bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of SIADH Induced by Mizoribin Administration
Authors: Fujino Yoko , Inaba Masaaki , Imanishi Yasuo , Nagata Mayumi , Goto Hitoshi , Kumeda Yasuro , Nakatani Tatsuya , Ishimura Eiji , Nishizawa Yoshiki
Published: April 2003

We describe a 74-year-old man with rheumatoid arthritis (RA) who developed syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 1.5 months after commencement of mizoribin prescription when his arthritis was improved. He noticed nausea and headache and serum Na fell as low as 118 mEq/l. Normal urinary Na excretion without hypotension or hemoconcentration negated the possibility of dehydration resulting from urinary Na loss. Serum antidiuretic hormone (ADH) remained elevated at 0.59 pg/ml in spite of a significant reduction in serum osmolality to 254 mosm/kg. He had no organic disease likely to cause SIADH. Despite infusion of hypertonic saline, his serum Na was not restored to normal. Shortly after mizoribin withdrawal, his serum Na increased significantly from 128 to 139 mEq/l and plasma osmolality from 265 to 287 mosm/kg. ADH hypersecretion in relation to plasma osmolality was reversed by mizoribin withdrawal, suggesting that bredinin might adversely induce SIADH. Additional predisposing factors were the patient’s age and difficulty in urination due to benign prostatic hypertrophy. In summary, we report herein the first case of SIADH believed to be an adverse effect of mizoribin, which may therefore needed to be added to the list of drugs which can induce SIADH.
Response to Delayed Fluid Therapy in Crush Syndrome
Authors: Ensari Cüneyt , Tüfekçioglu Omaç , Ayli Deniz , Gümüs Tülin , Izdes Seval , Turanli Sacit
Published: April 2003

Background: Although early treatment is valuable in the prognosis of crush syndrome, the diagnosis and treatment of many victims are inevitably delayed in major disasters. Patients and Methods: Among the 38 victims of the Marmara earthquake with crush injury, 27 were diagnosed as crush syndrome on the basis of findings of acute renal failure. Intensive intravenous fluid treatment was started in all patients on admission. Of these 27 patients, 10 required dialysis treatment while 17 did not. The laboratory data on admission were evaluated and compared between the two groups. Results: The mean admission time of 27 patients was 46.5 ± (SE) 3.08 h. There was no significant difference between the dialysis and the nondialysis groups with regard to patient’s age, trapped time or admission time. A significantly higher number of patients had crush injury in more than one extremity in the dialysis group. The dialysis group had significantly lower systolic blood pressure, central venous pressure but a higher heart rate together with higher levels of serum urea nitrogen, creatinine, creatinine kinase, C-reactive protein, fibrinogen on admission compared to the nondialysis group. Conclusion: Our results suggest that even delayed application of aggressive specific fluid treatment under close monitoring may prevent the development of established acute renal failure.
Doxorubicin-Docetaxel Sequential Schedule: Results of Front-Line Treatment in Advanced Breast Cancer
Authors: Palmeri S. , Leonardi V. , Tamburo De Bella M. , Morabito A. , Vaglica M. , Accurso V. , Ferraù F. , Failla G. , Agostara B. , Massidda B. , Valenza R. , Fanelli M. , Gasparini G.
Published: April 2003

Objective: We conducted a multi-institutional phase II study to evaluate the tolerability and activity of a sequential schedule of treatment with doxorubicin and docetaxel in chemotherapy-naive women with advanced breast cancer. Methods: A total of 73 patients with PS (ECOG) 0–2, aged <70 years and adequate bone marrow, renal, liver and cardiac functions were included in the study (13 stage III B and 60 stage IV). The schedule of administration was doxorubicin 50 mg/m2 by intravenous (i.v.) 30 min injection on day 1 followed the day after by docetaxel 75 mg/m2, by i.v. 60 min infusion. Cycles were repeated every 28 days. Results: Overall, the median number of administered cycles was 6 (range 1–14). The most common toxicity was hematological, with 56.2% of the patients who experienced grade 3–4 neutropenia. However, febrile neutropenia occurred only in 2.8% of the cases. The median cumulative dose of doxorubicin was 350 mg/m2 (range 50–700 mg/m2). Eleven patients (15.4%) were documented to have >10% but <20% decrease in the left ventricular ejection fraction. No case of congestive heart failure was recorded. No patient experienced treatment-related death. Among the 68 evaluable patients, the overall objective response rate was 73.5% (95% confidence limits: 63–84%): 10 patients (14.7%) obtained a complete remission and 40 (58.8%) had a partial response. Only 10 patients (14.7%) experienced progressive disease. The median duration of response was 10 months (2–54+). Conclusion: This sequential treatment with doxorubicin and docetaxel is an effective, feasible and a well-tolerated regimen. The main toxicity was neutropenia. The lack of cardiotoxicity is an important advantage of such a doxorubicin-docetaxel combination and it justifies phase III comparative studies with other anthracyclines/taxanes containing schedules in both advanced and early-stage breast cancer.
Knee Extension Strength Is a Significant Determinant of Static and Dynamic Balance as Well as Quality of Life in Older Community-Dwelling Women with Osteoporosis
Authors: Carter Nick D. , Khan Karim M. , Mallinson Arthur , Janssen Patti A. , Heinonen Ari , Petit Moira A. , McKay Heather A.
Published: April 2003

Background: Determinants of balance have not been well studied in women with osteoporosis yet falls are the major cause of fracture in this population. Objective: To describe the associations among knee extension strength, medication history, medical history, physical activity and both static and dynamic balance in women diagnosed with osteoporosis. Methods: We assessed health history, current medication and quality of life by questionnaire in 97 community-dwelling women with osteoporosis. Static balance was measured by computerized dynamic posturography (Equitest), dynamic balance by timed figure-eight run, and knee extension strength by dynamometry. Results: The 97 participants (mean (SD) age 69 (3.2) years) had a mean lumbar spine BMD of T = –3.3 (0.7) and total hip BMD of –2.9 (0.4). In stepwise linear regression, the significant determinants of static balance that explained 18% of total variance were knee extension strength (10%, p < 0.001), age (5%, p < 0.01) and tobacco use (3%, p < 0.05). The significant predictors of dynamic balance were knee extension strength (26%, p < 0.001), medications (6%, p < 0.05), age (4%, p < 0.05), height (4%, p < 0.001), as well as years of estrogen use (2%), tobacco use (2%) and weight (2%) (all p < 0.05). Knee extension strength was also associated with quality of life (r2 = 0.12, p < 0.001). Based on these models, a 1 kg/cm (∼3%) increase in mean knee extension strength was associated with 1.2, 2.4 and 3.4% greater static balance, dynamic balance and quality of life, respectively. Conclusions: Knee extension strength is a significant determinant of performance on static and dynamic balance tests in 65- to 75-year-old women with osteoporosis. In this cross-sectional study, knee extension strength explained a greater proportion of the variance in balance tests than did age. Investigation into the effect of intervention to improve knee extension strength in older women with osteoporosis is warranted.
Lateralization as a Factor in the Prognosis of Middle Cerebral Artery Territorial Infarct
Authors: Aszalós Zsuzsa , Barsi Péter , Vitrai József , Nagy Zoltán
Published: April 2003

The consequences of cerebral infarcts involving the left hemisphere differ from those of the right homologue areas. Data of 337 consecutive, unselected patients with acute ischaemic stroke in the territory of the right or left middle cerebral artery were analysed. Furthermore, lesion locations of 77 stroke patients with early death were compared with those of 315 patients followed for more than 28 days. Without any differences in stroke severity and in the volume of the lesions, the outcome of strokes of the right hemisphere was less favourable, and the case fatality rate was higher than in controls during a 10-year follow-up period. The rate of early death due to cardiogenic cause was relatively higher in the right hemispherical group. The asymmetry of the sympathetic nervous system, and the distinct psychosyndromes following the injury of the two hemispheres may underlie this difference in prognosis.
Dominant Negative Mutants of Filamin A Block Cell Surface Expression of the D2 Dopamine Receptor
Authors: Lin Ridwan , Canfield Victor , Levenson Robert
Published: April 2003

Protein interaction screens have revealed an interaction between the D2 dopamine receptor and the actin cross-linking protein filamin A. However, the physiological significance of this interaction has not been explained. To better understand the role of filamin A in D2 receptor-mediated signaling, we examined the effect of disrupting filamin A/D2 receptor interaction. Overexpression of a truncated form of filamin A (repeat units 18–19 containing the D2, but not the actin, binding domain) caused a marked reduction in both the number and half-life of cell surface D2 receptors. These results suggest that disruption of the linkage between D2 receptors and the actin cytoskeleton destabilizes plasma membrane-associated D2 receptors. Several missense mutations within repeat unit 19 of filamin A were identified that abrogate filamin A/D2 receptor interaction. Introduction of mutant and wild-type filamin A into filamin A-deficient M2 cells demonstrated that wild-type filamin A, but not the filamin A-binding mutants, was able to promote cell-surface expression of D2 receptors. Together, these studies provide evidence that filamin A/D2 receptor interaction is required for the proper targeting or stabilization of D2 dopamine receptors at the plasma membrane.
Severe Hypoxia Inhibits Prostaglandin I2 Biosynthesis and Vasodilatory Responses Induced by Ionophore A23187 in the Isolated Rabbit Ear
Authors: Juránek Ivo , Bauer Viktor , Donnerer Josef , Lembeck Fred , Peskar Bernhard A.
Published: April 2003

The present study was designed to test the hypothesis that lack of oxygen in severely hypoxic tissue may inhibit arachidonic acid oxygenation and thereby result in an inhibition of eicosanoid synthesis. Hypoxia was induced in the isolated rabbit ear, and arachidonate metabolism and peripheral resistance of the preparation were monitored simultaneously. Severe hypoxia completely inhibited the biosynthesis of prostaglandin I2 induced by ionophore A23187 and converted the vasodilatory response observed under normoxia into vasoconstriction. The cyclooxygenase 1 inhibitor SC560 (1 µmol/l) effectively inhibited the normoxic prostaglandin I2 biosynthesis, while the cyclooxygenase 2 inhibitor DFU (1 µmol/l) did not. Neither SC560 nor DFU affected normoxic vasodilatory responses, indicating no involvement of prostanoids. The nitric oxide (synthase inhibitor Nω-nitro-L-arginine methyl ester (100 µmol/l) converted the vasodilation into vasoconstriction, similar to what was observed under hypoxia, suggesting that the hypoxia-mediated conversion might occur due to the inhibition of nitric oxide.
Vascular Function in Women with Previous Gestational Diabetes mellitus
Authors: Hannemann Michael M. , Liddell William G. , Shore Angela C. , Clark Penny M. , Tooke John E.
Published: April 2003

It is hypothesised that vascular dysfunction, which characterises type 2 diabetes, may predate development of hyperglycaemia. 17 women with previous gestational diabetes mellitus, and thus at risk of developing type 2 diabetes, were matched with normal controls for body mass index, menstrual phase, smoking, age, blood pressure, and lipid profiles. All had normal glucose tolerance. Tests of microvascular and macrovascular function, including endothelium-dependent and -independent vasodilatation, were performed. Laser Doppler fluximetry of maximum skin microvascular hyperaemia in response to local heating of the dorsum of the foot to 42°C for 30 min was impaired in subjects compared to controls [subjects = 1.15 (0.73–1.73) V median (range) versus controls = 1.50 (0.95–2.29) V, p = 0.008]. There were no differences in laser Doppler perfusion imaging of responses to forearm skin iontophoresis of acetylcholine [subjects = 1.59 (0.32–2.55) V median (range) versus controls = 1.79 (0.72–2.06) V; p = 0.81] and sodium nitroprusside [subjects = 1.39 (0.8–3.14) V versus controls = 1.41 (0.34–2.19) V; p = 0.68], ultrasound estimation of brachial artery flow-mediated dilatation [subjects = 1.65 (–0.5–9.07)% versus controls = 2.77 (0.63–6.6)%; p = 0.42] and glyceryl trinitrate-induced dilatation [subjects = 15.20 (6.64–20.91)% versus controls = 15.92 (3.94–22.09)%; p = 0.48]. Microvascular maximum hyperaemia was impaired in the index group, suggesting the presence of a defect in vascular function. This defect was not explained by those aspects of endothelial function measured by the other techniques.
Cutaneous Electrical Stimulation of Acupuncture Points May Enhance Gastric Myoelectrical Regularity
Authors: Chang Chi-Sen , Chou Jen-Wei , Ko Chung-Wang , Wu Chun-Ying , Chen Gran-Hum
Published: April 2003

Background/Aim: Cutaneous electrical stimulation has been reported to be as effective as electroacupuncture. The aim of this study was to test whether cutaneous electrical stimulation had the same effect as electroacupuncture to enhance the regularity of myoelectrical activity. Methods: Fifteen healthy male volunteers were enrolled for this study. Electrogastrography (EGG) was performed for 30 min at the baseline, 30 min during electroacupuncture or cutaneous electrical stimulation, and for an additional 30 min thereafter. Results: During 3 Hz of electroacupuncture on the Zusanli point, there was a significant increase in the percentage of normal frequency. The percentage of normal frequency in the post-acupuncture period was also increased, but it was not statistically significant when compared to the baseline. There was a significant decrease in the tachygastric and bradygastric rhythm during electroacupuncture on the Zusanli points. There were similar changes of EGG parameters with cutaneous electrical stimulation on the Zusanli points. The percentage of normal frequency during cutaneous electrical stimulation increased significantly. However, the percentage of normal frequency in the post-cutaneous electrical stimulation period was similar to the baseline. There was a significant decrease in the percentage of tachygastric rhythm during cutaneous electrical stimulation on the Zusanli points. However, there was no significant change in the percentage of bradygastric rhythm during and after the cutaneous electrical stimulation periods. Conclusions: The effect of cutaneous electrical stimulation on the percentage of normal frequency and tachygastria is similar to electroacupuncture. Nonetheless, the changes of the percentage in bradygastria are not significant.
Frequency and Nature of Spontaneous Age-Related Eye Lesions Observed in a 2-Year Inhalation Toxicity Study in Rats
Authors: Wegener A. , Kaegler M. , Stinn W.
Published: April 2003

A group of 160 Wistar rats (both sexes) from a larger chronic inhalation toxicity study was monitored at baseline and after 1 and 2 years with a photo-slitlamp microscope and a direct ophthalmoscope to record spontaneous age-related eye lesions and treatment-related eye lesions over a period of 24 months. A second group from the same study was monitored at the start and after 5 months of a 6-month posttreatment period immediately following the inhalation period. Rats were nose-only exposed for 6 h/day, 7 days/week, for 2 years to low (3 µg/l) or high (10 µg/l) total particulate matter concentrations of room-aged cigarette sidestream smoke (RASS) or diesel engine exhaust (DEE). Control animals were exposed to filtered fresh air. All ophthalmological examinations were performed in mydriasis, and relevant observations were documented on color slide film. At baseline, all animals with eye lesions were excluded from the study. After 1 year, only minor lesions were found: retrolental opacities (14%) and a few cases of corneal dryness with reddish lid margins. After 2 years, 23% of the animals had unilateral or bilateral retrolental opacities, but the most frequent eye lesions were posterior subcapsular cataracts (PSC, 32%). Water clefts and spokes were found in 11% of the lenses and mature cataracts in 6%. All other eye lesions observed were much less frequent. There were a few cases of glaucoma, corneal dryness and stromal neovascularization. The frequency and type of lesion in animals monitored from the start of the posttreatment period was comparable to what was seen after 2 years. Toward the end of this period the frequency of mature cataracts went up to 9% and that of (secondary) glaucomas to 5%. None of the eye lesions observed showed any association in frequency or severity of expression to the treatment, either RASS or DEE, or to the sex of the animals. In comparison to the (limited) literature data available, far fewer corneal lesions were found in this study, but PSCs and mature cataracts were more frequent. Strain differences may influence these parameters. This study provided valuable information on the nature and frequency of spontaneous age-related eye lesions (0–56%, depending on the tissue) in long-term toxicity studies in Wistar rats.
Four Novel Mutations in the PITX2 Gene in Patients with Axenfeld-Rieger Syndrome
Authors: Phillips Jeffrey C.
Published: April 2003

Mutational screening and sequence analysis of the PITX2 gene was performed in four families previously diagnosed with Rieger syndrome. The results of this analysis identified four novel mutations within the coding sequence of PITX2. These mutations were not identified in the sequence of 50 control individuals. Two mutations were found in the homeobox and would be expected to result in nonconservative amino acid changes within the second and third helixes. The remaining two mutations were found in the region downstream of the homeobox and are also predicted to result in missense mutations. In conclusion, mutations within the homeobox sequence and the adjacent coding sequence of PITX2 lead to various Rieger syndrome phenotypes characterized by a high incidence of glaucoma.
Gene Therapy for Sarcoma
Authors: Fruehauf S. , Veldwijk M.R. , Berlinghoff S. , Basara N. , Baum C. , Flasshove M. , Hegewisch-Becker S. , Kröger N. , Licht T. , Moritz T. , Hengge U.R. , Zeller W. Jens , Laufs S.
Published: April 2003

Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy. To test this concept of supportive gene therapy in advance of a clinical study, we transduced mobilized peripheral blood progenitor cells (PBPC) with the retroviral vector SF91m3 containing the human MDR1 gene, transplanted these cells to immune-deficient mice, allowed 6 weeks for engraftment to occur and treated the animals with MDR1-based chemotherapy. In the MDR1-transduced group the human leukocytes were significantly protected from the toxicity of chemotherapy (p < 0.05). While the gene transfer rate was in the range of 10% and thus comparable to recent clinical trials, the gene expression was 59% of transduced cells and thus significantly higher than previously reported for less-advanced vectors. On the other hand, ifosfamide, a drug which has been used successfully for stem cell mobilization, is active in soft tissue sarcoma. Due to these favorable characteristics sarcoma is an attractive target to test the efficacy of MDR1 gene therapy in a clinical setting. Gene therapeutic strategies may also be used to directly target sarcoma cells, e.g. by transfer of suicide genes. We found that adenoassociated virus 2 (AAV-2) vectors efficiently transduce human HS-1 and HT1080 sarcoma cells (>90%) while other tumor cell lines and primary human PBPC were less susceptible. The thymidine kinase (TK) suicide gene was cloned into an AAV-2 vector and a complete kill of TK-transduced HS-1 and HT1080 cells was observed following exposure to aciclovir or ganciclovir (GCV), while >90% of mock-transduced HS-1 cells survived at these dosages. Transplantation of those sarcoma cells to nonobese diabetic (NOD)/LtSz-severe-combined immunodeficient (scid)/scid (NOD/SCID) mice resulted in a survival of >5 months in the AAV-TK-transduced/GCV-treated group, while the mice in the mock-transduced/GCV-treated group had died after 3 weeks. These data show that soft tissue sarcomas are a particularly suitable model system for the development and clinical testing of new gene therapeutic concepts.
Effect of Bremazocine, a Kappa-Opioid Receptor Agonist, on Inositol Phosphate Formation in Isolated Iris-Ciliary Bodies
Authors: Dortch-Carnes Juanita , Potter David E.
Published: April 2003

The goal of the current study was to examine the effect of the kappa-opioid agonist, bremazocine (BRE), on inositol phosphate (IP) formation in the rabbit iris-ciliary body (ICB). Concentrations of BRE (10–7 to 10–5M) augmented levels of IP. Incubation of ICBs with BRE (10–6M) produced a time-dependent increase in IP levels that peaked at 60 s and declined to basal levels by 5 min. The increase in IP levels produced by BRE (10–6M) was inhibited by the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI, 10–7 to 10–5M) and by activation of PKC with PDBu (10–7M). These results demonstrate that kappa-opioid receptor activation by BRE in the rabbit ICB is linked to IP production. Thus, opioid agonist-induced increases in IP activity could play a role in BRE-induced increases in atrial natriuretic peptide release and alterations in aqueous humor dynamics.
Epidemiology of Myasthenia gravis: A Population-Based Study in Stockholm, Sweden
Authors: Kalb B. , Matell G. , Pirskanen R. , Lambe M.
Published: April 2003

A regional database of myasthenia gravis (MG) patients was used to estimate the prevalence and selected characteristics of the disease in the county of Stockholm, Sweden. The prevalence of MG was 14.1/100,000 (17.1 for women and 10.8 for men). The mean age at onset for women and men was 34.9 and 48.5 years, respectively. About 60% of patients were diagnosed within the first year after initial symptoms. Generalized MG was found in 79% of patients, and 10% had severe symptoms. Almost two thirds of the patients had undergone thymectomy, and 30% needed immunosuppressive treatment. The increase in the prevalence of MG since the 1960s probably reflects an improvement in prognosis and higher detection rates of patients with milder symptoms. A delay in diagnosis indicates that early signs and symptoms of MG are still not well known by all doctors.
Prevalence of Multiple Sclerosis in Austria
Authors: Baumhackl U. , Eibl G. , Ganzinger U. , Hartung H.P. , Mamoli B. , Pfeiffer K.P. , Fazekas F. , Vass K.
Published: April 2003

The epidemiology of multiple sclerosis (MS) in Austria is almost unknown. We evaluated the prevalence of MS in Austria using data from questionnaires completed by neurologists, comprising information on a total of 1,006 MS patients who attended 30 out-patient specialized clinics nationwide. Additional data were collected from 2,414 MS patients, who received questionnaires from the Austrian MS Society or their doctor. A novel extrapolation model, based on frequencies of patients visits at MS clinics, was used to estimate the overall prevalence of MS. Considering either disability or the course of the disease, the prevalence of MS patients in Austria was estimated to be 98.5 per 100,000 people. The prevalence of MS in Austria was found to be similar to that of other countries in Central Europe. Epidemiological studies, such as this, provide a unique source of data from which key features of a disease and its impact on patients may be examined.
Annualized Incidence and Spectrum of Illness from an Outbreak Investigation of Bell’s Palsy
Authors: Morris Andrew M. , Deeks Shelley L. , Hill Michael D. , Midroni Gyl , Goldstein Warren C. , Mazzulli Tony , Davidson Ross , Squires Susan G. , Marrie Thomas , McGeer Allison , Low Donald E.
Published: April 2003

Background: There are limited clinical and epidemiological data on patients diagnosed with Bell’s palsy. While investigating an apparent clustering of Bell’s palsy, we sought to characterize the spectrum of illness in patients with this diagnosis. Methods: A telephone survey of persons with idiopathic facial (Bell’s) palsy in the Greater Toronto Area (GTA, population = 4.99 million) and Nova Scotia (population = 0.93 million) from August 1 to November 15, 1997 collected information on subject demographics, neurological symptoms, constitutional symptoms, medical investigation and management. Information regarding potential risks for exposure to infectious agents, past medical history, and family history of Bell’s palsy was also collected. Subjects with other secondary causes of facial palsy were excluded. Results: In the GTA and Nova Scotia, 222 and 36 patients were diagnosed with idiopathic facial (Bell’s) palsy, respectively. The crude annualized incidence of Bell’s palsy was 15.2 and 13.1 per 100,000 population in the GTA and Nova Scotia, respectively. There was no temporal or geographical clustering, and symptomatology did not differ significantly between the two samples. The mean age was 45 years, with 55% of subjects being female. The most common symptoms accompanying Bell’s palsy were increased tearing (63%), pain in or around the ear (63%), and taste abnormalities (52%). A significant number of patients reported neurological symptoms not attributable to the facial nerve. Conclusion: No clustering of cases of Bell’s palsy was observed to support an infectious etiology for the condition. Misdiagnosis of the etiology of facial weakness is common. Patients diagnosed with Bell’s palsy have a variety of neurological symptoms, many of which cannot be attributed to a facial nerve disorder.
Cognitive Functions and Depression as Predictors of Poor Outcome 15 Months after Stroke
Authors: Pohjasvaara T. , Vataja R. , Leppävuori A. , Kaste M. , Erkinjuntti T.
Published: April 2003

The prognostic predictors of poor outcome, as defined by death between 3 and 15 months and dependent living at 15 months, were examined in the Helsinki Stroke Aging Memory (SAM) study cohort. Death between 3 and 15 months was registered from the whole study group of 486 consecutive patients aged 55–85 years. Altogether 286 of the 486 patients went through a detailed follow-up examination both 3 and 15 months after stroke, including structured measures of emotion (Beck’s Depression Inventory, BDI), cognition (Mini-Mental State Examination, MMSE), dementia assessment according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and handicap (Rankin scale, RS). The only independent correlate of death between 3 and 15 months was dependent living at 3 months (OR 2.6, 95% CI 1.2–5.8), which also had the most powerful association with dependent living at 15 months (OR 5.8, 95% CI 2.6–13.1). Also, both worsening in cognition (change in MMSE, OR for each point of worsening 1.2, 95% CI 1.1–1.3) and worsening of depression (change in BDI, OR for each point of worsening 1.1, 95% CI 1.02–1.12), between 3 and 15 months follow-up, had an independent effect on dependent living 15 months after ischemic stroke. This challenges the care and rehabilitation of these items even at the stable period after stroke.
Atherothrombotic Risk Factors in Subjects with a Family History of Stroke
Authors: Lansbury Alastair J. , Grant Peter J. , Catto Andrew J.
Published: April 2003

Background: Subjects with stroke in a first-degree relative are at increased risk of atherothrombotic vascular disease. We aimed to examine atherothrombotic risk factors in such a population. Methods: 145 subjects with a first-degree relative with stroke and 143 controls were recruited. Measurements were made of features of the insulin resistance syndrome, haemostatic and fibrinolytic risk factors, and glucose tolerance tests. Results: The relatives had higher systolic blood pressure, HDL, 2-hour glucose, factor VII:C, fibrinogen, vWF and more had smoked. Differences remained in factor VII:C, systolic BP and 2-hour glucose after adjustment. Conclusions: This population demonstrates adverse thrombotic risk factors and increased FVII:C activity may contribute to increased cardiovascular risk.
Characteristics of Elderly People Readmitted to the Hospital during the First Year after Stroke
Authors: Claesson Lisbeth , Gosman-Hedström Gunilla , Lundgren-Lindquist Birgitta , Fagerberg Björn , Blomstrand Christian
Published: April 2003

Background and Purpose: Readmissions after acute stroke vary over time and with age and comorbidity. Knowledge of the reasons for readmissions and characteristics of readmitted patients is sparse. This 1-year prospective study examined whether readmissions were related to severity of the index stroke or to comorbidity and explored outcomes in readmitted patients with respect to daily life activities and health-related quality of life. Methods: The study included 216 elderly patients (aged ≧70 years) discharged to their homes or a nursing home after index stroke. The main outcomes were readmission rates and reported diagnoses, performance of daily life activities and health-related quality of life. Results: Nearly half (45%) of the patients were readmitted to the hospital after being discharged to their homes. One readmission was most common, and stroke-related diagnoses were most frequently reported as the reason for readmission. Different forms of heart disease were the next most common reason. The readmitted patients were significantly more dependent in daily life activities, and health-related quality of life was significantly lower among this group. Conclusions: Recurrent stroke and sequelae after stroke were major factors behind readmissions, followed by heart disease in elderly stroke patients. The readmitted patients were more dependent in daily life activities and reported a lower health-related quality of life compared with not readmitted patients.
Role of Porphyrin Sequestration in the Biogenesis of Iron-Laden Astrocytic Inclusions in Primary Culture
Authors: Schipper H.M. , Small L. , Wang X. , Brawer J.R.
Published: April 2003

Astrocytes in subcortical regions of the mammalian brain progressively accumulate iron-rich, autofluorecent cytoplasmic inclusions as a function of aging. Cysteamine (CSH) accelerates the appearance of this senescent glial phenotype in situ and in primary rat astroglial cultures. Porphyrins have been implicated as the source of orange-red autofluorescence in these glial inclusions. Yet, CSH has been shown to suppress porphyrin-heme biosynthesis in cultured astroglia. To determine whether porphyrin biosynthesis or sequestration participates in the biogenesis of these glial inclusions, the porphyrin precursor, 3H-δ-aminolevulinic acid (3H-ALA) was administered to CSH-exposed and control rat astroglial cultures followed by light and electron microscopic autoradiography. Control cultures exhibited faint orange-red autofluorescence, intense 3H-ALA labeling, numerous normal mitochondria and few cytoplasmic inclusions. In these cells, 3H-ALA labeling largely occurred over normal mitochondria. The CSH-treated astroglia exhibited diminished 3H-ALA labeling and contained numerous orange-red autofluorescent inclusions. The latter manifested internal compartments delimited by double membranes characteristic of damaged mitochondria. The complement of normal mitochondria in the CSH-exposed cells was markedly reduced. In the CSH-treated cells, 3H-ALA labeling predominated over the large multi-compartmental inclusions. CSH attenuates de novo porphyrin-heme biosynthesis in astroglia but may induce punctate orange-red autofluorescence in the cytoplasm of these cells by promoting large numbers of damaged, porphyrin-containing mitochondria to form tight aggregates within the nascent gliosomes.
Transferrin Regulates Transcription of the MBP Gene and Its Action Synergizes with IGF-1 to Enhance Myelinogenesis in the md Rat
Authors: Espinosa-Jeffrey A. , Kumar S. , Zhao P.M. , Awosika O. , Agbo C. , Huang A. , Chang R. , de Vellis J.
Published: April 2003

Myelin-deficient (md) rats and their unaffected littermates were injected at postnatal day 4 either with a single dose of transferrin (Tf) or insulin-like growth factor one (IGF-1) singly or combined. Two weeks later, their brains were perfused and coronal sections were analyzed for MBP by in situ hybridization and for transferrin and myelin basic protein (Tf and MBP) by double immunofluorescence. Each of the factors separately had an effect on mutant animals as seen by both increased OL maturation, and MBP mRNA and protein synthesis. The combination of factors resulted in a profound enhancement of the myelinogenic properties of oligodendrocytes (OL) with a consequent increase in the number of MBP-labeled fibers. The brains of unaffected littermates also responded to growth factor(s) injection either by increasing myelination in some brain areas or by regulating the synthesis of MBP in OL. Using rat OL cultures we studied the site of transferrin action for the expression of MBP gene. We found by run off transcription that the MBP mRNA was significantly increased at the nuclear level but the PLP message was unaffected. Thus, transferrin selectively regulates MBP at the transcriptional level and together with IGF-1 synergizes to increase both the maturation and myelinogenic properties of md and normal OL.
Mechanism and Developmental Changes in Iron Transport across the Blood-Brain Barrier
Authors: Morgan Evan H. , Moos Torben
Published: April 2003

Transferrin and iron uptake by the brain were measured using [59Fe-125I]transferrin injected intravenously in rats aged from 15 days to 22 weeks. The values for both decreased with age. In rats aged 18 and 70 days the uptake was measured at short time intervals after the injection. When expressed as the volume of distribution (Vd), which represents the volume of plasma from which the transferrin and iron were derived, the results for iron were greater than those of transferrin as early as 7 min after injection and the difference increased rapidly with time, especially in the younger animals. A very similar time course was found for uptake by bone marrow (femurs) where iron uptake involves receptor-mediated endocytosis of Fe-transferrin, release of iron in the cell and recycling of apo-transferrin to the blood. It is concluded that, during transport of transferrin-bound plasma iron into the brain, a similar process occurs in brain capillary endothelial cells (BCECs) and that transcytosis of transferrin into the brain interstitium is only a minor pathway. Also, the high rate of iron transport into the brain in young animals, when iron requirements are high due to rapid growth of the brain, is a consequence of the level of expression and rate of recycling of transferrin receptors on BCECs. As the animal and brain mature both decrease.
Deferoxamine Attenuates Iron-Induced Oxidative Stress and Prevents Mitochondrial Aggregation and α-Synuclein Translocation in SK-N-SH Cells in Culture
Authors: Sangchot P. , Sharma S. , Chetsawang B. , Porter J. , Govitrapong P. , Ebadi M.
Published: April 2003

One of the defining characteristics of neurodegenerative diseases, including Parkinson’s disease, is an abnormal accumulation of iron in the affected brain areas. By using SK-N-SH, a dopaminergic cell line, we have found that iron (100–250 µM FeSO4) decreased cell viability, increased lipid peroxidation, and the said effects were blocked by deferoxamine (DFO: 10 µM). Furthermore, DFO, in the absence of iron, enhanced the level of adenosine triphosphate (ATP), but caused chromatin condensation and cell death. Morphological studies revealed that iron (50–100 µM) altered mitochondrial morphology, disrupted nuclear membrane, and translocated α-synuclein from perinuclear region into the disrupted nucleus. The results of these studies suggest that DFO is able to block and attenuate iron-mediated oxidative stress. However, in the absence of excess iron, DFO itself may have deleterious effects on the morphology and hence integrity of dopaminergic neurons.
A Morphological Study of the Developmentally Regulated Transport of Iron into the Brain
Authors: Moos Torben , Morgan Evan H.
Published: April 2003

The distribution of transferrin, transferrin receptor, ferritin and ferric iron was studied in the developing rat brain. Transferrin immunoreactivity (IR) was observed diffusely in the brain from E16 until P10 from where it gradually decreased. The subcellular distribution of transferrin-IR in neurons was compatible with receptor-mediated uptake from P21 and onwards. Transferrin receptor-IR was observed prenatally on cells of neuroectodermal origin in the ventricular zone and in brain capillary endothelial cells (BCECs). In postnatal rats, transferrin receptor-IR in BCECs was most pronounced in rats aged P10–P21 but thereafter decreased in intensity. The neuronal transferrin-receptor IR in postnatal brains was not consistently expressed on neurons until from P21 and onwards. Transferrin receptor-IR was not observed in astrocytes, oligodendrocytes or ramified microglial cells at any age. Ferric iron and ferritin were present in BCECs already from E16, declined from P3–P5, and was absent by P10. There results are discussed with emphasis on the age-dependent transport of transferrin into the developing brain. The upregulated expression of transferrin receptors on BCECs in the second and third postnatal week is compatible with a high need for iron at this age. The neuronal transferrin receptor expression by P21 coincides with a drop in transferrin-IR and iron transport into the brain at this age, suggesting that neuronal transferrin receptor mRNA is posttranscriptionally regulated by the lowered iron availability from this developmental stage onwards.
Participation of the Intestinal Layers in Supplying of the Mechanical Strength of the Intact and Sutured Gut
Authors: Egorov V.I. , Schastlivtsev V. , Turusov R.A. , Baranov A.O.
Published: April 2003

The tensile properties of the intact and sutured human intestine were examined using Instron 1122 tensimeter on 471 cadaveric and 98 surgically removed specimens. By a constant strain rate method two maxima curves were received, which permit examination of the intestinal wall as a multi-layered structure. Repeatable results were generated for cadaveric and surgically removed intestines, whose mechanical properties were similar under certain storage conditions. The mechanical properties of intact intestine in axial and transversal directions were different. The mechanical strength of the intact intestinal wall was conditioned by the submucosa and muscularis, while the serosa and mucosa showed no significant strength. Comparison of axial specimens’ mechanical properties of the intact intestinal wall and intestinal wall with all layers sutured through determined that only the submucosa supplies mechanical strength to anastomosis. Other layers contribute no significant force to anastomotic strength. The strength applied to thread during knot tying does not change the participation of the intestinal layers in supplying suture-holding capacity for 8 and 12 mm stitch depth. It was shown graphically why sutures that don’t stitch onto the submucosa are unreliable.
Neoadjuvant Chemotherapy with Sequential Methotrexate and 5-Fluorouracil Scheduling, Epirubicin and Cisplatin for Locally Advanced Bladder Cancer
Authors: Nishiyama Tsutomu , Tanikawa Toshiki , Tomita Yoshihiko , Takahasi Kota
Published: April 2003

Introduction: Transitional cell carcinoma of the bladder is moderately sensitive to chemotherapy. Notably, the methotrexate, doxorubicin, vinblastine and cisplatin regimen was found to produce a high overall response rate and a modest survival advantage. However, toxicity was significant and the therapy rarely results in long-term disease-free survival. In several clinical series, sequentially delivered methotrexate and 5-fluorouracil followed by leucovorin rescue in expectation of a biochemical modulation has a higher response rate. Methods: The combination chemotherapy using sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin (MFAP regimen) for locally advanced bladder cancer was evaluated in a neoadjuvant setting. Thirty-seven patients (32 males and 5 females) were enrolled in this study. Results: Six (16.2%) of the patients had complete responses and 26 (70.3%) had partial responses to the therapy amounting to a response rate of 86.5%. At follow-up, 10 of 13 patients (76.9%) who underwent bladder preservation had not developed muscle-invasive recurrence of the disease and kept their bladder. There is no statistical difference of the survival rate between the cystectomy group and the bladder preservation group (p = 0.86). Toxicity was relatively mild but with some severe myelotoxic effects. Conclusions: MFAP represents an active regimen in the treatment of locally advanced bladder cancer with a moderate toxicity profile.
Irinotecan (CPT-11) and Cisplatin as First-Line Chemotherapy for Advanced Ovarian Cancer
Authors: Sugiyama Toru , Yakushiji Michiaki , Kamura Toshiharu , Ikeda Masanori , Umesaki Naohiko , Hasegawa Kazuo , Ishikawa Mutsuo , Saji Fumitaka , Hiura Masamichi , Takahashi Takeshi , Sato Shinji , Ochiai Kazunori , Kikkawa Fumitaka , Takeuchi Shoshichi , Ohashi Yasuo , Noda Kiichiro
Published: April 2003

Objective: To evaluate the efficacy and toxicity of a combination of irinotecan (CPT-11) and cisplatin as first-line chemotherapy in advanced ovarian cancer. Methods: Twenty-six patients with previously untreated advanced epithelial ovarian cancer were enrolled in this study. CPT-11 60 mg/m2 was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 on day 1. Cycles were repeated every 28 days for at least two cycles. The median patient age was 55 years (range, 37–75), and the median performance status was 1. Results: Objective responses were recorded in 19 of 25 eligible patients (76%; 95% confidence interval, 55–91%). Complete responses were obtained in 2 patients (8%), and partial response in 17 patients (68%). Stable disease was recorded in 2 patients (8%) and progressive disease in 2 (8%). The median time to response was 62 days (range, 28–234 days). The median survival time for all 25 patients was 30.9+ months (range, 4.1–60.0+ months). The major toxic effects were leukopenia, neutropenia, and diarrhea. Grade 3 or 4 leukopenia, neutropenia, and diarrhea occurred in 17 (68%), 20 (83.3%), and 5 patients (20%), respectively. Thrombocytopenia was less common. No treatment-related deaths occurred. Conclusion: The combination of CPT-11 and cisplatin showed significant activity in chemotherapy-naive patients with advanced ovarian cancer. Neutropenia was the dose-limiting adverse effect, whereas diarrhea was mainly mild to moderate.
Multicenter Phase I Study of Irinotecan plus Raltitrexed in Patients with 5-Fluorouracil-Refractory Advanced Colorectal Cancer
Authors: Aparicio Jorge , de las Peñas Ramón , Vicent José María , Garcerá Salvador , Llorca Cristina , Maestu Inmaculada , Yuste Ana L. , Farrés Jordi
Published: April 2003

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250–350 mg/m2 as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m2 as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3–4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m2) and raltitrexed (3 mg/m2) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.
High Level of Vascular Endothelial Growth Factor in Hemorrhagic Pleural Effusion of Cancer
Authors: Ishimoto Osamu , Saijo Yasuo , Narumi Ko , Kimura Yuichiro , Ebina Masahito , Matsubara Nobumichi , Asou Noboru , Nakai Yushi , Nukiwa Toshihiro
Published: April 2003

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.