media
Authors: Yagupsky P. , Katz O. , Peled N. , Dagan R.
Published: April 2003

Background: In recent years, novel fluoroquinolones with improved activity against gram-positive organisms have been introduced into clinical practice. These drugs may be of potential benefit for the treatment of pneumococcal otitis media, including infections caused by organisms resistant to conventional drugs. Methods: In vitro activity of 6 fluoroquinolones against 77 pneumococcal isolates from middle-ear fluid was determined by the E test. Results: Resistance to penicillin, co-trimoxazole, erythromycin, clindamycin, and tetracycline was present in 59 (76.6%), 47 (61.0%), 19 (24.7%), 11 (14.3%), and 17 (22.1%) isolates, respectively. Fluoroquinolone MIC50 and MIC90 (in µg/ml) were as follows: ciprofloxacin: 1.0 and 3.0, levofloxacin: 0.75 and 1.0, sparfloxacin: 0.25 and 0.38, grepafloxacin: 0.25 and 0.38, trovafloxacin: 0.094 and 0.125, and moxifloxacin: 0.19 and 0.25, respectively. Conclusions: Novel fluoroquinolones and especially trovafloxacin and moxifloxacin appear to be of potential value for the treatment of acute otitis media caused by pneumococci resistant to traditional antibiotics.
Variable Sensitivity of Lymphoblastoid Cells to Apoptosis Induced by Viscum album Qu FrF, a Therapeutic Preparation of Mistletoe Lectin
Authors: Duong Van Huyen Sooryanarayana Jean-Paul , Delignat Sandrine , Bloch Marie-Françoise , Kazatchkine Michel D. , Kaveri Srini V.
Published: April 2003

Background:Viscum album (VA) Qu FrF preparation consists of an aqueous extract of Viscum album, the European mistletoe. It has cytotoxic and immunomodulatory properties that support its usefulness in cancer therapy. However, only little information is available on the interaction between mistletoe lectin (ML) and the humoral compartment of the immune system. Methods: Inhibition of proliferation of cells was performed by incorporation of 3H-thymidine, and cell viability was assessed by the uptake of propidium iodide. Detection of Bcl-2 and related molecules was performed by SDS-PAGE followed by immunoblotting. Results: We demonstrated that B lymphocyte lines are insensitive to VA Qu FrF-induced apoptosis. We showed, using Fas-sensitive and Fas-resistant cell lines, that VA Qu FrF-induced apoptosis is Fas independent. In both B and T lymphocytes, treatment of the cells with VA Qu FrF was associated with decreased levels of Bcl-2 and Bcl-X. Conclusions: Our results suggest that B lymphocyte depletion is not involved in the modulation of humoral immunity by ML. These observations should be of value in appropriate designing of cancer therapy using compounds containing mistletoe extracts.
Epirubicin, Cisplatin and Continuous-Infusion 5-Fluorouracil (ECF Regimen) in the Treatment of Advanced Colorectal Cancer
Authors: Gargano Letizia , Menichetti Ettore Tito , Marcellini Massimo , Seminara Patrizia , Caporale Alessandro , Konstantatoy Ekaterini , Masciangelo Raffaele , Franchi Fabrizio
Published: April 2003

Thirty-one patients with advanced colorectal cancer were treated with a regimen of epirubicin, cisplatin and continuous-infusion (c.i.) 5-fluorouracil (5-FU) (ECF regimen). Twenty-seven patients were evaluable for response rate (RR), progression-free survival (PFS) and overall survival (OS). In this study, the ECF chemotherapy yielded a 51% RR with a PFS of more than 8 months, an OS of more than 11 months and tolerable toxicity. In spite of the perplexity concerning the use of anthracyclines in colorectal cancer, the ECF regimen seems to be a possible treatment even for this malignancy. Controlled studies with ECF versus standard treatments and versus 5-FU alone in c.i. are necessary.
Stroke Patterns in Northeast Malaysia: A Hospital-Based Prospective Study
Authors: Jaya Fauziah , Win M. Nyunt , Abdullah Mohd Riduan , Abdullah Mohamed Rusli , Abdullah Jafri Malin
Published: April 2003

All patients with a first-ever stroke admitted to the HUSM (Hospital Universiti Sains Malaysia) from 1997 to 1998 were included in this study. All risk factors were determined and analysed prospectively. There were 158 cases of stroke admitted during the study period. The majority of the patients were Malays (86.1%), with a male preponderance. The mean age (SD) of the patients with stroke was 59.3 (12.28) years. Hypertension was present in both cerebral infarct and intracerebral haemorrhage patients at almost the same rate (65.2 and 69.2%, respectively). The overall mortality was 37%, and most patients died in the 1st month after stroke (34%). We hope this study will highlight the problems associated with the presentation and management of stroke in Southeast Asia.
Impaired Olfaction Predicts Cognitive Decline in Nondemented Older Adults
Authors: Swan Gary E. , Carmelli Dorit
Published: April 2003

In 1992, the twelve-item Brief Smell Identification Test® and, in 1992 and 1996, a variety of measures of verbal learning and memory, executive control, and global function were administered to a total of 359 individuals (286 men and 73 women; mean age in 1992 74.3 years). Individuals with a history of stroke or impaired cognition at baseline were excluded from analyses. Impaired olfactory function (present or absent) was related to a greater 4.5-year decline on several indices of verbal memory, but not to a decline on measures of executive control or of global functioning after adjustment for baseline cognitive performance, age, education, gender, and history of smell difficulties. Olfactory loss remained associated with a decline in components of verbal memory, independently of the apolipoprotein E Ε4 status. The predictive utility of impaired smell identification in older adults appears to be specific to a decline in components of verbal memory.
Increased Levels of Adrenocortical and Gonadal Hormones in Mild to Moderate Alzheimer’s Disease
Authors: Rasmuson Sigbritt , Näsman Birgitta , Carlström Kjell , Olsson Tommy
Published: April 2003

Hormonal changes during normal aging include decreasing levels of gonadal hormones and adrenal androgens. These hormones influence multiple nervous functions, including cognition and mood. Related to this, abnormalities at several levels of the hypothalamic-pituitary-adrenal axis (HPA) have been reported in patients with Alzheimer’s disease (AD). We studied steroid hormones in 33 patients with mild to moderate AD (12 men; 21 women, 76.4 ± 7.8 years) and 22 healthy elderly controls (10 men; 12 women, 75.4 ± 7.5 years old, respectively). Basal levels of serum cortisol, dehydroepiandrosterone (DHEA) and androstenedione were significantly increased in AD patients. Women with AD had significantly higher levels of DHEA and androstenedione. Serum estradiol levels were non-significantly increased in women with AD. After adjustment for age and BMI women with AD had significantly increased levels of androstenedione and DHEA. Increased gonadal hormone levels in mild to moderate AD may reflect an increased secretion, and/or alterations in metabolism of these hormones. This may influence the symptomatology and progression of the disease.
Characteristics of Two Telephone Screens for Cognitive Impairment
Authors: Järvenpää Tarja , Rinne Juha O. , Räihä Ismo , Koskenvuo Markku , Löppönen Minna , Hinkka Susanna , Kaprio Jaakko
Published: April 2003

We studied 56 subjects, 30 patients with a clinical diagnosis of Alzheimer’s disease (AD) and 26 healthy controls, using two telephone screens for cognitive impairment, a self-report interview referred to as the TELE and the Telephone Interview for Cognitive Status (TICS). The sensitivity and specificity of the TELE to differentiate AD patients from healthy controls was 90.0 and 88.5% and those of the TICS were 86.7 and 88.5%, respectively. When receiver operator characteristic curves were constructed, the area under the curve for the TELE was 96.0% (SE 2.4%) and for the TICS 90.3% (SE 4.2%). Pearson’s correlation between the TELE and the Mini-Mental State Examination (MMSE) was 0.87 (p < 0.0001) and between the TICS and the MMSE 0.86 (p < 0.0001). The correlation between the TELE and the sum of the boxes of the Clinical Dementia Rating scale (CDR-SB) was –0.71 (p < 0.0001) and –0.75 between the TICS and the CDR-SB (p < 0.0001). These results indicate that both screens are sensitive and specific instruments for differentiating AD patients from healthy controls and have a strong correlation with face-to-face measures of cognitive function.
Examination of GABAergic and Dopaminergic Compounds in the Acquisition of Nicotine-Conditioned Hyperactivity in Rats
Authors: Palmatier Matthew I. , Bevins Rick A.
Published: April 2003

In rats, a distinct environment repeatedly paired with nicotine (0.421 mg/kg base, s.c.) comes to evoke an increase in activity in the absence of any drug. This hyperactivity indicates a Pavlovian-conditioned association between the environment and nicotine. We investigated whether a dopamine D1 receptor antagonist (SCH-23390), a D2/D3 antagonist (eticlopride) or a GABAB agonist (baclofen) would prevent the acquisition of nicotine-conditioned hyperactivity. In saline-pretreated rats, acute nicotine suppressed activity during the conditioning phase (i.e. environment-nicotine pairings); chronic nicotine stimulated activity. Pretreatment with SCH-23390 (0.01 mg/kg, i.p.) attenuated the activating effects of nicotine without affecting controls. Eticlopride (0.03–0.07 mg/kg, i.p.) and baclofen (0.625 and 1.25 mg/kg, i.p.) did not affect nicotine-induced activity in a selective manner. Regardless of the pretreatment drug, rats acquired the environment-nicotine association as indexed in a drug-free test. The inability of SCH-23390 to block the acquisition of nicotine-conditioned locomotor activity is notable because in past research SCH-23390 blocked expression of the learned association.
Obesity Associated with Hypertension or Hyperlipidemia Accelerates Renal Damage
Authors: Sasatomi Yoshie , Tada Masaru , Uesugi Noriko , Hisano Satoshi , Takebayashi Shigeo
Published: April 2003

Obesity is known as a risk factor for nephropathy, especially nephrotic syndrome and focal segmental glomerulosclerosis, and can aggravate renal dysfunction. However, whether these changes are caused by obesity itself or by the associated hypertension (HT) and hyperlipidemia (HC) remains unclear at present. We investigated the influence of HT and HC in obesity on glomerular morphometry. The study included cases with obesity alone (O, body mass index more than 25 kg/m2, n = 16), O+HC (n = 8), O+HT (n = 17), HC (n = 10) alone, HT (n = 7) alone, and normal subjects (N, n = 11). Renal biopsies were examined and the glomerular diameter, and length and diameter of the glomerular capillary loop were determined using image analysis software. Clinically related data were obtained from medical records at the time of biopsy. Obesity was associated with dilatation of glomerular diameter due to glomerular loop elongation. However, end-stage renal disease (ESRD) was not noted in patients with obesity only. In contrast, ESRD requiring hemodialysis was noted in group O+HT within a 7.7-year follow-up period. Furthermore, enlargement of loop diameter was noted in group O+HC, but not in HC alone. These results suggest that obesity alone may not result in glomerular hyperfiltration or renal dysfunction, but obesity associated with hypertension or hyperlipidemia may accelerate renal damage.
Decreased Expression of E-Cadherin and Yamamoto-Kohama’s Mode of Invasion Highly Correlates with Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma
Authors: Kaihara Tsukasa , Kusaka Toshihiro , Kawamata Hitoshi , Oda Yasushi , Fujii Shigehiko , Morita Katsuo , Imura Johji , Fujimori Takahiro
Published: April 2003

Objectives: A reduction in cell–cell adhesion in cancer cells is an essential step in the progression from localized malignancy to metastatic disease. E-Cadherin is an important component of cell–cell adhesion molecules and may be a crucial determinant of tumor invasion and metastasis. E-Cadherin expression is reported to be correlated with lymph node metastasis in esophageal squamous cell carcinoma (SCC). The objective of this experiment is to examine the factors that are associated with invasion and metastasis of esophageal SCC. Methods: Forty-six cases of esophageal SCC were examined by immunohistochemical staining for E-cadherin. The relationship between E-cadherin-staining patterns, conventional clinicopathological parameters and Yamamoto-Kohama’s (Y-K’s) mode of invasion were examined. Results: The expression of E-cadherin on the cell membrane was reduced or lost in some of the esophageal SCC. Lymph node metastasis was highly correlated with the expression pattern of E-cadherin (p = 0.0002) and also highly correlated with Y-K’s mode of invasion (p = 0.0078). However, lymph node metastasis was not correlated with any conventional clinicopathological parameters for invasion. Conclusions: These results indicate that E-cadherin plays a crucial role in invasion and metastasis in esophageal SCC, and that Y-K’s mode of invasion highly reflects the invasiveness and metastatic potentials of esophageal SCC cells. Therefore, examination of the expression of E-cadherin and Y-K’s mode of invasion would be helpful in predicting lymph node metastasis in esophageal SCC.
Preventive Effects of Bifidobacterium- and Lactobacillus-Fermented Milk on the Development of Inflammatory Bowel Disease in Senescence-Accelerated Mouse P1/Yit Strain Mice
Authors: Matsumoto Satoshi , Watanabe Nami , Imaoka Akemi , Okabe Yoshio
Published: April 2003

Background/Aims: We recently discovered inflammatory bowel disease (IBD) in the ileum and cecum of SAMP1/Yit strain mice under specific pathogen-free (SPF) conditions. To determine the effect of lactic acid bacteria (LAB – Bifidobacterium breve, Bifidobacterium bifidum and Lactobacillus acidophilus)-fermented milk on the prevention of IBD in SAMP1/Yit strain mice, we compared the disease severity on the intestinal inflammation among the group of mice fed saline, unfermented milk or LAB-fermented milk. Methods: Three-week-old SAMP1/Yit strain mice (n = 72) were subdivided into three groups, that were fed saline, unfermented milk and LAB-fermented milk, respectively. The diets were orally administered daily via a gastric tube. When the mice reached 20 weeks of age, they were sacrificed and the IBD scores were compared among the three groups. Results: Administration of the LAB-fermented milk to SAMP1/Yit strain mice reduced histological injury score, compared with those in saline-treated or unfermented milk-treated SAMP1/Yit strain mice. Ileal tissue weight and myeloperoxidase activity also reduced by treatment of LAB-fermented milk. Moreover, the tissue contents of immunoglobulins such as IgG1 and IgG2a were lower in the inflammatory regions in the SAMP1/Yit strain group fed LAB-fermented milk than that fed saline and unfermented milk. Cytokine-specific ELISA assays indicated the production of T-helper 1 cytokines such as interferon-γ and tumor necrosis factor-α in the culture supernatants of MLN cells in the SAMP1/Yit strain group fed LAB-fermented milk was lower than those fed saline and unfermented milk. On the contrary, the production of interleukin-10 in MLN cells increased by prevention with LAB-fermented milk. Conclusion: LAB-fermented milk is beneficial for the treatment of murine IBD and this effect may be modulated through stabilization of the mucosal immunity by LAB.
Risk of Disease in Siblings of Patients with Hereditary Hemochromatosis
Authors: Nelson Richard L. , Persky Victoria , Davis Faith , Becker Eugene
Published: April 2003

Background: Parents of hereditary hemochromatosis (HH) homozygote patients, who are predominantly HH heterozygotes, have been found to have an increased risk of colonic neoplasia, diabetes, stroke death, stomach cancer and leukemia. The health histories of siblings of HH patients are reported. Methods: Individuals homozygous for HH were mailed questionnaires concerning the health histories of their siblings. Spouses of the HH homozygotes were asked to complete accompanying questionnaires concerning their siblings. The frequencies of serious illness and, when specified, each reported disease were determined by zygosity, odds ratios and 95% confidence intervals estimated. Results: Data were available for 279 siblings known to be HH homozygotes (HHs), and 1,265 other siblings of HH patients, who are predominantly hemochromatosis heterozygotes (HHhet). Controls consisted of 1,338 spouse siblings in whom only the general population prevalence of HH homozygosity and heterozygosity existed. Odds ratios comparing HH strata to controls were elevated for serious illness (1.12 in HHhet, 1.71 in HHs), diabetes (0.78, 2.45), arthritis (2.10, 1.69), and hepatoma (1.06, 11.96). Conclusions: There was a significant trend for increased risk of serious illness among siblings of HH patients with increasing exposure to the HH gene, especially for diabetes, arthritis and hepatoma.
Pneumatosis intestinalis following Cytotoxic or Immunosuppressive Treatment
Authors: Galm O. , Fabry U. , Adam G. , Osieka R.
Published: April 2003

Pneumatosis intestinalis (PI) is an uncommon condition characterized by the presence of gas within the bowel wall. We describe 5 cases of PI that occurred after cytotoxic or immunosuppressive treatment for hematological disorders. All patients were neutropenic shortly before or at the time of diagnosis of PI, but did not show specific symptoms. The diagnosis was made by conventional X-ray and confirmed by abdominal computed tomography. Since there were no signs of secondary complications such as peritonitis, ischemia, or perforation, conservative treatment with broad-spectrum antibiotics and parenteral nutrition was initiated. All patients but 1 achieved complete resolution of PI after recovery from myelosuppression. Benign pneumoperitoneum due to PI should be considered in the differential diagnosis of free intra-abdominal air after chemotherapeutic or immunosuppressive therapy. It can be managed successfully by conservative treatment in the absence of secondary complications, if there is recovery of myelopoiesis.
The Fine Form of Helicobacter pylori on the Metaplastic Duodenal Mucosa Is Associated with Recurrent Duodenal Ulcers
Authors: Sano Shuichi , Nishimori Isao , Kosaki Takuhiro , Fujikawa-Adachi Kiyomi , Onishi Saburo
Published: April 2003

Background/Aim: It is well known that Helicobacter pylori changes its shapes according to various environmental conditions. The aim of this study was to examine the morphological differences between H. pylori in the duodenum and that in the stomach. Methods: Duodenal biopsy specimens were obtained from patients with duodenal mucosal lesions, and these specimens were then histopathologically examined. Morphological and genetic properties of cultured H. pylori isolates were analyzed. Results:H. pylori was identified in 16 out of 50 duodenal biopsy specimens. Along with the regular form, we found a fine form of H. pylori in the gastric metaplastic mucosa of ten duodenal specimens that was shorter in length and thinner in diameter than the regular helical form. There were no detectable differences between the ureA-ureB polymorphism of the duodenal fine form and that of gastric regular form in a single patient. As compared with patients without H. pylori in the duodenum, the prevalence of recurrent duodenal ulcers significantly increased in patients with the fine form (p < 0.05), but not in patients with the regular form. Conclusion: The fine form of H. pylori in the metaplastic duodenal mucosa could result from its adaptation to the duodenal environment and may be associated with the recurrence of a duodenal ulcer.
R116C Mutation of Cationic Trypsinogen in a Turkish Family with Recurrent Pancreatitis Illustrates Genetic Microheterogeneity of Hereditary Pancreatitis
Authors: Tautermann G. , Ruebsamen H. , Beck M. , Dertinger S. , Drexel H. , Lohse P.
Published: April 2003

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC→CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.
Chronic Porcine Two-Hit Model with Hemorrhagic Shock and Pseudomonas aeruginosa Sepsis
Authors: Eissner B. , Matz K. , Smorodchenko A. , Röschmann A. , v. Specht B.U.
Published: April 2003

Background: Sepsis is still a major cause of death despite well-developed therapeutical strategies such as antibiotics and supportive medication. The aim of this study was to characterize the long-term effects of a two-hit porcine sepsis model with a hemorrhagic shock as ‘first hit’ followed by a Pseudomonas aeruginosa infusion as ‘second hit’. Materials and Methods: Twelve juvenile healthy pigs were anesthetized and hemodynamically monitored. The two-hit group (n = 6) underwent a hemorrhagic shock with a 50% reduction of the mean arterial pressure and/or cardiac index for 45 min, followed by resuscitation, while the control group (n = 6) received no pretreatment. All chronically catheterized conscious pigs were challenged with a P. aeruginosa infusion (1.6 × 107 CFU/kg/h for the first 24 h followed by 1.6 × 106 CFU/kg/h for the next 24 h) and observed for another 48 h. Results: The two-hit group showed the following significant differences to the control group: higher APACHE II scores prior to sepsis induction, increased persisting mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) during bacterial challenge. In contrast, systemic vascular resistance (SVRI) was reduced at the end of the study. Throughout the observation period, the mean arterial pressure (MAP) was significantly reduced. Conclusions: The present study shows that the clinical course and hemodynamic effects of a P. aeruginosa sepsis will be aggravated by a preceding hemorrhagic shock during an oberservation period of 96 h. This two-hit model represents a valid, clinically relevant experimental protocol in sepsis research.
Nonhuman Primate Models of Skeletal and Reproductive Aging
Authors: Black A. , Lane M.A.
Published: April 2003

Background: Bone loss, osteoarthritis (OA) and age-related changes in reproduction are some of the most apparent and troubling results of advancing age in the human population. The significance of these changes underscores the need for developing appropriate animal models to study aging of bone and the reproductive system. Objective: This review surveys the literature regarding the current state of nonhuman primates (NHP) as models for skeletal and reproductive aging in humans. Results: Several species of NHP exhibit age-related bone loss as well as changes in the mineral content and architecture of bone that are similar to those reported in humans. In addition, since aged females of some species of NHP exhibit cessation of menses and serum hormone profiles consistent with those described in peri- and premenopausal women, they provide useful models of postmenopausal bone loss. Sensitivity to surgical estrogen depletion and hormone replacement has also been demonstrated in female NHP. Spontaneous development of degenerative arthritis, analogous to humans in age at onset, joint involvement and histologic changes, suggest that NHP are suitable for the study of human OA. Many similarities exist between female NHPs and women in age-related changes in reproductive function including hormone concentrations, menstrual cycling, fertility and the development of endometriosis. Changes in male sexual behavior and fertility with age are also comparable in men and male NHP. Conclusions: Genetic similarity, long lives and similar reproductive endocrinology suggest that NHPs are likely candidates as models of skeletal and reproductive aging in humans. Current data confirm that several species of NHP exhibit changes in bone and reproduction that are comparable to those known to occur in humans.
Detection of Hemodynamic Turbulence in Experimental Stenosis: An in vivo Study in the Rat Carotid Artery
Authors: May Philippe , Arrouvel Claudine , Revol Marc , Servant Jean Marie , Vicaut Eric
Published: April 2003

In a previous study, we have demonstrated that turbulences in arteries less than 1.5 mm in diameter perfused ex vivo by an oscillated flow can be determined using nonlinear mathematical models. The hypothesis tested here was that nonlinear analyses enable the in vivo detection of turbulences in blood flow in vessels with dimensions affected by microsurgery. Twenty Wistar male rats were studied. After an intraperitoneal anesthesia (50 mg/kg sodium pentobarbital), each right carotid artery was dissected and a transit time flowmeter was used to measure blood flow. Arteries were studied in control conditions and graded stenoses, which were performed by a collar system and progressively increased from 0 to 95%. For each flow signal, time delay, false-nearest neighbors, correlation dimension and the largest Lyapunov exponent were computed to characterize the level of turbulence. The level of turbulence was highly correlated with the degree of stenosis induced (p < 0.001). The correlation dimensions of all the flow signals varied between 3 and 5, thus implying that more than three independent noninteger control variables were necessary to account for the complexity of rat carotid artery dynamics. Turbulence flow significantly increased in arteries with 40–95% stenosis. Nonlinear analysis may be useful to determine the turbulence level of an in vivo flow in arteries less than 1.5 mm in diameter and might be clinical useful for turbulence detection after microsurgery.
Effect of a High Salt Diet on Microvascular Antioxidant Enzymes
Authors: Lenda Deborah M. , Boegehold Matthew A.
Published: April 2003

High dietary salt intake decreases the endothelium-dependent dilation of skeletal muscle arterioles by inhibiting local nitric oxide (NO) activity without changing vascular smooth muscle responsiveness to NO. Under these conditions, microvascular walls show evidence of oxidative stress, and scavengers of reactive oxygen species (ROS) abolish this oxidative stress and restore normal arteriolar responses to acetylcholine (ACh). We tested the hypothesis that the salt-dependent appearance of microvascular ROS, and accompanying reduction in endothelium-dependent dilation, is due to a decrease in antioxidant enzyme expression or activity. We studied spinotrapezius muscle microvessels in rats fed normal (NS) (0.45%) or high (HS) (7%) salt diets for 4–5 weeks. Western analysis of arteriolar and venular protein showed no difference between groups in the content of superoxide dismutase (Cu/Zn SOD), catalase, or glutathione peroxidase. The catalase inhibitor 3-amino-1,2,4-triazole (3AT) increased arteriolar and venular oxidant activity (assessed by tetranitroblue tetrazolium reduction) by the same amount in both groups, suggesting similar levels of catalase activity. 3AT did not affect arteriolar responses to ACh in either group. The Cu/Zn SOD inhibitor diethyldithiocarbamate increased arteriolar and venular oxidant activity to a lesser extent in HS rats, suggesting reduced Cu/Zn SOD activity in this group. Cu/Zn SOD inhibition decreased arteriolar responses to ACh only in NS rats. These findings suggest that endogenous Cu/Zn SOD preserves the endothelium-dependent control of arteriolar tone in NS rats, and that a reduction in Cu/Zn SOD activity contributes to the loss of arteriolar NO activity in HS rats.
Lesions in Lateral Hypothalamic Areas Increase Splenocyte Apoptosis
Authors: Tsuboi Hirohito , Miyazawa Hitoshi , Wenner Marcus , Iimori Hirofumi , Kawamura Noriyuki
Published: April 2003

Objective: The lateral hypothalamic area (LHa) is involved in various functions such as feeding, drinking, sexual and reward behavior, among others. Recently, we demonstrated that the LHa can regulate cellular immunity in the spleen. In experiments involving the LHa, it was noticed that the spleen shrinks noticeably after LHa destruction. To explore this phenomenon further, the effect of LHa lesioning on splenocyte apoptosis was investigated. Methods: Male Wistar-King-Aptekman rats underwent bilateral lesioning of their LHa and consequent spleen weights, splenocyte numbers and apoptosis were measured. For the detection of splenocyte apoptosis, both ELISA, which measures DNA fragmentation within the splenocytes, and flow cytometry, which measures the percentage of apoptotic lymphocytes in the spleen, were used. Results: In the LHa-lesioned rats, spleen weights and the number of splenocytes decreased significantly within 24 h. Additionally, in the spleen, lymphocyte apoptosis significantly increased compared to the control after 6 h. Conclusion: These results suggest that the LHa may play a role in immunoregulation by affecting lymphocytes in the spleen through apoptosis and may be relevant to the pathway of stress-induced apoptosis.
Immunomodulatory Effects of Cold Stress on Mice Infected Intraperitoneally with a 50% Lethal Dose of Toxoplasma gondii
Authors: Aviles Hernan , Monroy Fernando P.
Published: April 2003

Cofactors such as stress have been suspected to play a role in the susceptibility to opportunistic infections. Toxoplasma gondii is one of the major opportunistic infectious agents in immunocompromised individuals, and infection can be modulated by external factors such as stress. Objective: The purpose of this study was to examine the in vivo and in vitro role of cold stress (CS) in the pathogenesis of T. gondii infection and its impact on regulatory cytokines in this model. Methods: Mice subjected to CS and control animals were infected intraperitoneally with an LD50 of PD2 T. gondii tachyzoites, and the outcome of the infection was determined. In addition, peritoneal macrophages obtained from CS and non-stressed mice were infected in vitro with T. gondii. The number of infected macrophages, the number of intracellular parasites and the production of interferon (IFN)-γ, interleukin (IL)-12, and tumor necrosis factor (TNF)-α were determined. Results: CS applied before intraperitoneal inoculation increased susceptibility against T. gondii infection. Peritoneal cells from CS mice contained significantly higher numbers of intracellular parasites and infected macrophages compared to those from non-stressed animals. IFN-γ production was initially high in the CS group but decreased significantly after 36 h. Opposite results were found in the non-stressed group. Macrophages from CS mice persistently produced high levels of TNF-α and IL-12 and peaked after 36 h. Levels of these cytokines were lower or absent in the non-stressed group. Conclusion: These results suggest that CS increased the host susceptibility to intraperitoneal T. gondii infection by modulating the function of macrophages and the production of cytokines (IFN-γ) involved in the early control of infection.
Concentration of Soluble Adhesion Molecules (sVCAM-1, sICAM-1 and sL-Selectin) in the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis and Systemic Lupus erythematosus with Central Nervous Involvement
Authors: Baraczka Krisztina , Nékám Kristóf , Pozsonyi Teréz , Jakab Lajos , Szongoth Mariann , Seszták Magdolna
Published: April 2003

Objectives: The aim of the present study was to investigate the role of soluble adhesion molecules in the pathogenesis of multiple sclerosis (MS) and systemic lupus erythematosus (SLE) with demyelinating syndrome. Methods: Paired cerebrospinal fluid (CSF) and serum samples were analysed by an ELISA method to determine the concentrations of sVCAM-1, sICAM-1 and sL-selectin. Intrathecal syntheses of the adhesion molecules were calculated. Results: Elevated serum and CSF concentrations of sVCAM-1 were present in all patient groups. Intrathecal synthesis of sVCAM-1 was present in the relapsing-remitting and secondary progressive forms of MS. Intrathecal synthesis of sICAM-1 was observed in all clinical forms of MS. MS patients with progressive forms of the disease and SLE patients were characterised by intrathecal synthesis of sL-selectin. Conclusions: The data presented suggest that (1) blood-brain barrier damage can be assumed both in systemic disease and organ-specific disease (sVCAM-1), (2) clinical forms of MS differ from each other in respect to concentrations of adhesion molecules and (3) similar immunological events in the central nervous system of SLE patients with demyelinating syndrome and progressive forms of MS can be assumed (sL-selectin).
Immune-Induced Flavor Aversion in Mice: Modification by Neonatal Capsaicin Treatment
Authors: Basso Alexandre Salgado , de Sá-Rocha Luiz Carlos , Palermo-Neto João
Published: April 2003

Objective: This study was designed to evaluate the role of c-sensitive fibers in the establishment of immune-induced flavor aversion in mice. Methods: Mice were treated neonatally with capsaicin in order to destroy c-sensitive fibers; after such treatment, adult animals, immunized or not with ovalbumin, were submitted to a two-bottle preference test, with a choice between water and a sweetened egg white solution. Results: Neonatal capsaicin treatment was unsuccessful in preventing the development of immune-induced aversion to the sweetened solution containing the antigen. Nonetheless, amongst immunized mice, those which had been previously treated with capsaicin showed a significant increment in the preference for the sweetened egg white solution. Furthermore, our data showed that neonatal capsaicin treatment did not interfere with either IgG1 or IgE production. Conclusion: The present results suggest that c-sensitive fibers have a role in the transmission of the signals generated by this immune response to the central nervous system, thus contributing to the development of a flavor aversion in mice.
Hepatocyte Growth Factor Protects Functional and Histological Disorders of HgCl2-Induced Acute Renal Failure Mice
Authors: Yamasaki Naoki , Nagano Tomokazu , Mori-Kudo Ikue , Tsuchida Atsushi , Kawamura Takao , Seki Hitoshi , Taiji Mutsuo , Noguchi Hiroshi
Published: April 2003

Hepatocyte growth factor (HGF) enhances proliferation of renal epithelial cells as well as hepatocytes. HGF accelerates recovery from acute renal failure (ARF) in animal models. However, pharmacological profiles of HGF including its action mechanism has not been studied in detail. An HgCl2-induced ARF mouse was used in this study to evaluate the efficacy of HGF. Single administrations of recombinant human HGF or vehicle were given to ARF mice 30 min after HgCl2 injection. Renal function was monitored by measuring serum creatinine, blood urea nitrogen and creatinine clearance. In the ARF mice, there was a deterioration of renal function biochemical parameters and histological evidence of renal damage including acute tubular necrosis of proximal tubules. These were both significantly ameliorated by a single HGF administration. The effect of HGF was noticeable in the early phase of ARF (1 day after onset) when there was no histological evidence of increased labeling indexes in renal tubular epithelial cells. Western blot analysis of the c-Met/HGF receptor showed that tyrosine phosphorylation was enhanced immediately after HGF administration indicating direct activation of renal epithelial cells. HGF prevented increase of apoptotic nuclei with DNA fragmentation in renal epithelial cells which suggests cytoprotective activity of HGF on renal epithelial cells in the ARF mice.
Combination Therapy with Benazepril and Oral Adsorbent Ameliorates Progressive Renal Fibrosis in Uremic Rats
Authors: Aoyama Isao , Shimokata Kaoru , Niwa Toshimitsu
Published: April 2003

Background/Aims: The administration of an angiotensin-converting enzyme (ACE) inhibitor or an oral adsorbent, AST-120 (Kremezin), prevents the progression of renal failure. This study was designed to determine the additional effects of AST-120 combined with an ACE inhibitor, benazepril, on the progression of renal fibrosis in uremic rats. Methods: 5/6-nephrectomized uremic rats were divided into control uremic rats (CRF group), benazepril-treated uremic rats (CRF+B group) and uremic rats receiving benazepril and AST-120 (CRF+BK group). After 14 weeks of treatment renal function and pathological changes were investigated. Results: The progression of renal dysfunction was delayed in both the CRF+B and CRF+BK groups as compared with the CRF group. In the CRF+BK group, the level of serum and urinary indoxyl sulfate and the tubular accumulation of indoxyl sulfate decreased. Both the CRF+B and CRF+BK groups showed lower glomerular sclerosis indices than the CRF group. In the CRF+BK group, but not the CRF+B group, the interstitial fibrosis area and the expression of transforming growth factor (TGF) β1 and tissue inhibitor of metalloproteinases (TIMP) 1 were decreased as compared with the CRF group. Furthermore, the CRF+BK group showed a smaller interstitial fibrosis area and a lower renal osteopontin expression than the CRF+B group. Conclusion: Combination therapy of benazepril and AST-120 is more effective than benazepril alone in retarding the progression of interstitial fibrosis by reducing the expression of TGF-β1, TIMP-1 and osteopontin.