bluuebunny/crossref_metadata_2025 huggingface dataset:
38 Long‐term Follow‐up of Renal Transplant Artery Stenosis: Case Controlled Study
Authors: Župunski A , Kandus A , Buturović‐Ponikvar J
Published: February 2005

Background  Renal transplant artery stenosis is relatively frequent. It can cause hypertension, deterioration of renal function or graft loss. It seems that it can be treated conservatively provided graft perfusion is not jeopardized. The aim of our retrospective clinical study was to assess a long‐term course of renal transplant artery stenosis by duplex‐Doppler and its influence upon serum creatinine, hemoglobin concentration, and hypertension, as well as to investigate possible association between stenosis and the number of acute rejections.

Methods  Thirty‐four renal transplant recipients, aged 43 ± 13 years, with significant (>50%) renal transplant artery stenosis on Doppler were compared with 34 renal transplant recipients, in whom stenosis was excluded on Doppler; patients of both groups were matched by age, sex, time of transplantation, type of renal transplant and number of previous transplantations. We analyzed peak systolic velocity in renal transplant artery, resistance index at the level of intrarenal arteries, serum creatinine, hemoglobin concentration, blood pressure, number of antihypertensive medications, and number of acute rejections on a yearly basis.

Results  In the stenosis group, peak systolic velocity was 2.1 ± 0.5 m/s at 1 year after transplantation (controls 1.1 ± 0.4 m/s), 1.9 ± 0.5 m/s at 2 years (0.9 ± 0.4 m/s), 1.9 ± 0.5 m/s at 3 years (0.9 ± 0.4 m/s); resistance index was 62 ± 10% at 1 year (controls 68 ± 7%), 65 ± 9% at 2 years (67 ± 7%), 63 ± 9% at 3 years (67 ± 7); serum creatinine was 128 ± 58 µmol/L at 1 year (controls 129 ± 43 µmol/L), 119 ± 47 µmol/L at 2 years (121 ± 33 µmol/L), 125 ± 54 µmol/L at 3 years (127 ± 32).

Conclusion  Long‐term course of renal transplant artery stenosis (>50%), treated medically or interventionally, seems to be stable and nonprogressive (during 3‐year follow‐up). Spontaneous regression of stenosis to nonsignificant level is possible. No significant difference in graft function, blood pressure, or the number of acute rejections was observed when comparing the stenotic and nonstenotic group.
50 Twenty‐four‐hour Ambulatory Blood Pressure Monitoring in Healthy Infants
Authors: Varda N Marčun , Gregorič A
Published: February 2005

Objectives  Ambulatory blood pressure monitoring (ABPM) has been increasingly used in the assessment of elevated blood pressure (BP) in adults as well as in children. Normal ABPM reference values for school children have been published. However, there is little reported experience with this method in children under the age of 6 years, especially in infants. The aim of our study was to investigate the feasibility of ABPM in healthy infants.

Design and methods  Ambulatory blood pressure monitoring recordings were performed in 97 infants with no history of disease or drugs affecting BP. The medical history was taken and gender, age, height, and weight were recorded. A minimum of 22 hours of recording time and at least 40 recordings were required. An accurate oscillometric device (SpaceLabs 90207) was used in all infants with an appropriate cuff, attached to the non‐dominant arm. Measurements were performed every 20 minutes during the day and every 30 minutes during the night.

Results  Ninety‐seven infants, aged from 2 to 30 months (mean 13 ± 3 months), were included. A satisfactory ABPM profile was obtained in 84 (86.7%) infants. In five infants the number of recordings was < 40, while in eight infants the recording time was too short. There were, on average, 54 (75.4%) satisfactory recordings. The mean ± SD systolic and diastolic BP was 100 ± 6/63 ± 5 mmHg during the day‐time and 96 ± 5/58 ± 4 mmHg at night. The height of the infants ranged from 57 to 95 cm (mean 75 ± 2 cm). The infants were divided into four groups according to height. The mean systolic and diastolic values showed a slight, but significant increase with body height. The day to night decline of the mean systolic BP was 3.0 to 6.0% and the mean diastolic fall was 3.4 to 10.6% in the different height groups.

Conclusions  Ambulatory blood pressure monitoring is a useful tool for the assessment of BP in very young children. The method was well tolerated and the measurements were technically acceptable. We confirmed the increase in BP with body height and the nocturnal decrease in BP. To obtain normal data for ABPM for this age group a much larger number of infants are needed.
Treatment of Depression Improves Physical Functioning in Older Adults
Authors: Callahan Christopher M. , Kroenke Kurt , Counsell Steven R. , Hendrie Hugh C. , Perkins Anthony J. , Katon Wayne , Noel Polly Hitchcock , Harpole Linda , Hunkeler Enid M. , Unützer Jürgen ,   for the IMPACT Investigators
Published: February 2005

Objectives: To determine the effect of collaborative care management for depression on physical functioning in older adults.

Design: Multisite randomized clinical trial.

Setting: Eighteen primary care clinics from eight healthcare organizations.

Participants: One thousand eight hundred one patients aged 60 and older with major depressive disorder.

Intervention: Patients were randomized to the Improving Mood: Promoting Access to Collaborative Treatment (IMPACT) intervention (n=906) or to a control group receiving usual care (n=895). Control patients had access to all health services available as part of usual care. Intervention patients had access for 12 months to a depression clinical specialist who coordinated depression care with their primary care physician.

Measurements: The 12‐item short form Physical Component Summary (PCS) score (range 0–100) and instrumental activities of daily living (IADLs) (range 0–7).

Results: The mean patient age was 71.2, 65% were women, and 77% were white. At baseline, the mean PCS was 40.2, and the mean number of IADL dependencies was 0.7; 45% of participants rated their health as fair or poor. Intervention patients experienced significantly better physical functioning at 1 year than usual‐care patients as measured using between‐group differences on the PCS of 1.71 (95% confidence interval (CI)=0.96–2.46) and IADLs of −0.15 (95% CI=−0.29 to −0.01). Intervention patients were also less likely to rate their health as fair or poor (37.3% vs 52.4%, P<.001). Combining both study groups, patients whose depression improved were more likely to experience improvement in physical functioning.

Conclusion: The IMPACT collaborative care model for late‐life depression improves physical function more than usual care.
Economic Evaluation of Oseltamivir Phosphate for Postexposure Prophylaxis of Influenza in Long‐Term Care Facilities
Authors: Risebrough Nancy A. , Bowles Susan K. , Simor Andrew E. , McGeer Alison , Oh Paul I.
Published: February 2005

Objectives: To compare the cost‐effectiveness of oseltamivir postexposure prophylaxis during influenza A outbreaks with that of amantadine postexposure prophylaxis or no postexposure prophylaxis in long‐term care facilities (LTCFs).

Design: Cost‐effectiveness analysis based on decision analytic model from a government‐payer perspective.

Setting: A Canadian LTCF, with high staff vaccination, at the beginning of influenza season.

Participants: Elderly, influenza‐vaccinated patients living in a Canadian LTCF.

Measurements: Incremental costs (or savings) per influenza‐like illness case avoided compared with usual care.

Results: From a government‐payer perspective, this analysis showed that oseltamivir was a dominant strategy because it was associated with the fewest influenza‐like illness cases, with cost savings of $1,249 per 100 patients in 2001 Canadian dollars compared with amantadine and $3,357 per 100 patients compared with no prophylaxis. Costs for amantadine dose calculation and hospitalization for adverse events contributed to amantadine being a more‐expensive prophylaxis strategy than oseltamivir. Both prophylaxis strategies were more cost‐effective than no prophylaxis.

Conclusion: Despite high influenza vaccination rates, influenza outbreaks continue to emerge in LTCFs, necessitating cost‐effective measures to further limit the spread of influenza and related complications. Although amantadine has a lower acquisition cost than oseltamivir, it is associated with more adverse events, lower efficacy, and individualized dosing requirements, leading to higher overall costs and more influenza‐like illness cases than oseltamivir. Therefore the use of oseltamivir postexposure prophylaxis is more cost‐effective than the current standard of care with amantadine prophylaxis or no prophylaxis.
Energy Requirements Are Not Greater in Elderly Patients Suffering from Pressure Ulcers
Authors: Dambach Bernd , Sallé Agnès , Marteau Cécile , Mouzet Jean‐Baptiste , Ghali Ali , Favreau Anne‐Marie , Berrut Gilles , Ritz Patrick
Published: February 2005

Objectives: To estimate energy requirements in diseased elderly patients with pressure ulcers (PUs).

Design: Open, case‐control study.

Setting: University Hospital of Angers (France).

Participants: Twenty‐nine patients with PUs (Norton index risk=14.3±3.3) and 27 controls hospitalized for various diseases (Norton=13.9±3.3).

Measurements: Energy requirements were estimated using measured resting metabolic rate (RMR) and multiplied by 1.26 and 1.5 to range between minimal World Health Organization (WHO) requirements and those of adults undergoing light physical activity. Energy intakes were estimated using 3‐day food weight records. Measured RMR was compared with the prediction equations of Harris‐Benedict, WHO, and Schofield.

Results: Measured RMR did not differ between the two groups (P=.48), and was not related to grade or size of the PUs. The WHO equation (82 kcal/d, P=.006) and the Schofield formula (57 kcal/d, P=.05) slightly underestimated calculated RMR, but the Harris‐Benedict equation (40 kcal/d, P=.13) accurately estimated it. Energy requirements therefore ranged between 1,536±340 kcal/d and 1,828±405 kcal/d, (25–30 kcal/kg body weight per day). Energy intake was lower than energy requirements by 176 to 479 kcal/d.

Conclusion: Diseased elderly patients with PUs do not have greater energy expenditure, with their requirements suggested to range between 25 and 30 kcal/kg body weight per day. Malnutrition within this population is most likely the result of low energy intake.
Multidimensional Attitudes of Medical Residents and Geriatrics Fellows Toward Older People
Authors: Lee Ming , Reuben David B. , Ferrell Bruce A.
Published: February 2005

Objectives: To examine dimensions of a validated instrument measuring geriatric attitudes of primary care residents and performances on these dimensions between residents and fellows.

Design: Cross‐sectional and longitudinal studies.

Setting: An academic medical center.

Participants: Two hundred thirty‐eight primary care residents (n=177) and geriatrics fellows (n=61) participated in the study from 1995 to 2000.

Measurements: A 14‐item, 5‐point Likert scale previously validated for measuring primary care residents' attitudes toward older people and geriatric patient care was used.

Results: Factor analysis showed four dimensions of the scale, labeled Social Value, Medical Care (MC), Compassion (CP), and Resource Distribution, which demonstrated acceptable reliability. Both groups of subjects showed significantly (P<.001) positive (mean>3) attitudes across the dimensions and times, except for residents, who had near‐neutral (mean=3) attitudes on MC. Residents' mean attitude scores on the overall scale and the MC and CP subscales were significantly (P<.001) lower than those of fellows over time. Residents and fellows showed different change patterns in attitudes over time. Residents' attitudes generally improved during the first 2 years of training, whereas fellows' attitudes declined slightly. Personal experience was a strong predictor of residents' attitudes toward older patients. Ethnicity, academic specialty, professional experience, and career interest in geriatrics were also associated with residents' attitude scores.

Conclusion: The multidimensional analysis of the scale contributes to better understanding of medical trainees' attitudes and sheds light on educational interventions.
Effect of Implant Angulation upon Retention of Overdenture Attachments
Authors: Gulizio Michael P. , Agar John R. , Kelly J. Robert , Taylor Thomas D.
Published: February 2005

Introduction
: Overdentures supported and retained by endosteal implants depend upon mechanical components to provide retention. Ball attachments are frequently described because of simplicity and low cost, but retentive capacity of these components may be altered by a lack of implant parallelism.

Purpose
: The aim of this in vitro study was to investigate the retention of gold and titanium overdenture attachments when placed on ball abutments positioned off‐axis.

Methods and Materials
: Four ball abutments were hand‐tightened onto ITI dental implants and placed in an aluminum fixture that allowed positioning of the implants at 0°, 10°, 20°, and 30° from a vertical reference axis. Gold and titanium matrices were then coupled to the ball abutments at various angles and then subjected to pull tests at a rate of 2 mm/second; the peak loads of release (maximum dislodging forces) were recorded and subjected to statistical analyses. A balanced and randomized factorial experimental design testing procedure was implemented.

Results
: Statistically significant differences in retention of gold matrices were noted when ball abutments were positioned at 20° and 30°, but not at 0° and 10°. Statistically significant differences were noted among the titanium matrices employed for the testing procedure, as well as for the 4 ball abutments tested. Angle was not a factor affecting retention for titanium matrices.

Conclusions
: (1) The gold matrices employed for the testing procedures exhibited consistent values in retention compared to titanium matrices, which exhibited large variability in retention. (2) Angle had an effect upon the retention of gold matrices, but not for titanium matrices.
Expression of CD13/aminopeptidase N on human gingival fibroblasts and up‐regulation upon stimulation with interleukin‐4 and interleukin‐13
Authors: Kunii Ryotaro , Nemoto Eiji , Kanaya Sousuke , Tsubahara Taisuke , Shimauchi Hidetoshi
Published: February 2005

Background and objectives:  Aminopeptidase N (APN)/CD13 is a multifunctional ectoenzyme that is involved in anti‐inflammatory reactions, control of immune reactions and differentiation of many cellular systems. Here, we hypothesized that CD13/APN would be expressed on human gingival fibroblasts (hGF) and would contribute to the regulation of immune responses in periodontal tissue.

Methods and results:  CD13/APN was expressed on hGF at the mRNA and protein levels as determined by reverse transcriptase–polymerase chain reaction (RT–PCR) and flow cytometry, respectively. Enzymatic activities accompanying the expression were assessed by colorimetrical analysis using the synthetic substrate Leu‐p‐nitroanilide. We examined the possible regulation of CD13/APN expression on hGF in response to T cell‐derived cytokines. T helper (Th) 2 cell type cytokines such as interleukin‐4 and interleukin‐13, but not interleukin‐2 or interleukin‐15, preferentially increased the expression of proteins as well as the enzymatic activities of CD13/APN in a dose‐dependent manner. Receptors for these cytokines, the interleukin‐4 receptor α chain, interleukin‐13 receptor α1 chain, and interleukin‐2R common γ chain, were expressed on hGF assessed by RT–PCR or flow cytometry. hGF exhibited inhibitory effects for formyl‐methionyl‐leucyl‐phenylalanine (FMLP)‐induced polymorphonuclear leukocyte‐activation that was evaluated by Mac‐1 expression, and this inhibitory effect was partially recovered by pre‐treatment with the APN‐specific inhibitor bestatin.

Conclusions:  These findings suggested that CD13/APN expressed by hGF could contribute to the anti‐inflammatory response in periodontal tissue, and may be involved in disease processes mediated by Th2 cells.
Keratinocyte growth factor‐1 expression in healthy and diseased human periodontal tissues
Authors: Li Min , Firth James D. , Putnins Edward E.
Published: February 2005

Objectives:  Keratinocyte growth factor‐1 (KGF‐1) is up‐regulated in chronic inflammation and specifically stimulates epithelial cell proliferation by signaling through the epithelial‐specific keratinocyte growth factor receptor (KGFR). We examined KGF‐1 and KGFR protein and gene expression in healthy and diseased periodontal tissues.

Methods:  Tissues were collected from patients with periodontal health or disease, immediately frozen and stained for KGF‐1 and KGFR protein expression. Laser capture microdissection of epithelial and connective tissue cells with reverse transcription–polymerase chain reaction (RT–PCR) examined KGF‐1 and KGFR gene expression profiles and enzymatic digestion with heparitinase, chondroitinase ABC or pre‐treatment with suramin examined epithelial surface molecule interactions with KGF‐1.

Results:  In tissues collected from healthy patients, KGF‐1 protein localized to areas of junctional and basal oral epithelial cells and was significantly increased in periodontal pocket epithelium (p < 0.01) and in the oral epithelium (p < 0.05) of disease‐associated tissues. KGFR localized to the junctional and the parabasal cells of oral epithelium, with the relative staining intensity being increased in disease‐associated pocket epithelium (p < 0.05). Laser capture microdissection with RT–PCR confirmed KGF‐1 and KGFR were specifically expressed by connective tissue and epithelium, respectively. KGF‐1 localization to epithelial cells was largely eliminated by suramin pre‐treatment, indicating interaction with the KGFR.

Conclusions:  KGF‐1 and KGFR proteins are expressed in healthy periodontal tissues but significantly increased in diseased periodontal tissues. We hypothesize up‐regulation of KGF‐1 and KGFR protein associated with disease regulates epithelial cell behavior associated with onset and progression of periodontal pocket formation.
Up‐regulation of Vascular Endothelial Growth Factor‐C by Nicotine in Cervical Cancer Cell Lines
Authors: Lane Derrick , Gray Elizabeth A. , Mathur Rajesh S. , Mathur Subbi P.
Published: February 2005

Problem:  Smoking and infection with human papilloma virus (HPV) are major risk factors for cervical cancer. Our earlier work shows that nicotine enhances cellular proliferation of cervical cancer cell lines by up‐regulating epidermal growth factor (EGF) and its receptor EGF‐R, which leads to increased insulin‐like growth factor II in vitro. We found that the vascular endothelial growth factor (VEGF)‐C, one of the five isoforms of VEGF, may be specifically involved in lymphogenic metastasis of cervical cancer. This has prompted us to study if in vitro nicotine treatment will up‐regulate VEGF‐C alongside EGF‐R levels, while down regulating the anti‐proliferative transforming growth factor (TGF)‐β levels in HPV positive cervical cancer cell lines.

Method of study:  Cervical cancer cell lines CaSki, HeLa and ME‐180, were cultured in serum free DMEM medium for 24‐hr, and treated with 10 ng/mL nicotine in the medium supplemented with 10% fetal bovine serum. A group of untreated cells served as controls. The cells were cultured in chamber slides (for immunofluorescent antibody assay) as well as microtiter plate wells (for BrdU cell proliferation assay). The cellular levels of VEGF‐C, TGF‐β, EGF‐R and HPV‐E6 (early protein 6) were measured by a semi‐quantitative immunofluorescent antibody assay. The cell proliferation and immunofluorescent assay data were analyzed by a Student's t‐test.

Results:  Cell proliferation was significantly increased after nicotine treatment in all the cell lines. The VEGF‐C levels were significantly increased, while TGF‐β levels were decreased by nicotine in all the cell lines (P < 0.00001). EGF‐R levels were also significantly increased after nicotine treatment in HeLa and ME‐180, while HPV‐E6 levels remained unchanged in all three.

Conclusions:  Nicotine up regulates expression of cell proliferative VEGF‐C and EGF‐R, while down‐regulating anti‐proliferative TGF‐β. Our data suggest that nicotine in circulation and in cervical squamous epithelial cells may promote not only rapid tumor growth but its lympho‐angiogenic spread (VEGF‐C) as well. It appears that nicotine does not promote HPV spread in the cervical cancer cells.
Symptomatic Bradycardia Probably Due to Tizanidine Hydrochloride in a Chronic Hemodialysis Patient
Authors: Kitabata Yukiko , Orita Hikari , Kamimura Motohiro , Shiizaki Kazuhiro , Narukawa Nobuhiko , Abe Takaya , Kobata Hirotsugu , Akizawa Tadao
Published: February 2005

Abstract:  A 71‐year‐old woman was admitted to the Wakayama Medical University Hospital with dizziness and loss of body balance. She had started hemodialysis at the age of 70. During the 33 days before admission, she received oral tizanidine hydrochloride at 3 mg/day for leg cramps. An admission electrocardiogram (ECG) demonstrated sinus bradycardia of 47 bpm. A 24‐h ECG showed a total number of heartbeats of 68 779 and an average heart rate of 48 bpm. The maximum RR interval was 3720 msec. The electrophysiology test demonstrated slight sinus node dysfunction. There was no major organic heart disease. We suspected that tizanidine was the cause of bradycardia and stopped administration of this drug. After discontinuation symptoms gradually disappeared. The serum concentration of the tizanidine showed a higher trough of 1.78 ng/mL. In conclusion, because there was a disappearance of symptoms and a lightening of bradycardia due to the discontinuation of this medication, tizanidine was strongly suspected as the cause of severe bradycardia.
Challenges in the Therapy of Secondary Hyperparathyroidism
Authors: Wood Carla , González Esther A , Martin Kevin J
Published: February 2005

Abstract:  Derangements in mineral metabolism are known to occur early in the course of chronic kidney disease (CKD). Recent clinical practice guidelines are designed to focus on the problem early in the course of kidney disease, when it is recommended to evaluate the levels of parathyroid hormone (PTH) and to try to intervene early if the levels are elevated. To begin early intervention for hyperparathyroidism in chronic kidney disease will require involvement of primary care physicians and other subspecialty groups to identify the patients at risk and begin to intervene with measures to control hyperparathyroidism and its consequences on mineral metabolism. It has recently been demonstrated that chronic kidney disease is a significant risk factor for vitamin D deficiency and since abnormalities in vitamin D metabolism are important in the generation of hyperparathyroidism, this is an issue that needs direct attention. Studies are needed to assess the effects of correcting this vitamin D deficiency in early CKD. As kidney disease progresses, efforts to control hyperparathyroidism will likely need to be intensified and several therapeutic options are available, such as phosphate binders, repletion of vitamin D, the use of active vitamin D sterols, or the use of vitamin D analogs. In addition, it is important to define the appropriate PTH values that need to be achieved to minimize complications on bone. Such studies are in progress at the present time to validate the current more specific PTH assays.

Strict guidelines have been proposed for the management of bone and mineral metabolism in patients with CKD stage V on dialysis, and although these challenging recommendations were initially opinion‐based, there is mounting evidence which provides confirmation of these targets as relevant. Treatment options for patients on dialysis involve the full spectrum of agents which include phosphate binders, active vitamin D sterols (often given parenterally), the use of calcimimetic agents, surgical parathyroidectomy, and evaluation of appropriate levels of dialysate calcium. Similar to early stages of CKD, studies are in progress to refine the PTH targets with the newer PTH assays. With increased focus on the complications of bone and mineral metabolism as part of the continuum of chronic kidney disease, and with a variety of new therapies available, it is anticipated that improved patient outcomes should be achievable in this patient group.
Is 2.5 mEq/L the Optimal Calcium Concentration of Dialysate in the Use of Sevelamer Hydrochloride? A Study of the Dialysate Calcium Concentration Recommended by K/DOQI Guidelines
Authors: Izumi Masaaki , Shirai Kenichi , Ito Katsukiyo , Miyamoto Takashi , Matsumoto Akihide , Takenaka Yoshiaki , Nakagawa Kiyohiko , Yamanashi Toshiaki , Takamitsu Yoshihiro , Nakanish Takeshi
Published: February 2005

Abstract:  We tested the effect of three different dialysate calcium concentrations on calcium–phosphorus metabolism during the use of sevelamer hydrochloride. After a calcium‐containing phosphate binder was switched to sevelamer, the serum calcium, phosphorus, and intact parathyroid hormone levels and the markers of bone turnover were measured in the patients whose dialysate calcium concentrations were 2.5, 2.75, and 3.0 mEq/L. As a result, in the 2.75‐mEq/L group, the serum calcium concentrations decreased and the intact parathyroid hormone level increased significantly. In the 2.5‐mEq/L group, transient hypocalcemia occurred and the levels of both bone‐alkaline phosphatase and osteocalcin increased. In the 3.0‐mEq/L group, the serum calcium concentrations did not change significantly and only bone‐alkaline phosphatase increased. If a calcium‐containing phosphate binder is completely switched to sevelamer, dialysis using a dialysate calcium concentration below 3.0 mEq/L may result in hypocalcemia and acceleration  of  bone  turnover.
Combination Therapy with Sevelamer Hydrochloride and Calcium Carbonate in Japanese Patients with Long‐Term Hemodialysis: Alternative Approach for Optimal Mineral Management
Authors: Ogata Hiroaki , Koiwa Fumihiko , Shishido Kanji , Kinugasa Eriko
Published: February 2005

Abstract:  Calcium (Ca) overload by Ca‐containing phosphorus (P) binder has been suggested to be implicated in the pathogenesis of soft tissue and vascular calcification, which contribute to increased morbidity and mortality of cardiovascular disease in patients undergoing dialysis. Recently, a noncalcium P binder, sevelamer hydrochloride (sevelamer), has become available in Japan. However, Japanese patients undergoing dialysis might be less tolerant of sevelamer treatment, and it is likely to cause hypocalcemia because their dietary Ca intake is less than that in European and American patients. We evaluated the effects of combination therapy with sevelamer and calcium carbonate (CC) on mineral metabolism in Japanese hemodialysis patients, as an alternative form of P management. A total of 210 hemodialysis patients were enrolled, and were given a small dose of sevelamer (0.75–1.5 g/day) on CC treatment. Sevelamer dose was gradually increased, while CC decreased during 24 weeks. Five patients discontinued sevelamer treatment because of severe constipation, anorexia, and parathyroidectomy for severe secondary hyperparathyroidism. After 24 weeks, the dose of sevelamer was significantly increased to 3.29 g/day (initial dose: 1.47 g/day), while CC was decreased by 54%. Adjusted serum Ca significantly decreased (9.63 ± 0.57–9.45 ± 0.67 mg/dL; P = 0.0012), although serum P increased (5.89 ± 1.32–6.25 ± 1.32 mg/dL; P = 0.017). Serum intact PTH (iPTH) significantly increased in patients with a low or normal iPTH level (≤300 pg/mL), while it did not change in patients with secondary hyperparathyroidism (>300 pg/mL). The results suggest that the therapeutic regimen is more tolerant and reduces Ca load in Japanese hemodialysis patients while avoiding hypocalcemia. In addition, the mitigated Ca overload could improve PTH hyposecretion in patients with adynamic bone disease, which is associated with soft tissue calcification and higher mortality in uremia
Evidence for a Great Medieval Earthquake (~1100 A.D.) in the Central Himalayas, Nepal
Authors: Lavé J. , Yule D. , Sapkota S. , Basant K. , Madden C. , Attal M. , Pandey R.
Published: February 2005

The Himalayan orogen has produced three thrust earthquakes with moment magnitude (
M
w
) 7.8 to 8.5 during the past century, yet no surface ruptures associated with these great earthquakes have been documented. Here, we present paleoseismic evidence from east central Nepal that, since ∼700 A.D., a single earthquake ruptured the Frontal Thrust fault at ∼1100 A.D., with a surface displacement of ∼17 (+5/–3) meters and a lateral extent and size that could have exceeded 240 kilometers and ∼
M
w
8.8, respectively. Ruptures associated with
M
w
<8.2 events would contribute to the frontal Himalayas folding but would stop before reaching the surface. These findings could require substantial modifications to current regional seismic hazard models.
Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease
Authors: Stokin Gorazd B. , Lillo Concepción , Falzone Tomás L. , Brusch Richard G. , Rockenstein Edward , Mount Stephanie L. , Raman Rema , Davies Peter , Masliah Eliezer , Williams David S. , Goldstein Lawrence S. B.
Published: February 2005

We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-β peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of β-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.
Composition and Dynamics of Plasma in Saturn's Magnetosphere
Authors: Young D. T. , Berthelier J.-J. , Blanc M. , Burch J. L. , Bolton S. , Coates A. J. , Crary F. J. , Goldstein R. , Grande M. , Hill T. W. , Johnson R. E. , Baragiola R. A. , Kelha V. , McComas D. J. , Mursula K. , Sittler E. C. , Svenes K. R. , Szegö K. , Tanskanen P. , Thomsen M. F. , Bakshi S. , Barraclough B. L. , Bebesi Z. , Delapp D. , Dunlop M. W. , Gosling J. T. , Furman J. D. , Gilbert L. K. , Glenn D. , Holmlund C. , Illiano J.-M. , Lewis G. R. , Linder D. R. , Maurice S. , McAndrews H. J. , Narheim B. T. , Pallier E. , Reisenfeld D. , Rymer A. M. , Smith H. T. , Tokar R. L. , Vilppola J. , Zinsmeyer C.
Published: February 2005

During Cassini's initial orbit, we observed a dynamic magnetosphere composed primarily of a complex mixture of water-derived atomic and molecular ions. We have identified four distinct regions characterized by differences in both bulk plasma properties and ion composition. Protons are the dominant species outside about 9
R
S
(where
R
S
is the radial distance from the center of Saturn), whereas inside, the plasma consists primarily of a corotating comet-like mix of water-derived ions with ∼3% N
+
. Over the A and B rings, we found an ionosphere in which O
2
+
and O
+
are dominant, which suggests the possible existence of a layer of O
2
gas similar to the atmospheres of Europa and Ganymede.
Composition of Saturnian Stream Particles
Authors: Kempf Sascha , Srama Ralf , Postberg Frank , Burton Marcia , Green Simon F. , Helfert Stefan , Hillier Jon K. , McBride Neil , McDonnell J. Anthony M. , Moragas-Klostermeyer Georg , Roy Mou , Grün Eberhard
Published: February 2005

During Cassini's approach to Saturn, the Cosmic Dust Analyser (CDA) discovered streams of tiny (less than 20 nanometers) high-velocity (∼100 kilometers per second) dust particles escaping from the saturnian system. A fraction of these impactors originated from the outskirts of Saturn's dense A ring. The CDA time-of-flight mass spectrometer recorded 584 mass spectra from the stream particles. The particles consist predominantly of oxygen, silicon, and iron, with some evidence of water ice, ammonium, and perhaps carbon. The stream particles primarily consist of silicate materials, and this implies that the particles are impurities from the icy ring material rather than the ice particles themselves.
Unveiling Extensive Clouds of Dark Gas in the Solar Neighborhood
Authors: Grenier Isabelle A. , Casandjian Jean-Marc , Terrier Régis
Published: February 2005

From the comparison of interstellar gas tracers in the solar neighborhood (HI and CO lines from the atomic and molecular gas, dust thermal emission, and g rays from cosmic-ray interactions with gas), we unveil vast clouds of cold dust and dark gas, invisible in HI and CO but detected in γ rays. They surround all the nearby CO clouds and bridge the dense cores to broader atomic clouds, thus providing a key link in the evolution of interstellar clouds. The relation between the masses in the molecular, dark, and atomic phases in the local clouds implies a dark gas mass in the Milky Way comparable to the molecular one.
Herpes Simplex Virus Thymidine Kinase Mutations Associated with Resistance to Acyclovir: a Site-Directed Mutagenesis Study
Authors: Frobert E. , Ooka T. , Cortay J. C. , Lina B. , Thouvenot D. , Morfin F.
Published: February 2005

Mutations in the thymidine kinase (TK) gene of herpes simplex virus (HSV) may confer resistance to acyclovir (ACV). Because of the high genetic polymorphism of this gene, discriminating between mutations related to resistance and mutations related to gene polymorphism can be difficult, especially when no sensitive strain has been previously isolated from the same patient. To assess the role of the mutations located at codons 51, 77, 83, and 175, previously detected in HSV-1 clinical isolates (F. Morfin, G. Souillet, K. Bilger, T. Ooka, M. Aymard, and D. Thouvenot, J. Infect. Dis. 182:290-293, 2000), in the acquisition of resistance to ACV, four mutants with site-directed mutations at these respective codons were constructed. The enzymatic activity of the proteins, produced using both a reticulocyte lysate system and a bacterial system, was evaluated using [
3
H]thymidine as substrate. This site-directed mutagenesis revealed that mutations at codons 51, 83, and 175 induce a loss of HSV-1 TK activity and are thus clearly involved in the acquisition of resistance to ACV. On the other hand, the mutation at codon 77 does not affect enzyme activity.
Synthesis and Antileishmanial Activities of Novel 3-Substituted Quinolines
Authors: Tempone André Gustavo , Pompeu da Silva Ana Cláudia Melo , Brandt Carlos Alberto , Martinez Fernanda Scalzaretto , Treiger Borborema Samanta Etel , Barata da Silveira Maria Amélia , de Andrade Heitor Franco
Published: February 2005

The antileishmanial efficacy of four novel quinoline derivatives was determined in vitro against
Leishmania chagasi
, using extracellular and intracellular parasite models. When tested against
L. chagasi
-infected macrophages, compound 3b demonstrated 8.3-fold greater activity than did the standard pentavalent antimony. No significant activity was found for compounds 3a, 4a, and 4b. The antilesihmanial effect of compound 3b was independent of host cell activation, as demonstrated by nitric oxide production. Ultrastructural studies of promastigotes treated with compound 3b showed mainly enlarged mitochondria, with matrix swelling and reduction in the number of cristae. Synthetic analogues based on the quinoline ring structure, already an established template for antiparasitic drugs, could provide further useful compounds.
Alpha Interferon and Ribavirin Combination Therapy of Chronic Hepatitis D
Authors: Kaymakoglu Sabahattin , Karaca Cetin , Demir Kadir , Poturoglu Sule , Danalioglu Ahmet , Badur Selim , Bozaci Murvet , Besisik Fatih , Cakaloglu Yilmaz , Okten Atilla
Published: February 2005

The success of alpha interferon (IFN-α) monotherapy for the treatment of chronic hepatitis D is very limited. In this study, the efficacy of IFN-α and ribavirin combination therapy for chronic hepatitis D was investigated. Nineteen patients (15 males; mean age ± standard deviation, 36.8 ± 12.8 years) with chronic hepatitis D who were treated with IFN-α2b (10 million U, three times/week, subcutaneously) and ribavirin (1,000 to 1,200 mg/day, orally) for 24 months were studied. All patients had compensated liver disease (15 were precirrhotic), elevated transaminase levels, and hepatitis D virus RNA positivity at baseline. Genotypic analyses revealed hepatitis D virus genotype I and hepatitis B virus genotype D. All patients completed the 24 months of treatment and at least 6 months (7 to 19 months) of a follow-up period. Biochemical responses were observed in eight patients (42.1%) at the end of treatment and in seven patients (36.8%) at the end of follow-up. Eight patients (42.1%) at the end of treatment and four patients (21%) at the end of follow-up had virological responses. In conclusion, combination treatment of IFN-α and ribavirin for chronic hepatitis D is not able to induce virological responses at a sufficient rate, despite its partial effectiveness in improving biochemical responses, and is not superior to IFN-α monotherapy.
Inducible Metronidazole Resistance and
nim
Genes in Clinical
Bacteroides
fragilis
Group Isolates
Authors: Löfmark Sonja , Fang Hong , Hedberg Maria , Edlund Charlotta
Published: February 2005

Nitroimidazole resistance (
nim
) genes were detected in 2% of 1,502 clinical
Bacteroides
fragilis
group strains isolated from 19 European countries, and a novel
nim
gene was identified. High metronidazole resistance could be induced in
nim
-positive strains, which emphasizes the importance of acknowledging metronidazole resistance in the clinical setting.
Induction of Fibronectin Adhesins in Quinolone-Resistant
Staphylococcus aureus
by Subinhibitory Levels of Ciprofloxacin or by Sigma B Transcription Factor Activity Is Mediated by Two Separate Pathways
Authors: Li Dongmei , Renzoni Adriana , Estoppey Tristan , Bisognano Carmelo , Francois Patrice , Kelley William L. , Lew Daniel P. , Schrenzel Jacques , Vaudaux Pierre
Published: February 2005

We recently reported on the involvement of a RecA-LexA-dependent pathway in the ciprofloxacin-triggered upregulation of fibronectin-binding proteins (FnBPs) by fluoroquinolone-resistant
Staphylococcus aureus
. The potential additional contribution of the transcription factor sigma B (SigB) to the ciprofloxacin-triggered upregulation of FnBPs was studied in isogenic mutants of fluoroquinolone-resistant strain RA1 (a topoisomerase IV gyrase double mutant of
S. aureus
NCTC strain 8325), which exhibited widely different levels of SigB activity, as assessed by quantitative reverse transcription-PCR of their respective
sigB
and SigB-dependent
asp23
transcript levels. These mutants were Tn
551
insertion
sigB
strain TE1 and
rsbU

+

complemented strain TE2, which exhibited a wild-type SigB operon. Levels of FnBP surface display and fibronectin-mediated adhesion were lower in
sigB
mutant TE1 or higher in the
rsbU

+

-restored strain TE2 compared to their
sigB
+
but
rsbU
parent, strain RA1, exhibiting low levels of SigB activity. Steady-state
fnbA
and
fnbB
transcripts levels were similar in strains TE1 and RA1 but increased by 4- and 12-fold, respectively, in strain TE2 compared to those in strain RA1. In contrast, fibronectin-mediated adhesion of strains TE1, RA1, and TE2 was similarly enhanced by growth in the presence of one-eighth the MIC of ciprofloxacin, which led to a significantly higher increase in their
fnbB
transcript levels compared to the increase in their
fnbA
transcript levels. Increased SigB levels led to a significant reduction in
agr
RNAIII; in contrast, it led to a slight increase in
sarA
transcript levels. In conclusion, upregulation of FnBPs by increased SigB levels and ciprofloxacin exposure in fluoroquinolone-resistant
S. aureus
occurs via independent pathways whose concerted actions may significantly promote bacterial adhesion and colonization.
Mechanism of Action of T-705 against Influenza Virus
Authors: Furuta Yousuke , Takahashi Kazumi , Kuno-Maekawa Masako , Sangawa Hidehiro , Uehara Sayuri , Kozaki Kyo , Nomura Nobuhiko , Egawa Hiroyuki , Shiraki Kimiyasu
Published: February 2005

T-705, a substituted pyrazine compound, has been found to exhibit potent anti-influenza virus activity in vitro and in vivo. In a time-of-addition study, it was indicated that T-705 targeted an early to middle stage of the viral replication cycle but had no effect on the adsorption or release stage. The anti-influenza virus activity of T-705 was attenuated by addition of purines and purine nucleosides, including adenosine, guanosine, inosine, and hypoxanthine, whereas pyrimidines did not affect its activity. T-705-4-ribofuranosyl-5′-triphosphate (T-705RTP) and T-705-4-ribofuranosyl-5′-monophosphate (T-705RMP) were detected in MDCK cells treated with T-705. T-705RTP inhibited influenza virus RNA polymerase activity in a dose-dependent and a GTP-competitive manner. Unlike ribavirin, T-705 did not have an influence on cellular DNA or RNA synthesis. Inhibition of cellular IMP dehydrogenase by T-705RMP was about 150-fold weaker than that by ribavirin monophosphate, indicating the specificity of the anti-influenza virus activity and lower level of cytotoxicity of T-705. These results suggest that T-705RTP, which is generated in infected cells, may function as a specific inhibitor of influenza virus RNA polymerase and contributes to the selective anti-influenza virus activity of T-705.
The StcE Protease Contributes to Intimate Adherence of EnterohemorrhagicEscherichia coliO157:H7 to Host Cells
Authors: Grys Thomas E. , Siegel Matthew B. , Lathem Wyndham W. , Welch Rodney A.
Published: February 2005

EnterohemorrhagicEscherichia coli(EHEC) O157:H7 is a diarrheal pathogen that causes attaching and effacing (A/E) lesions on intestinal epithelial cells. Strains of the O157 serogroup carry the large virulence plasmid pO157, which encodes theetptype II secretion system that secretes the genetically linked zinc metalloprotease StcE. The Ler regulator controls expression of many genes involved in A/E lesion formation, as well as StcE, suggesting StcE may be important at a similar time during colonization. Our laboratory has previously demonstrated that StcE cleaves C1-esterase inhibitor, a regulator of multiple inflammation pathways. Here we report two new substrates for StcE, mucin 7 and glycoprotein 340, and that purified StcE reduces the viscosity of human saliva. We tested the hypothesis that StcE contributes to intimate adherence of EHEC to host cells by cleavage of glycoproteins from the cell surface. The fluorescent actin stain (FAS) test was used to observe the intimate adherence represented by fluorescently stained bacteria colocalized with regions of bundled actin formed on HEp-2 cells. AnE. coliO157:H7 strain with astcEgene deletion was not affected in its ability to generally adhere to HEp-2 cells, but it did score threefold lower on the FAS test than wild-type or complemented strains. Addition of exogenous recombinant StcE increased intimate adherence of the mutant to wild-type levels. Thus, StcE may help block host clearance ofE. coliO157:H7 by destruction of some classes of glycoproteins, and it contributes to intimate adherence ofE. coliO157:H7 to the HEp-2 cell surface.
CD4+T Cells and Toll-Like Receptors RecognizeSalmonellaAntigens Expressed in Bacterial Surface Organelles
Authors: Bergman Molly A. , Cummings Lisa A. , Barrett Sara L. Rassoulian , Smith Kelly D. , Lara J. Cano , Aderem Alan , Cookson Brad T.
Published: February 2005

A better understanding of immunity to infection is revealed from the characteristics of microbial ligands recognized by host immune responses. Murine infection with the intracellular bacteriumSalmonellagenerates CD4+T cells that specifically recognizeSalmonellaproteins expressed in bacterial surface organelles such as flagella and membrane vesicles. These naturalSalmonellaantigens are also ligands for Toll-like receptors (TLRs) or avidly associated with TLR ligands such as lipopolysaccharide (LPS). PhoP/PhoQ, a regulon controllingSalmonellavirulence and remodeling of LPS to resist innate immunity, coordinately represses production of surface-exposed antigens recognized by CD4+T cells and TLRs. These data suggest that genetically coordinated surface modifications may provide a growth advantage forSalmonellain host tissues by limiting both innate and adaptive immune recognition.
Escherichia coliNissle 1917 Distinctively Modulates T-Cell Cycling and Expansion via Toll-Like Receptor 2 Signaling
Authors: Sturm Andreas , Rilling Klaus , Baumgart Daniel C. , Gargas Konstantinos , Abou-Ghazalé Tay , Raupach Bärbel , Eckert Jana , Schumann Ralf. R. , Enders Corinne , Sonnenborn Ulrich , Wiedenmann Bertram , Dignass Axel U.
Published: February 2005

Although the probioticEscherichia colistrain Nissle 1917 has been proven to be efficacious for the treatment of inflammatory bowel diseases, the underlying mechanisms of action still remain elusive. The aim of the present study was to analyze the effects ofE. coliNissle 1917 on cell cycling and apoptosis of peripheral blood and lamina propria T cells (PBT and LPT, respectively). Anti-CD3-stimulated PBT and LPT were treated withE. coliNissle 1917-conditioned medium (E. coliNissle 1917-CM) or heat-inactivatedE. coliNissle 1917. Cyclin B1, DNA content, and caspase 3 expression were measured by flow cytometry to assess cell cycle kinetics and apoptosis. Protein levels of several cell cycle and apoptosis modulators were determined by immunoblotting, and cytokine profiles were determined by cytometric bead array.E. coliNissle 1917-CM inhibits cell cycling and expansion of peripheral blood but not mucosal T cells. Bacterial lipoproteins mimicked the effect ofE. coliNissle 1917-CM; in contrast, heat-inactivatedE. coliNissle 1917, lipopolysaccharide, or CpG DNA did not alter PBT cell cycling.E. coliNissle 1917-CM decreased cyclin D2, B1, and retinoblastoma protein expression, contributing to the reduction of T-cell proliferation.E. coliNissle 1917 significantly inhibited the expression of interleukin-2 (IL-2), tumor necrosis factor α, and gamma interferon but increased IL-10 production in PBT. Using Toll-like receptor 2 (TLR-2) knockout mice, we further demonstrate that the inhibition of PBT proliferation byE. coliNissle 1917-CM is TLR-2 dependent. The differential reaction of circulating and tissue-bound T cells towardsE. coliNissle 1917 may explain the beneficial effect ofE. coliNissle 1917 in intestinal inflammation.E. coliNissle 1917 may downregulate the expansion of newly recruited T cells into the mucosa and limit intestinal inflammation, while already activated tissue-bound T cells may eliminate deleterious antigens in order to maintain immunological homeostasis.