bluuebunny/crossref_metadata_2025 huggingface dataset:
Naphazoline-Induced Neuroendocrine Changes: Increases in ANP and cGMP Levels, but Suppression of NE, 3H-NE, and cAMP Levels in Rabbit Eyes
Authors: Ogidigben Miller J. , Chu Teh-Ching , Potter David E.
Published: April 2003

The objective of this study was to determine whether naphazoline, an alpha 2 (α2)/imidazoline (I1) agonist, can alter endogenous levels of atrial natriuretic peptide (ANP) and norepinephrine (NE) in aqueous humor and cyclic nucleotide (cAMP, cGMP) accumulation and NE overflow inthe iris-ciliary body (ICB) of the rabbit eye. Topical naphazoline (25, 75, and 250 µg) caused a dose-dependent elevation of the ANP levels (36, 54, and 137 pg/ml, respectively) in aqueous humor. This effect was antagonized by pretreatment with efaroxan, an antagonist of I1/α2 receptors. Another α2/I1 agonist, moxonidine (75 µg topically), caused significant increases in ANP levels in aqueous humor, whereas other relatively selective α2-adrenergic receptor agonists, brimonidine (50 µg topically) and oxymetazoline (75 µg topically), did not. In naphazoline (75 µg) pretreated eyes, the NE levels in aqueous humor were attenuated by 36% (from 6.0 to 3.8 pg/ml). Furthermore, naphazoline (1, 10, and 100 µmol/l) caused a dose-related inhibition of NE release from ICBs: 25, 45, and 80%, respectively. The isoproterenol (1 µmol/l) stimulated cAMP accumulation was inhibited 53% by naphazoline (100 µmol/l). In contrast, naphazoline significantly increased the cGMP levels in ICBs. These data demonstrate that naphazoline acts on I1 receptors to increase ANP and to reduce NE levels in aqueous humor. The former effect could also contribute to elevation of cGMP levels and inhibition of cAMP accumulation in the ICB. Further studies will be required to determine if elevation of ANP levels is a critical component of naphazoline-induced alteration of aqueous humor dynamics.
Protective Effect of Resveratrol against Pentylenetetrazole-Induced Seizures and Its Modulation by an Adenosinergic System
Authors: Gupta Y.K. , Chaudhary Geeta , Srivastava Ajay K.
Published: April 2003

The effect of trans-resveratrol (resveratrol), a polyphenolic compound with potent antioxidant activity, was investigated against pentylenetetrazole (PTZ) induced seizures in rats. Resveratrol (20, 40, and 80 mg/kg i.p.) administered 20 min prior to convulsive challenge with PTZ (60 mg/kg i.p.) dose dependently reduced the percent incidence of generalized tonic-clonic convulsions. Resveratrol (40 mg/kg) also potentiated the effect of sodium valproate (150 mg/kg) and diazepam (2 mg/kg) against PTZ-induced seizures. Since adenosine, an endogenous anticonvulsant, has been demonstrated to modulate the action of various antiepileptics, experiments were also carried out to determine whether an adenosinergic mechanism is involved in the anticonvulsant action of resveratrol. When a subanticonvulsant dose of adenosine (500 mg/kg) was administered together with resveratrol, a significant reduction in the percent incidence of generalized tonic-clonic convulsions was observed. Moreover, the nonspecific adenosine receptor antagonist theophylline (50 mg/kg i.p.) significantly reversed the resveratrol-induced protection, whereas the specific adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (1 mg/kg i.p.) could not reverse the resveratrol-induced protection. The findings of the present study suggest an antiepileptic potential of resveratrol and that an adenosinergic mechanism may play a role in its anticonvulsant activity.
Expression of nm23-H1 in Hydatidiform Mole and Its Relationship with the Development of Postmolar Disease
Authors: Iwase Katsutoshi , Okamoto Tomomitsu , Nui Rong , Mizutani Shigehiko
Published: April 2003

The aim of the present study was to investigate the expression of nm23-H1 in human placenta, hydatidiform mole and choriocarcinoma cells. Nm23-H1 protein was localized in the cytotrophoblast, but not in the syncytiotrophoblast. In the hydatidiform mole cases with subsequent spontaneous remission, nm23-H1 mRNA levels were significantly lower than those in first-trimester placentas. However, its levels were elevated in the hydatidiform mole cases that progressed to persistent gestational trophoblastic disease and were comparable to those of first-trimester placentas, and they were further elevated in choriocarcinoma cells. The present data suggest an association of nm23-H1 for the proliferation activity of trophoblast, and its increased expression may influence the development of persistent trophoblastic disease.
Detection of Aberrations of Chromosome 17 and p53 Gene Expression and Their Correlation to Histologic Grading and Prognosis in Primary Invasive Squamous Cell Carcinoma of the Cervix
Authors: Boabang P. , Kurbacher C.M. , Waida A. , Amo-Takyi B.K.
Published: April 2003

We analyzed tumor tissues from 14 patients with invasive squamous cell carcinoma of the cervix for aberrations of chromosome 17 and p53 expression. All but 3 patients were negative for p53 protein expression, the protein being detected in 2 International Federation of Obstetrics and Gynecology stage IIa cancers and 1 stage Ib G3 carcinoma. Significant cytogenetic aberrations in the form of losses and gains of chromosome 17 were diagnosed in 9 and 7 patients, respectively. There was no correlation with tumor prognosis, clinical stage or histologic grade. According to most reports, almost all cervical carcinomas contain integrated human papilloma virus (HPV) and express E6 oncoproteins. Increasing evidence suggests that E6 protein interaction leads to p53 mutation in HPV-infected cervical epithelium. Since most cervical tumors are infected with HPV, and the tumors originate through p53 gene mutation caused by the said interaction, which leads subsequently to the overexpression of p53 oncoprotein, lack of the latter in the remaining 11 cervical tumors may either be the result of technical shortcomings, or the tumor may arise in such circumstances through a p53-independent pathway. On the other hand, 2 of 3 stage IIa cancers and 1 Ib G3 carcinoma were found to be p53 positive, thus supporting the notion that p53 inactivation is a relatively late event in the progression of cervical cancer.
Phenotypic and Functional Analysis of Tumor-Infiltrating Lymphocytes Compared with Tumor-Associated Lymphocytes from Ascitic Fluid and Peripheral Blood Lymphocytes in Patients with Advanced Ovarian Cancer
Authors: Santin A.D. , Hermonat P.L. , Ravaggi A. , Bellone S. , Roman J.J. , Smith C.V. , Pecorelli S. , Radominska-Pandya A. , Cannon M.J. , Parham G.P.
Published: April 2003

To investigate and compare the phenotype and function of lymphocytes collected from patients harboring advanced ovarian cancer, leukocytes from peripheral blood (n = 18), ascitic fluid (n = 13) and tumor tissues (n = 13) were evaluated for the relative proportions of lymphocyte subsets, including CD3+, CD4+, CD8+, CD19+, CD56 and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells. The ability to synthesize type 1 cytokines (IFN-γ and IL-2) and a type 2 cytokine (IL-4) was assessed by flow cytometry. In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in peripheral blood lymphocytes (PBL) and tumor-associated lymphocytes (TAL) but not in tumor-infiltrating lymphocytes (TIL) (CD4:CD8 ratios: 3.0 vs. 2.0 vs. 1.0, respectively). CD19+ lymphocytes (B cells) and CD56+ lymphocytes (NK cells) were significantly higher in PBL compared to TAL and TIL (p < 0.05). TAL and TIL had a higher proportion of T cells expressing the late activation marker HLA-DR compared to PBL. In contrast, no significant differences were detected in PBL, TAL and TIL in the expression of the early activation marker CD25. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-γ+ T cells in TAL and TIL compared to PBL (p < 0.01), and a higher proportion of IL-2+ T cells in PBL compared with TAL and TIL (p < 0.05). Low percentages of IL-4+ T cells (i.e. Th2) were detected in each tissue. Taken together, these data demonstrate the recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in TAL and TIL compared to PBL. However, low surface expression of IL-2 receptor (i.e. CD25), as well as depressed intracellular IL-2 production in chronically stimulated TAL and TIL suggests that the impaired antitumor function commonly detected in these lymphocyte populations may be secondary to an acquired dysregulation of the IL-2 pathway.
Prognostic Factors for Survival in Invasive Squamous Cell Vulvar Carcinoma: A Univariate Analysis
Authors: Kouvaris J. , Kouloulias V. , Loghis C. , Sykiotis C. , Balafouta M. , Vlahos L.
Published: April 2003

The charts of 50 women with invasive squamous cell vulvar carcinoma were reviewed retrospectively, and pathologic, medical and life style factors were analyzed for their possible influence on survival using the Cox regression univariate model. The median age of the cohort was 73.5 years. The patient distribution according to stage was as follows: stage I: 17; stage II: 16; stage III: 12, and stage IVa: 5 patients. The median follow-up was 61 months. The univariate analysis revealed that the overall survival was decreased by age ≧73.5 years (p = 0.0185), advanced stage (p = 0.0026), grade III differentiation (p < 0.0001), ulcerative type of the tumor (p = 0.0055), tumor diameter >40 mm (p = 0.0053), obesity (p = 0.011), smoking (p = 0.0177), diabetes (p = 0.0122) and hypertension (p = 0.044), but not with clitoral involvement.
Pregnancy in Hyperprolactinemic Infertile Women Treated with Vaginal Bromocriptine: Report of Two Cases and Review of the Literature
Authors: Ricci Giuseppe , Giolo Elena , Nucera Giuseppe , Pozzobon Cristina , De Seta Francesco , Guaschino Secondo
Published: April 2003

Vaginal bromocriptine has proven safe and effective in treating hyperprolactinemic women. However, there has been no long-term clinical assessment regarding the influence of daily vaginal bromocriptine administration on the ability to conceive. This article presents two cases of successful pregnancy resulting from this alternative treatment. An infertile woman with an empty sella and hyperprolactinemia was treated with vaginal bromocriptine because of intolerance to oral administration. Prolactin levels were quickly normalized and no side effects occurred. Repeated postcoital tests during treatment proved normal. Twelve months later, the patient conceived. The therapy was discontinued during pregnancy, without complications. Although bromocriptine treatment was not resumed after delivery, postpartum prolactin levels were lower than before treatment and magnetic resonance imaging revealed an unchanged empty sella. Another patient with infertility and pituitary microadenoma with intolerance to oral dopaminergic agonists received the same treatment. Prolactin quickly fell to within the normal range. Vaginal bromocriptine was well tolerated and postcoital test results were not impaired. Tumor regression occurred and 10 months later the patient conceived. Despite bromocriptine withdrawal, no significant complications occurred during pregnancy. It can therefore be concluded that a couple’s fertility does not appear to be significantly affected by the persistent local presence of bromocriptine.
Disseminated Intravascular Coagulation Associated with Intratumoral Hemorrhage of Ovarian Cancer
Authors: Matsushita Hiroshi , Kurabayashi Takumi , Tomita Masatoshi , Yamamoto Yasuaki , Aoki Yoichi , Tanaka Kenichi
Published: April 2003

Background: Ovarian carcinoma usually presents in an indolent manner. A patient with ovarian cancer rarely shows acute clinical features which require immediate medical intervention. Case: We present a 36-year-old Japanese woman with an ovarian tumor, who suffered general fatigue and increased abdominal girth on admission. Her hemoglobin, platelet count and fibrinogen were decreased, and fibrin/fibrinogen degradation products were elevated, which determined the diagnosis of disseminated intravascular coagulation (DIC). Since computed tomography scan and magnetic resonance imaging revealed an intratumoral hemorrhage, an emergency laparotomy was performed. The patient was found to have ovarian cancer with a massive intratumoral hemorrhage, and DIC improved immediately after the operation. Conclusion: The clinician should be alert to the possibility that intratumoral bleeding of ovarian cancer might be associated with DIC.
Genital Tuberculosis Can Present as Disseminated Ovarian Carcinoma with Ascites and Raised Ca-125: A Case Report
Authors: Manidakis L.G. , Angelakis E. , Sifakis S. , Stefanaki P. , Kalogeraki A. , Manidaki A. , Koumantakis E.
Published: April 2003

In women with an adnexal mass, ascites and elevated Ca-125 levels, ovarian carcinoma must be ruled out. However, several other conditions, including genital tuberculosis, may present similarly. A 41-year-old woman with weight loss, ascites and elevated levels of Ca-125 was evaluated for ovarian cancer. Computerized tomography revealed an adnexal mass, ascites and lymphnodes on the peritoneal surface. Paracentesis of the ascitic fluid revealed a lymphocytic exudate but failed to show any malignant cells. At laparotomy, frozen sections of tissue biopsies were negative for malignancy; however, a total hysterectomy plus adnexectomy was performed. Postoperatively histologic examination revealed typical features of genital tuberculosis. Antituberculosis treatment was effectively given to the patient. Serum levels of Ca-125 were undetectable 12 weeks after treatment. In conclusion, genital tuberculosis can be misdiagnosed and confused with ovarian cancer. Intraperitoneal tuberculosis should be considered in the differential diagnosis in cases in which ovarian cancer is suspected, even when malignancy-associated risk factors are present.
Growth Problems in Children with Asthma
Authors: Wolthers Ole D.
Published: April 2003

Growth problems are often seen in children with asthma. Rarely, these problems may be caused by poor asthma control. Negatively-deviating growth curves in asthmatic boys aged 8–15 years are often associated with a chronic delay in growth and puberty. Daily treatment with any dose of systemic corticosteroids suppresses the growth rate for as long as the treatment is maintained. The risk of growth rate suppression due to inhaled corticosteroids depends on the dose, administration regimen and delivery device. The risk becomes significant with ≧800 µg budesonide from a metered-dose inhaler with a spacer, and with ≧400 µg budesonide or fluticasone propionate from a dry-powder inhaler. Regardless of the treatment modality applied, all children with asthma should have their height growth measured at least every 6 months, and indications for endocrine work-up should follow general criteria for a growth-insufficient child.
Small Bowel Enterocyte Apoptosis and Proliferation Are Increased in the Elderly
Authors: Ciccocioppo R. , Di Sabatino A. , Luinetti O. , Rossi M. , Cifone M.G. , Corazza G.R.
Published: April 2003

Background: It is known that in the elderly the small bowel does not reveal structural and functional deteriorations in normal conditions, whereas the absorptive function is impaired in stress conditions. Objective: The balance between enterocyte apoptosis and proliferation being responsible for the maintenance of tissue size, mucosal morphology and function in the gastrointestinal tract, the aim of our study was to evaluate the rates of enterocyte apoptosis and proliferation in the duodenal mucosa of aged human beings in comparison to adults. Methods: For this purpose, the terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick end labelling (TUNEL) technique and immunohistochemistry for MIB-1 detection were applied on histological sections of endoscopic duodenal biopsy specimens obtained from 12 healthy elderly subjects (mean age 77.6 years; M/F 7/5) and 12 healthy adult subjects (mean age 37.7 years; M/F 8/4). Counts were performed, at a constant magnification (×200), by computer-aided analysis and the results expressed as median percentages of positive enterocytes. Results: The results showed a significant increase in enterocyte apoptosis in the elderly (15.3 vs. 2.1% in the adults, p < 0.001) which was positively correlated (rs = 0.65, p < 0.05) with a significant increase in enterocyte proliferation (37.7 vs. 15.8% in the adults, p < 0.0001). Conclusions: These data suggest that the maintenance of mucosal architecture throughout the process of aging is due to either a hyperproliferative state or an exaggerated apoptosis with a consequent cellular immaturity, which may impair the absorptive function observed in stress conditions.
A Novel Mutation in a Patient with Werner’s Syndrome
Authors: Nakayama Tomohiro , Ochiai Toyoko , Takahashi Yoshiko , Ohkubo Kimie , Hironaga Takashi , Kokubun Shinichiro
Published: April 2003

Background: Werner’s syndrome, a rare autosomal recessive disorder, is characterized by features of premature aging. Seventy-five percent of the alleles of Japanese patients with Werner’s syndrome have one of three major mutations. Objective: To determine the genotype of a patient with Werner’s syndrome. Methods: We diagnosed Werner’s syndrome in a 47-year-old Japanese man who had juvenile cataracts, skin sclerosis and hyperpigmentation of the feet, a high-pitched voice, characteristic bird-like appearance of the face with a beak-shaped nose, thinning of the skin over the whole body and hyperkeratoses on the soles of the feet, hyperlipidemia, and diabetes mellitus. None of his immediate family had entered into a consanguineous marriage. He had undergone surgery to treat duodenal perforation. We screened his family for three major mutations (mutations 1, 4, 6) in the WRN gene by polymerase chain reaction-restriction fragment length polymorphism. Automated DNA sequencing fluorescence-labeled dideoxy terminators proceeded for abnormally migrating bands. Results: The patient and his mother had mutation 1 (nonsense mutation) in one chromosome. Although mutations 4 and 6 were undetectable, screening for mutation 4 revealed an abnormally migrating band. Consequently, we discovered a novel 4-bp deletion in exon 25 only in the patient. This mutation was not detected in any other family member. Conclusion: This is the first description of a patient with Werner’s syndrome who has a compound heterozygote of mutation 1 and a novel deletion mutation.
Feasibility, Acceptability and Internal Consistency Reliability of the Nottingham Health Profile in Dementia Patients
Authors: Bureau-Chalot Florence , Novella Jean-Luc , Jolly Damien , Ankri Joël , Guillemin Francis , Blanchard François
Published: April 2003

Background: Few studies have evaluated subjective health status in dementia patients. Objectives: The aim of the study was to determinate the feasibility, acceptability and internal consistency reliability of measuring subjective health status in dementia patients with the Nottingham Health Profile (NHP). Design: The French version of the NHP was administered to 145 dementia patients and their proxies (family caregivers and formal caregivers). Measures: The refusal rate, type of administration and time for completion were used as indicators of feasibility. Internal consistency reliability was determined with Cronbach’s α coefficient and test-retest reliability assessed with the intraclass correlation coefficient for test-retest values. The measurements obtained were compared by source of information (patient and proxies). Results: The 145 subjects had an average age of 82 and 78% were women. 73% had a Mini-Mental State <16. Ninety-four percent of the items were correctly filled in, but an interviewer had to be present because of problems in attention or comprehension. The test-retest reliability for subjects was good (ρ < 0.7), but response agreement between patients and their proxies was just acceptable for physical domains (ρ < 0.6) and poor for psychological and social domains (ρ < 0.4). Conclusions: Self-rating of perceived health status by dementia patients seems feasible with the questionnaire with adaptations in the administration, but other methods are needed to approach the more subjective domains of the quality of life.
Self-Reported Sexual Symptoms in Women Attending Menopause Clinics
Authors: Nappi Rossella E. , Verde Jole Baldaro , Polatti Franco , Genazzani Andrea R. , Zara Carlo
Published: April 2003

The aim of the present cross-sectional study was to investigate the frequency of self-reported sexual symptoms in women (n = 355; age range 46–60 years) attending menopausal clinics in Italy and to relate them to other vasomotor, psychological, physical, and genital complaints. Each subject completed a visual scale for sexual symptoms and for other complaints frequently occurring at menopause. Pain during sexual intercourse (29.8%) and low libido/lack of arousal (22%) were significantly more frequent with age (χ2 = 8.0, p < 0.02; χ2 = 6.2, p < 0.04, respectively) and years since menopause (χ2 = 13.0, p < 0.005; χ2 = 11.3, p < 0.01, respectively). Reduction of sexual pleasure/satisfaction (45.9%) was common with age, but was more frequent with longer time since the menopause (χ2 = 19.9, p < 0.001). By examining the intensity of sexual symptoms according to the presence of other complaints, we found that physical, psychological, and genital well-being significantly affects components of sexual response after the menopause. For example, loss of fitness, urogenital symptoms, a negative self-image (increase of facial hair), and depressive symptoms were more common in women with sexual complaints. Given the concomitant role of hormonal and aging determinants, a comprehensive approach to female health is needed when facing climacteric sexual dysfunction.
Uterine Arteriovenous Malformation: Ultrasonographic, Magnetic Resonance and Radiological Findings
Authors: Nasu Kaei , Fujisawa Kayo , Yoshimatsu Jun , Miyakawa Isao
Published: April 2003

Uterine arteriovenous malformation (AVM) is a rare disease. However, it is important to make a rapid and precise diagnosis when it does occur, because life-threatening massive genital bleeding may occasionally be a symptom of this disease. In this case report, we present a case of uterine AVM diagnosed by means of ultrasonographic, magnetic resonance imaging (MRI) and angiographic studies. A 47-year-old Japanese woman was admitted complaining of severe hypermenorrhea that had been occurring for 5 years. Her last pregnancy was an uncomplicated term delivery at 32 years of age. Transvaginal and transabdominal ultrasonography demonstrated a thickening of the anterior wall of the uterine corpus with numerous cystic lesions. Color Doppler ultrasound, dynamic MRI and magnetic resonance angiography as well as pelvic angiography were useful for detecting the hypervascular lesions in this case. She was treated by a total hysterectomy and bilateral salpingo-oophorectomy under the diagnosis of uterine AVM. These noninvasive techniques should be performed initially when this rare disease is suspected.
A Cross-Sectional Study on Biochemical Parameters of Bone Turnover and Vitamin D Metabolites in Healthy Dutch Children and Young Adults
Authors: van der Sluis Inge M. , Hop Wim C. , van Leeuwen Johannes P.T.M. , Pols Huib A.P. , de Muinck Keizer-Schrama Sabine M.P.F.
Published: April 2003

Aim: To provide reference data of biochemical markers of bone turnover and vitamin D metabolites for children and young adults. Methods: Blood samples were taken from 176 healthy Dutch children and young adults (age range 7.6–25.3 years) to assess serum calcium, alkaline phosphatase, inorganic phosphate, osteocalcin, collagen type I cross-linked N-telopeptide, N-terminal propeptide of type I procollagen , 25-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3 levels. Cross-linked telopeptide of type I collagen and carboxy-terminal propeptide of type I procollagen were assessed in 286 subjects (age range 1.4–25.3 years). Results: Calcium and vitamin D levels were independent of age. The peak concentrations for collagen type I cross-linked N-telopeptide, cross-linked telopeptide of type I collagen, carboxy-terminal propeptide of type I procollagen, N-terminal propeptide of type I procollagen, alkaline phosphatase, and osteocalcin were found during puberty, in girls approximately 2.5 years earlier than in boys. Strong correlations were found between the markers of bone turnover, while no correlation was found between the markers of bone turnover and bone mineral density measured by dual-energy X-ray absorptiometry. Conclusions: Single measurements of bone markers cannot predict bone density. Reference data according to gender, age, and Tanner stage are given which allow calculating standard deviation scores adjusted for age and gender.
Coexistence of 21-Hydroxylase and 11β-Hydroxylase Deficiency in Adrenal Incidentalomas and in Subclinical Cushing’s Syndrome
Authors: Dall’Asta Chiara , Barbetta Laura , Libé Rossella , Passini Elena , Ambrosi Bruno
Published: April 2003

Objective: The prevalence of steroid secretion abnormalities was studied by evaluating the 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (S) responses to adrenocorticotropic hormone (ACTH) stimulation in 48 patients with ‘nonfunctioning’ incidentalomas and in 10 patients with ‘subclinical’ Cushing’s syndrome. Methods: In all patients the cortisol, 17-OHP, and S levels were measured after ACTH test. Eight patients were reinvestigated after surgery. Results: In patients with nonfunctioning lesions, the ACTH test induced 17-OHP and S peaks higher than in normals (p < 0.005). In 10 cases an augmented rise of 17-OHP and S was observed. In patients with subclinical Cushing’s syndrome, the 17-OHP peak after ACTH was greater than in patients with nonfunctioning lesions and in normals (p < 0.005); the S peak was also higher than in controls (p < 0.005). In 7 of 8 operated patients, the exaggerated 17-OHP peak was normalized. Conclusions: A combined impairment of different enzyme activities is frequently present in adrenal incidentalomas; the alteration of enzymatic pathways can also coexist with the presence of partial cortisol autonomy.
Nonselective Beta-Adrenergic Blockade Augments Fasting Hyperkalemia in Hemodialysis Patients
Authors: Nowicki Michał , Miszczak-Kuban Joanna
Published: April 2003

Background/Aim: Fasting hyperkalemia in patients with end-stage renal failure is a well-documented phenomenon. Both a decreased secretion of insulin and decreased β-adrenergic receptor sensitivity may take part in this effect. Methods: Twelve anuric, long-term (6.4 ± 2.7 years; mean ± SD) hemodialysis patients underwent three periods of 18-hour fasting (from 6 p.m. to 12 a.m.). At the beginning of each fasting period a single dose of the nonselective β-blocker, nadolol (80 mg), or the β1-selective blocker, betaxolol (20 mg), or placebo were given in a random order and in blinded fashion. The wash-out period was 7 days. Results: The mean decrease in blood pressure was similar after nadolol and betaxolol (18 ± 10 vs. 19 ± 11 mm Hg) as was a decrease in heart rate (20 ± 3 and 19 ± 6, respectively). Serum potassium was not different before each of the fasting periods. The increase in serum potassium during fasting was highly significant in each case. The mean increase in serum potassium was 1.2 ± 0.4 mmol/l after nadolol, 0.9 ± 0.6 after betaxolol and 0.6 ± 0.6 after placebo. This effect was significantly larger after nadolol than after placebo (p = 0.01), but this relation was not significant with respect to betaxolol (p = 0.30). Serum insulin as well as glucose decreased significantly and to a similar extent during each fasting period. Plasma aldosterone was unchanged. Conclusion: Nonselective β-adrenergic blockade increases the hyperkalemic effect of fasting in hemodialysis patients.
Predominance of Type-2 Immune Response in Idiopathic Membranous Nephropathy
Authors: Hirayama Kouichi , Ebihara Itaru , Yamamoto Satoshi , Kai Hirayasu , Muro Kaori , Yamagata Kunihiro , Kobayashi Masaki , Koyama Akio
Published: April 2003

Background: The Th1/Th2 paradigm is proving increasingly useful in the understanding of infectious diseases and many autoimmune diseases. Th1 cells predominantly produce interleukin-2 (IL-2) and interferon-γ (IFN-γ) and are instrumental in initiating delayed-type hypersensitivity and activating macrophages. Th2 cells secrete other cytokines, such as IL-4, IL-5, IL-10 and IL-13 that trigger B-cell activation and immunoglobulin synthesis. It has been shown that in patients with membranous nephropathy, there may be a predominance of Th2, because of the presence of IgG, particularly IgG4, which belongs to a subclass of the type-2 immune response, and complement deposits in glomeruli. In this study, we investigated the immunoresponse of helper T cells, i.e. Th predominance in patients with idiopathic membranous nephropathy. Methods: We used flow cytometry to assess the levels of circulating Th cells in patients with idiopathic membranous nephropathy (n = 8) and in normal individuals (n = 23) based on the expression of intracellular type-1 and type-2 cytokines. Because the production of each of these cytokines has a specific time course, we observed the cytokine synthesis at 3, 6, 9 and 12 h after stimulation. Results: The percentages of IL-2+/CD4+ cells from patients with idiopathic membranous nephropathy were significantly lower than those from normal individuals at 6, 9 and 12 h, with the difference becoming more significant over time. IFN-γ+/CD4+ cells and IL-4+/CD4+ cells were not significantly different between the two groups. In patients with idiopathic membranous nephropathy, the percentages of IL-10+/CD4+ cells were significantly higher than those in normal individuals at each point in time. Conclusion: Increased IL-10-producing Th cells may lead to suppression of delayed-type hypersensitivity and activate suppressor cells and IgG4 synthesis, resulting in idiopathic membranous nephropathy.
Papillary Glioneuronal Tumour in a 4-Year-Old
Authors: Barnes Nicholas Peter , Pollock Jonathan Robert , Harding Brian , Hayward Richard David
Published: April 2003

The recently described ‘papillary glioneuronal tumour’ is not currently included in the WHO classification of tumours of the CNS. We present the youngest recorded case to date, and only the 3rd documented in the paediatric population. The incorporation of this neoplasm into the WHO classification would facilitate its wider recognition, providing an opportunity to elucidate its natural history and determine an evidence-based approach to treatment.
Neonatal Subependymal Giant Cell Astrocytoma
Authors: Medhkour Azedine , Traul David , Husain Muhammad
Published: April 2003

Subependymal giant cell astrocytoma (SEGCA) is a benign, slow-growing glial tumor that manifests with signs and symptoms of obstructive hydrocephalus most often in adolescent patients with tuberous sclerosis complex (TSC). Neonatal highly aggressive SEGCA is very rare. We report a 5-month-old child with TSC presenting with a cystic mass lesion in the left frontal lobe as well as multiple other periventricular masses. After initial conservative treatment, the child was readmitted with intractable seizures, a massive increase in the size of the left frontal lobe tumor and obstructive hydrocephalus. Despite surgical interventions, the child succumbed to the intracranial lesions. In this report, we discuss the challenges of managing SEGCA and the importance of further studies, including genetic studies, that may lead to a better understanding of its pathophysiology.
The Role of Epstein-Barr Virus in Neoplastic Transformation
Authors: Knecht Hans , Berger Christoph , Rothenberger Sylvia , Odermatt Bernhard F. , Brousset Pierre
Published: April 2003

In this review, we focus on new data from basic, translational and clinical research relating to the Epstein-Barr virus (EBV). Beside its well-known tropism for B lymphocytes and epithelial cells, EBV also infects T lymphocytes, monocytes and granulocytes. After primary infection, EBV persists throughout the life span in resting memory B cells, from where it is reactivated upon breakdown of cellular immunity. In the process of neoplastic transformation, the EBV-encoded latent membrane protein 1 (LMP1) oncogene represents the major driving force. LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor-associated factor (TRAF) family. TRAF2-mediated NF-ĸB activation, AP-1 induction and JAK3/STAT activation may result in sustained proliferation leading to lymphoma. The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin’s disease and angioimmunoblastic lymphadenopathy. The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders (PTLDs). Cytotoxic T lymphocytes directed against well-characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV-associated lymphomas, in particular PTLDs.
Single-Agent Gemcitabine Is Active in Previously Treated Metastatic Breast Cancer
Authors: Spielmann Marc , Llombart-Cussac Antonio , Kalla Salima , Espié Marc , Namer Moïse , Ferrero Jean-Marc , Diéras Véronique , Fumoleau Pierre , Cuvier Caroline , Perrocheau Geneviève , Ponzio Anne , Kayitalire Louis , Pouillart Pierre
Published: April 2003

Background: This phase II study was designed to assess the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC) previously treated with an anthracycline- or anthracenedione-containing regimen as first-line therapy for metastatic disease. Patients and Methods: Forty-seven patients with MBC were enrolled in five French centers. Patients were eligible if they had received one prior chemotherapy regimen with an anthracycline or anthracenedione for metastatic disease, if they had responded to that prior regimen, and if they had relapsed at least 6 months after the first response. Fifteen patients received more than one prior anthracycline regimen; thus, gemcitabine was third-line therapy for 30% of patients. Gemcitabine 1,200 mg/m2 was administered as a 30-min intravenous infusion on days 1, 8, and 15 of a 28-day cycle for a maximum of eight cycles after the best response was obtained. Results: Objective responses were seen in 12 of 41 assessable patients (4 complete responses and 8 partial responses), for an objective response rate of 29% (95% confidence interval, 16–46%). The median response duration was 8.1 months (range: 2.5–27.4 months). Serious hematological toxicity was minimal, with grade 4 neutropenia in 2% of the patients (no neutropenic fever), grade 3 neutropenia in 28% of the patients, and grade 3 thrombocytopenia in 6% of the patients. Among the nonhematological toxicities, asthenia was the most common. Conclusions: Gemcitabine given at this dose and schedule is a well-tolerated treatment with definitive antitumor activity in pretreated MBC patients. This result warrants future exploration of the use of gemcitabine as a single agent and in combination in patients with MBC.
Combination Gemcitabine and Docetaxel Therapy in Advanced Adenocarcinoma of the Pancreas
Authors: Sherman William H. , Fine Robert L.
Published: April 2003

Objective: To determine the clinical and laboratory response rate of a gemcitabine and docetaxel combination in human adenocarcinoma of the pancreas in vitro and in vivo. Methods: Fifteen patients with unresectable pancreatic cancer were treated with gemcitabine, 900 mg/m2, and docetaxel, 90 mg/m2, every 3 weeks. Two human pancreatic cancer lines were tested in MTT assays for their response to titrations of gemcitabine and/or docetaxel at different time points and scheduling for biochemical synergy or additional antitumor effects. Results: In vitro testing showed that these two agents were minimally effective alone but when combined, they displayed additional biochemical antiproliferative effects in MTT assays. With intent-to-treat analysis of all 15 patients, 4 patients (27%) achieved an objective response by CT scan, including one complete response. Seven patients (47%) had subjective improvement and decreased serum marker levels of CA 19-9. None of the 12 patients without prior therapy developed nadir white blood cell counts below 1,000/mm3; 2 of 3 patients with prior radiation therapy developed nadir white blood cell counts below 1,000/mm3. Conclusion: This regimen is well tolerated and appears to have a significant objective response rate. Gemcitabine and docetaxel antitumor effects are additive in vitro, which may help to explain the response rate.
Immunohistochemical Evaluation of Cadherin and Catenin Expression in Early Gastric Carcinomas: Correlation with Clinicopathologic Characteristics and Helicobacter pylori Infection
Authors: Shun Chia-Tung , Wu Ming-Shiang , Lin Min-Tsan , Chang Ming-Chu , Lin Jaw-Town , Chuang Sou-Ming
Published: April 2003

Dysfunction of E-cadherin and catenin has been linked to invasiveness and differentiation of tumors. This study aimed to characterize the expression of cadherins and catenins in early gastric carcinoma and their relationship to clinicopathologic characteristics and Helicobacter pylori infection. E-cadherin and α-, β- and γ-catenins were strongly expressed in normal epithelium but abnormal immunoreactivity of at least one of these four proteins was noted in 48 (90.6%) of 53 early gastric carcinomas. Only 5 cases with intestinal-type tumors had intact expression of E-cadherin and α-, β-, and γ-catenins. Abnormal immunoreactivity in the tumor tissue was observed in 18 patients (34.0%) for E-cadherin, in 35 (66.0%) for α-catenin, in 20 (37.7%) for β-catenin, and in 37 (69.8%) for γ-catenin. In diffuse-type tumors, abnormal expression of E-cadherin (60.9 vs. 13.3%, p < 0.0005), α-catenin (82.6 vs. 53.3%, p < 0.05) and γ-catenin (91.3 vs. 53.3%, p < 0.005) was more frequent than in the intestinal type. Ten tumors with lymph node metastasis showed a relatively higher frequency of abnormal expression of E-cadherin (70 vs. 25.6%, p < 0.05) but a lower frequency of abnormal expression of β-catenin (10 vs. 44.1%, p = 0.07) than those without metastasis. No significant association was found between cadherin/catenin expression and the depth of invasion or the H. pylori status. It was concluded that abnormal expression of E-cadherin and the catenin-mediated cell-cell adhesion system occurs frequently in early gastric carcinogenesis and may play an important role in the genesis of histologic differentiation and in the mode of metastasis of early gastric carcinomas.
Disruption of the p16/Cyclin D1/Retinoblastoma Protein Pathway in the Majority of Human Hepatocellular Carcinomas
Authors: Azechi Hidemasa , Nishida Naoshi , Fukuda Yoshihiro , Nishimura Takafumi , Minata Mutsuko , Katsuma Hirokazu , Kuno Masato , Ito Teruaki , Komeda Toshiki , Kita Ryuichi , Takahashi Rei , Nakao Kazuwa
Published: April 2003

p16, cyclin D1 and retinoblastoma protein (pRB) regulate G1 to S transition and are commonly targeted in various cancers. However, few studies have simultaneously examined all components of the p16/cyclin D1/pRB pathway (RB pathway) in hepatocellular carcinoma (HCC). To clarify the role of the disruption of the RB pathway in HCC, we analyzed p16, pRB and cyclin D1 in 47 HCCs. Inactivation of p16 was detected in 30 of 47 HCCs (64%) by Western blot analysis and significantly correlated with hypermethylation of the promoter of this gene. pRB expression was found to be absent in 13 of 47 HCCs (28%) by immunohistochemistry. We found that 38 of 47 HCCs (81%) contained at least one inactivation in either pRB or p16. Furthermore, there was a significant inverse correlation between p16 and pRB inactivation (p = 0.041). Overexpression of cyclin D1 was detected in 5 of 47 HCCs (11%) by immunohistochemistry. The cases with cyclin D1 overexpression exhibited an advanced clinicopathological appearance and also contained inactivation of pRB and/or p16. These findings suggest that inactivation of pRB and/or p16 is a major event in human hepatocarcinogenesis, while cyclin D1 overexpression may confer additional growth advantages to the tumor in addition to pRB and/or p16 inactivation in HCC.
Localization, genomic organization, and alternative transcription of a novel human SAM-dependent methyltransferase gene on chromosome 2p22→p21
Authors: Zhang Y. , Gorry M.C. , Hart P.S. , Pettenati M.J. , Wang L. , Marks J.J. , Lu X. , Hart T.C.
Published: April 2003

As part of our studies to identify the gene responsible for hereditary gingival fibromatosis, GINGF (OMIM 135300), we have identified and cloned a novel human gene that contains the highly conserved methyltransferase domain characteristic of S-adenosylmethionine-dependent methyltransferases. We localized this gene (C2orf8 encoding 288L6 SAM-methyltransferase) to chromosome 2p22→p21 by FISH, and sublocalized it to BAC RP11 288L6 flanked by D2S2238 and D2S2331. Computational analysis of aligned ESTs identified ten exons in the hypothetical C2orf8 gene. Results of RACE analyses in placenta identified multiple transcripts of this gene with heterogeneity at the 5′-UTR. Alternative transcription and tissue specific expression of C2orf8 were detected by RT-PCR and Northern blot analyses. C2orf8 is expressed in a variety of tissues including brain, colon, gingiva, heart, kidney, liver, lung, placenta, small intestine, spleen, and thymus. Open reading frame analysis of the alternative transcripts identified a shared coding region spanning exons 6–10. This ORF consists of 732 nucleotides encoding a putative 244 amino acid protein. Bioinformational searches of both C2orf8 and the putative protein product identified three methyltransferase motifs conserved across many prokaryotic and eukaryotic species. Sequence analyses of C2orf8 excluded coding region mutations as causative of GINGF.
Molecular cloning and characterization of the human NIMA-related protein kinase 3 gene (NEK3)
Authors: Kimura M. , Okano Y.
Published: April 2003

NEKs (NIMA-related kinases) are a group of protein kinases sharing high amino acid sequence identities with NIMA (never in mitosis gene a) which control mitosis in Aspergillus nidulans. We have cloned a cDNA for human NEK3, a novel human gene structurally related to NIMA, by RT-PCR. Its open reading frame encodes a protein of 489 amino acid residues with the calculated molecular mass of 56.0 kDa and a predicted pI of 6.58. Phylogenetic analysis suggests that mouse and human NEK3s constitute a subfamily within the NIMA family of protein kinases. The expression pattern of NEK3 was studied by RT-PCR and a high level of expression was detected in testis, ovary, and brain, with low-level expression being detected in most of the tissues studied. NEK3 mRNA was detected in all the proliferating cell lines studied, and the amount did not change during the cell cycle. The human NEK3 gene was assigned to human chromosome 13 by somatic cell hybrids and 13q14.2 by radiation hybrid mapping.
Prenatal Diagnosis in Rett Syndrome
Authors: Armstrong J. , Aibar E. , Pineda M. , Pérez M.M. , Geán E. , Carrera M. , Casas C. , Martínez F. , Monrós E.
Published: April 2003

Background/Aim: Rett syndrome (RTT) is an X-linked neurodevelopmental dominant disorder that affects almost exclusively girls. The disease is mainly sporadic, caused by de novo mutations at MECP2 gene (Xq28), but a low percentage of familial cases have been reported. We present the results of RTT prenatal diagnosis in three families and discuss the usefulness of such analyses in diseases caused mainly by de novo mutations. Methods: For adult individuals, DNA was extracted from peripheral lymphocytes; for fetus analysis it was obtained from cultured amniotic fluid or from chorionic biopsy specimens. Mutation detection at MECP2 gene was first carried out in the patients by SSCP/HD analysis and subsequent sequencing. Family studies and prenatal diagnoses were done by direct analysis of previously characterized patients’ mutations using SSCP/HD or restriction analysis. Results: Heterozygous mutations identified in the 3 patients were: 1061del96bp, 473C→T, and 763C→T, respectively. Mutations were not present in the mothers’ DNAs obtained from peripheral lymphocytes. None of the 3 fetuses analyzed carried the mutation of the affected sister. Conclusions: Recurrence within RTT families can be due to asymptomatic nonpenetrant carrier mothers or to parental germinal mosaicism for the MECP2 mutation. Since germline mosaicism can neither be predicted nor detected, families with 1 affected patient whose RTT-causing mutation has been previously identified can benefit from prenatal diagnosis which contributes to a decrease in the recurrence risk in a new pregnancy comparable to that of the normal population.
Multifetal Gestation – Maternal and Perinatal Outcome of 112 Pregnancies
Authors: Strauss Alexander , Paek Bettina W. , Genzel-Boroviczény Orsolya , Schulze Andreas , Janssen Udo , Hepp Hermann
Published: April 2003

Purpose: Multifetal pregnancy reduction is a widespread ‘therapy’ to diminish the risk of prematurity and adverse outcome for the survivors in higher order multiple gestation. The aim of our study was to determine the maternal and neonatal outcome of multifetal pregnancies under a conservative pregnancy management. Study Design: A retrospective review of 112 multifetal pregnancies is presented. All higher order multiple pregnancies delivered after 25 weeks of gestation and managed at a single institution between 1982 and 1999 are included. Results: Triplets, quadruplets and quintuplets were delivered at a mean gestational age of 31 + 5, 29 + 5 and 28 + 4 weeks, respectively. The perinatal mortality was 14 for triplets and 36 for quadruplets. No quintuplet died in the perinatal period. Respiratory distress syndrome occurred in 23% of triplets, 65% of quadruplets and 75% of quintuplets, intracranial hemorrhage was diagnosed in 14% of triplets, 15% of quadruplets and 10% of quintuplets and retinopathy of prematurity was found in 10% of triplets, 9% of quadruplets and 25% of quintuplets. Discussion: Despite a low neonatal mortality, morbidity of higher order multiple gestations remains significant. Mortality and morbidity are related to preterm delivery but do not exceed the rates of singletons or twins of an identical gestational age. Favorable prognostic landmarks are a gestational age >30 weeks and a number of fetuses per pregnancy ≤4. Conclusion: The risks of multifetal pregnancies are significant. Therefore, evidence-based counseling of couples seeking treatment for infertility and prevention of higher order multiple pregnancies through the prudent use of reproductive techniques attains paramount importance.