bluuebunny/crossref_metadata_2025 huggingface dataset:
Orange juice substantially reduces the bioavailability of the β‐adrenergic–blocking agent celiprolol
Authors: Lilja Jari J. , Juntti‐Patinen Laura , Neuvonen Pertti J.
Published: March 2004

Background

Grapefruit juice was recently found to decrease plasma concentrations of the β‐adrenergic receptor–blocking agent celiprolol. Our objective was to investigate the effect of orange juice on the pharmacokinetics of celiprolol in healthy subjects.

Methods

In a randomized crossover study with 2 phases and a washout of 2 weeks, 10 healthy volunteers ingested either 200 mL normal‐strength orange juice or water 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of 200 mL orange juice or water, each subject ingested 100 mg celiprolol with either 200 mL orange juice or water. In addition, 200 mL orange juice or water was ingested at 4, 10, 22, and 27 hours after celiprolol intake. The concentrations of celiprolol in plasma and its excretion into urine were measured up to 33 hours after its dosing. Systolic and diastolic blood pressures and heart rate were recorded up to 10 hours.

Results

Orange juice reduced the mean peak plasma concentration of celiprolol by 89% (P < .01) and the mean area under the plasma celiprolol concentration–time curve by 83% (P < .01). The time to peak concentration of celiprolol increased from 4 to 6 hours (P < .05), and the half‐life was prolonged from 4.6 to 10.8 hours (P = .05) after ingestion of orange juice. Orange juice reduced the urinary excretion of celiprolol by 77% (P < .01). No significant differences were observed in the hemodynamic variables between the phases.

Conclusions

Orange juice substantially reduces the bioavailability of celiprolol, but the mechanism of this interaction remains to be resolved. For example, modulation of intestinal pH and of function of transporters implicated in the absorption of celiprolol may be involved. Because of the great extent of the orange juice–celiprolol interaction and a wide use of orange juice, this interaction is likely to have clinical importance in some patients, although hemodynamic consequences were not seen in young healthy subjects.

Clinical Pharmacology & Therapeutics (2004) 75, 184–190; doi: 10.1016/j.clpt.2003.11.002
Torsades de pointes associated with fluoroquinolones: Importance of concomitant risk factors
Authors: Amankwa Kwadwo , Krishnan Subramaniam C. , Tisdale James E.
Published: March 2004

The fluoroquinolone antibiotics sparfloxacin, grepafloxacin, gatifloxacin, and levofloxacin have been reported to cause torsades de pointes. Pre‐existing risk factors increase vulnerability to this life‐threatening arrhythmia. In a 65‐year‐old woman with a history of hypertension, coronary artery disease, systemic lupus erythematosus, and osteomyelitis, QTc interval prolongation (605 ms) and torsades de pointes developed after the initiation of levofloxacin, 250 mg intravenously once daily. The patient was hypokalemic and mildly hypomagnesemic before the initiation of levofloxacin and at the time of occurrence of torsades de pointes. The QTc interval decreased to 399 ms within hours of discontinuation of the levofloxacin, after which she had no further arrhythmias. In this and the majority of other published cases of fluoroquinolone‐associated torsades de pointes, patients had at least 1 risk factor for the arrhythmia, and most had multiple risk factors. Fluoroquinolone antibiotics should be avoided whenever possible in patients with pre‐existing risk factors for torsades de pointes.

Clinical Pharmacology & Therapeutics (2004) 75, 242–247; doi: 10.1016/j.clpt.2003.11.376
Desmin‐free cardiomyocytes and myocardial dysfunction in end stage heart failure
Authors: Di Somma S. , Di Benedetto M.P. , Salvatore G. , Agozzino L. , Ferranti F. , Esposito S. , La Dogana P. , Scarano M.I. , Caputo G. , Cotrufo M. , De Santo L. , de Divitiis O.
Published: March 2004

Our aim was to evaluate the desmin content in the myocardial tissue of patients with end‐stage heart failure of ischaemic origin and to assess its role on cardiac function. We studied 18 explanted hearts from patients transplanted for end‐stage heart failure due to ischaemic cardiomyopathy (ICM). Control myocardial tissue was obtained from the cardiac biopsies of six women with breast cancer taken prior to commencing chemotherapy with anthracyclines, four male donors for heart transplantation and two autoptic hearts from patients who died due to non‐cardiac events. Myocardial tissue, obtained from the left ventricle (remote zone from infarcted area), was analyzed by light and confocal immunochemistry (desmin) microscopy. The desmin content of myocardial tissue was obtained by real‐time PCR. Cardiac function was evaluated by echocardiographic and right heart catheterization data, obtained before heart transplantation. Confocal microscopy evaluation showed a significant decrease in the number of desmin‐positive myocytes (P<0.01) in ICM hearts compared to controls. At real‐time PCR evaluation, there was a reduction (P<0.01) in desmin content in the ICM patients compared to controls. A negative correlation was found between desmin‐free cardiomyocytes and ejection fraction (EF) (r=−0.834; P<0.02) on echocardiogram. A negative relationship (r=−0.688) was also found between desmin‐negative myocytes and capillary wedge pressure. In conclusion, the myocardial tissue of patients with end‐stage heart failure of ischaemic origin, shows a decreased number in desmin‐positive myocytes at immunochemistry evaluation compared to normal individuals. This deficiency in cytoskeletal intermediate filament content is associated with reduced cardiac function.
Disease outcome and cytokine responses in cats immunized with an avirulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8
Authors: Kiss I. , Poland A.M. , Pedersen N.C.
Published: February 2004

Eight cats were immunized with an avirulent strain of feline infectious peritonitis virus (FIPV)-UCD1, then challenge-exposed to a highly virulent cat passaged strain (FIPV-UCD8). Th1 and Th2 cytokine profiles in the peripheral blood mononuclear cells (PBMCs) were measured throughout in the experiment. No clinical signs of FIP were evident in the experimental cats after immunization. After challenge, the immunized cats demonstrated one of four clinical outcomes: (1) classical effusive FIP; (2) accelerated FIP; (3) non-effusive FIP, or (4) resistance to challenge. Only minor cytokine changes were observed following immunization, however, several cytokine changes occurred following challenge-exposure. The most noteworthy changes were in tumor necrosis factor-alpha (TNF- α) and interferon gamma (IFN- γ) levels. Our preliminary findings suggest that immunity against FIP is associated with TNF- α and IFN- γ response imbalance, with high TNF- α/low IFN- γ mRNA responses favouring disease and low TNF- α/high IFN- γ mRNA responses being indicative of immunity.
Tissue distribution of a feline AGP related protein (fAGPrP) in cats with feline infectious peritonitis (FIP)
Authors: Paltrinieri S , Giordano A , Ceciliani F , Sironi G
Published: February 2004

Feline α1-acid glycoprotein (fAGP) increases during feline infectious peritonitis (FIP). We have recently identified a 29 kDa protein that we named feline AGP-related protein (fAGPrP) due to its cross-reactivity with an anti-human AGP monoclonal antibody. In this work we describe the tissue distribution of fAGPrP during FIP, and its relationship with feline coronavirus (FCoV) and myeloid cells. Tissues from five control cats and from 15 cats with FIP were examined by immunohistochemistry using monoclonal antibodies against human AGP, FCoV and myeloid antigens. Diffuse fAGPrP positivity within the lesions, likely due to vascular plasma leakage, endothelial and epithelial lining were detectable. Compared to controls, fAGPrP-expressing cells often increased in number and were diffusely distributed in lymph nodes, as usually occurs for IgM-producing plasma cells during early immune responses. These findings did not depend on the presence of FCoVs or of myeloid cells, suggesting that fAGPrP is not directly involved in the pathogenesis of FIP.
The use of real-time PCR in the diagnosis and monitoring of Mycoplasma haemofelis copy number in a naturally infected cat
Authors: Braddock J.A. , Tasker S. , Malik R.
Published: February 2004

A 5-year-old male neutered cat was diagnosed with severe anaemia due to acute Mycoplasma haemofelis infection. Inflammatory respiratory disease was present concurrently. The cat was treated successfully using a fresh transfusion of whole blood and a 6 week course of doxycycline. The patient made a rapid recovery although the allergic airway disease subsequently required specific therapy consisting of inhaled fluticasone and salbutamol. Real-time quantitative PCR assays confirmed the presence of M. haemofelis DNA copies in the blood at presentation. Repeat PCR assays showed a reduction in copy number during treatment and negative PCR results were obtained both 91 and 425 days after presentation. The report describes, for the first time, the use of real-time PCR in the diagnosis and monitoring of natural M. haemofelis copy number, as well as the induction of long-term negative PCR status.
Congenital phimosis in a cat
Authors: Bright S.R. , Mellanby R.J.
Published: February 2004

An 8-week-old domestic shorthair cat was presented with a history of pollakiuria and polydipsia. No abnormalities were detected during the clinical examination other than the penis could not be extruded from the prepuce. Urine culture demonstrated a growth of E. coli, which was treated with a prolonged course of amoxycillin. The polydipsia resolved and the pollakiuria improved but did not completely abate after antibiotic treatment and the cat had occasional bouts of haematuria. Because of the history of pollakiuria and polydipsia and the ongoing, occasional bouts of haematuria, the cat underwent surgical correction of the congenital phimosis. A small wedge of the dorsal prepuce was removed and the ipsilateral edges of the prepuce were apposed using a simple interrupted pattern. The procedure was quick, easy to perform and led to a resolution of the occasional bouts of haematuria and pollakiuria.
Recommendations from workshops of the second international feline coronavirus/feline infectious peritonitis symposium
Authors: Addie Diane D , Paltrinieri Saverio , Pedersen Niels C
Published: February 2004

In August 2002, scientists and veterinarians from all over the world met in Scotland to discuss feline coronavirus (FCoV) and feline infectious peritonitis (FIP). The conference ended with delegates dividing into three workshops to draw up recommendations for FCoV control, diagnosis and treatment and future research. The workshops were chaired by the three authors and the recommendations are presented in this paper.
Feline leucocyte antigen class II polymorphism and susceptibility to feline infectious peritonitis
Authors: Addie Diane D , Kennedy Lorna J , Ryvar Ruth , Willoughby K , Gaskell R.M. , Ollier W.E.R. , Nart Pablo , Radford Alan D.
Published: February 2004

There are four outcomes to feline coronavirus (FCoV) infection: the development of feline infectious peritonitis (FIP, which is immune-mediated), subclinical infection, development of healthy lifelong carriers and a small minority of cats who resist infection (Addie and Jarrett, Veterinary Record 148 (2001) 649). Examination of the FCoV genome has shown that the same strain of virus can produce different clinical manifestations, suggesting that host genetic factors may also play a role in the outcome of infection. FIP is most prevalent amongst pedigree cats, although how much of this is due to them living in large groups (leading to higher virus challenge and stress which predisposes to FIP) and how much is due to genetic susceptibility is not known. If host genetics could be shown to play a role in disease, it may allow the detection of cats with a susceptibility to FIP and the development of increased population resistance through selective breeding. The feline leucocyte antigen (FLA) complex contains many genes that are central to the control of the immune response. In this preliminary study, we used clonal sequence analysis or reference strand conformational analysis (RSCA) to analyse the class II FLA–DRB of 25 cats for which the outcome of FCoV exposure was known. Individual cats were shown to have between two and six FLA–DRB alleles. There was no statistically significant association between the number of alleles and the outcome of FCoV infection. No particular allele appeared to be associated with either the development of FIP, resistance to FCoV, or the carrier status. However, the analysis was complicated by apparent breed variation in FLA–DRB and the small number of individuals in this study.
Modified vaccinia virus Ankara as a vaccine against feline coronavirus: Immunogenicity and efficacy
Authors: Hebben Matthias , Duquesne Véronique , Cronier Joëlle , Rossi Bernard , Aubert André
Published: February 2004

Feline infectious peritonitis virus (FIPV) is a coronavirus that induces a fatal systemic disease mediated by an inappropriate immune response. Most previous vaccination attempts against FIPV were unsuccessful because IgG antibodies against the surface protein enhance the infection. However, two studies have shown that poxvirus vectors (vaccinia WR and canarypox) expressing only the FIPV membrane (M) protein can elicit a partially protective immunity which is supposed to be cell-mediated (Virology 181 (1991) 327;International patent WO 97/20054 (1997)). In our study, we report the construction of another poxvirus, the modified vaccinia virus Ankara (MVA), as an expression vector for the FIPV M protein. In this vector, the M gene has been inserted downstream a strong early/late promoter, whereas the two previously described poxviruses expressed the M protein during their early stage only. The immunogenicity of the recombinant MVA-M was evaluated in the murine model which revealed an effect of the vector on the Th1/Th2 balance. The vaccine was then tested in cats to evaluate its efficacy in an FIPV 79-1146 challenge. Vaccinated kittens developed FIPV-specific antibodies after immunization, however, none of them was protected against FIPV. Our results suggest a crucial role for the type of poxviral promoter that must be used to induce an effective immune response against FIPV.
Tissue Reaction to Titanium Debris Following Swanson Arthroplasty in the Hand: A Report of Two Cases
Authors: KHOO C. T. K. , DAVISON J. A. , ALI M.
Published: March 2004

Silicone abrasion particles are known to cause inflammatory changes following Swanson arthroplasty. Titanium grommets were introduced to protect the implants from wear and abrasion. Two cases with histological evidence of symptomatic titanium particulate tissue inflammation following Swanson joint replacement with grommets are presented.
Thenar Flap for Severe Finger Tip Injuries in Children
Authors: FITOUSSI F. , GHORBANI A. , JEHANNO P. , FRAJMAN J. M. , PENNEÇOT G. F.
Published: March 2004

Twelve children aged between 18 months and 11 years old who had sustained a severe fingertip amputation with total or subtotal pulp loss were treated with a distal-based thenar flap. The injuries were palmar oblique amputations or avulsion injuries involving the pulp and the nail bed. The pedicles of the thenar flaps were divided after 18 to 25 days and none suffered any necrosis. At the final follow-up, no interphalangeal joint contractures were found, the average two point discrimination was 5 mm, the thenar scar was asymptomatic and the subcutaneous tissue of the thenar flap was providing sufficient bulk to produce a rounded contour, like a normal fingertip. The thenar flap is a useful technique for use with severe fingertip injuries when local flaps cannot provide enough soft tissue and replantation is not possible.
Radiographic Changes after Resection of the Distal Ulna in Rheumatoid Arthritis
Authors: RAHIMTOOLA Z. O. , JANSEN S. P. L. , ROZING P. M. , NELISSEN R. G. H. H.
Published: March 2004

Progressive ulnar translocation of the carpus and problems with the ulnar stump have been reported after resection of the distal ulna in rheumatoid arthritis (RA). However this has only occasionally been quantitatively assessed. In this study 24 wrists in 21 patients with RA were followed up for an average of 100 months after resection of the distal ulna. An additional 24 wrists in 14 non-operated RA patients were followed up for 92 months. In a retrospective radiographic analysis we demonstrate similar increases in ulnar translocation and ulnar-carpal distances in both groups.
Dash and Boston Questionnaire Assessment of Carpal Tunnel Syndrome Outcome: What is the Responsiveness of an Outcome Questionnaire?
Authors: GREENSLADE J. R. , MEHTA R. L. , BELWARD P. , WARWICK D. J.
Published: March 2004

This prospective study evaluates if the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire is an adequately responsive outcome measure in carpal tunnel syndrome by comparing it with the disease-specific Boston questionnaire (BQ). To measure responsiveness (sensitivity to clinical change), 57 patients with a clinical diagnosis of carpal tunnel syndrome completed the DASH and BQ preoperatively and again 3 months after open carpal tunnel decompression. A second group of 31 patients completed the questionnaires in the outpatient clinic and again 2 weeks later to assess test–retest reliability. The time to complete all questionnaires was recorded. Responsiveness of the DASH is comparable with the BQ with standardized response means of 0.66, 1.07 and 0.62 for the DASH, BQ-symptoms and BQ-function, respectively. Test–retest data show both questionnaires are reliable. Mean times to complete questionnaires were 6.8 minutes (DASH) and 5.6 minutes (BQ). This study concludes that the DASH questionnaire is a reliable, responsive and practical outcome instrument in carpal tunnel syndrome.
A Simple Tendon Retrieval Method
Authors: IWUAGWU F. C. , GUPTA A.
Published: March 2004

This report describes a simple technique of retrieving retracted proximal flexor tendon ends in Zone II injuries. This technique utilizes steel wires that are readily available in any hand set in the operating room. We have found that this is a consistently successful and atraumatic technique.
Open Reduction and Screw Fixation of Mallet Fractures
Authors: KRONLAGE S. C. , FAUST D.
Published: March 2004

Twelve patients with mallet fractures treated by open reduction and internal fixation with small screws were reviewed at an average of 31 months after surgery. The indication for surgery was a fracture involving more than one-third of the distal phalanx articular surface or with subluxation of the distal interphalangeal joint. Loss of reduction occurred in one patient and in another one screw loosened slightly without loss of reduction. There were no nail deformities, infections, or secondary procedures. The mean range of motion was from 6° (range, 0–30°) (extensor lag) to 70° (range, 60–90°) flexion. Ten patients had no evidence of degenerative changes, one had minor joint space narrowing and one had significant deformity. Open reduction and screw fixation with small screws can lead to satisfactory outcome in appropriate patients.
Tension Band Wiring of Unstable Transverse Fractures of the Proximal and Middle Phalanges of the Hand
Authors: PEHLIVAN O. , KIRAL A. , SOLAKOGLU C. , AKMAZ I. , KAPLAN H.
Published: March 2004

Twenty-three isolated, unstable and closed transverse middle and proximal phalangeal shaft fractures in 23 patients were treated by tension band wiring. The tension band was applied with two transverse Kirschner wires that did not cross the fracture line. All of the fractures united and achieved satisfactory functional outcomes. No patient required either physiotherapy or tenolysis or capsulotomy surgery.
Tumoral Calcinosis Infiltrating the Biceps Brachii Tendon – Excision and Reconstruction with Allograft: A Case Report
Authors: AYDIN A. , TUNCER S. , ERER M. , BILGIC B.
Published: March 2004

Two patients with limited elbow motion due to tumoral calcinosis underwent resection of calcified masses around the elbow joints. This necessilated removal of the distal two thirds and three fourths of the biceps muscles. The resulting defects were reconstructed with homologous Achilles tendon grafts. Both patients regained M4 muscle power and no recurrences were observed.
Evaluation of a Novel Tourniquet Device for Bloodless Surgery of the Hand
Authors: BOIKO M. , ROFFMAN M.
Published: March 2004

This study evaluates a new device (S-MART™) for exsanguination and occlusion of the blood flow to the arm for hand surgery. The device consists of a silicone ring wrapped within a sterile stockinette and pull straps. It is applied by placing it on the patient’s fingers and rolling it up the limb to the desired occlusion site by pulling on the straps. The time for placement and removal of the device was measured during trigger release and carpal tunnel surgery and the quality of exsanguination was evaluated. The device could be placed and removed quickly and provided an excellent bloodless field. At follow-up examination no signs or symptoms were seen at the site of the S-MART™ occlusion and no complications were observed in any patient.
Plating of Metacarpal Fractures: Unicortical or Bicortical Screws?
Authors: DONA E. , GILLIES R. M. , GIANOUTSOS M. P. , WALSH W. R.
Published: February 2004

Mid-shaft transverse osteotomies were performed in 18 cadaveric metacarpals and randomly divided into two groups. Using dorsally applied plates for repair, one group was secured using 6 mm unicortical screws, while bicortical screws were used in the second group. The metacarpals were tested to failure with a four-point bending protocol using a servo-hydraulic testing machine and a 1 kN load cell. The mean load to failure was 596 N (SD=142) for the unicortical and 541 N (SD=171) for the bicortical group. The stiffness was 333 N/mm (SD=116) for the unicortical and 458 N/mm (SD=158) for the bicortical group. Both load to failure and stiffness were not statistically significant between the two groups. Failure occurred by fracture at the screw-bone interface in all specimens: no screw pull-out was observed. No biomechanical advantage was found when using bicortical screws in metacarpal fracture plating.
Darier’s Disease, An Unusual Problem and Solution
Authors: SPROWSON A. P. , JEFFERY S. L. A. , BLACK M. J. M.
Published: February 2004

A 46-year-old woman with Darier’s disease was referred suffering from severe nail involvement. The patient suffered constant nail infections and an intolerable cycle of progressively more deformity.

On examination the patient’s nails and nail folds were badly deformed.

Initially, as a test, a procedure was undertaken on the thumb alone. The operation was performed under tourniquet control with a digital nerve block. An eponychial flap was raised and nail complex excised. A full thickness skin graft was obtained from the groin. This was sutured into place with the proximal border of graft tucked under the eponychial fold. The results were excellent both surgically and cosmetically.

Subsequently, procedures were performed on the remaining nine digits.

Darier’s disease is extremely variable in its degree of nail involvement. This case highlights a surgical intervention that may help people with intractable associated nail disease.
Bioactive cement or ceramic/porous coating vs. Conventional cement to obtain early stability of the acetabular cup Randomised study of 96 hips followed with radiostereometry
Authors: Digas Georgios , Thanner Jonas , Anderberg Christian , Kärrholm Johan
Published: February 2004

Ninety patients (96 hips) scheduled for THA were stratified to fixation of the acetabular component in three main groups of about equal size. Fluoride cement, porous coated press‐fit cup with ceramic coating or Palacos cum Gentamicin cement were used. All patients received Spectron EF stem. The migration of the cups and the femoral head penetration into the socket were measured with radiostereometric analysis. At 2 years the choice of fixation did not influence the migration or rotation of the cup. Patients with compromised bone quality showed increased three‐dimensional (3D or total) migration. Proximal and 3D penetration rates were increased in cemented compared with the uncemented cups (p < 0.001), which probably not could be related to the choice of fixation. Appearance of radiolucent lines was almost equal in the two cemented groups. Uncemented cups had less radiolucent lines at 2 years. Fluoride containing cement or uncemented fixation did not improve the early postoperative stability of the socket. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
The interaction between opening call auctions and ongoing trade: Evidence from the NYSE
Authors: Brooks Raymond M. , Moulton Jonathan
Published: February 2004

We investigate the impact that the opening batch has on trading for the remainder of the day and what impact the prior day's trading has on the subsequent day's open. Traders have an interest in these trading impacts as their trades may cluster around opening and closing time periods. We find that the larger the volume in the opening batches, the greater the volume across the day. We also find the prior day's volume being positively related to the subsequent day's opening volume. Combined, these results suggest a continuing pattern of trade volume rolling from one day to the next. Additionally, we find that the spread in the continuous market can be partially attributed to the price change in the opening batch. We also find evidence of opening trade price reversals. Combined with the absence of price reversals following the opening trade, we conclude that the opening process may be more efficient at handling information than the continuous market.
AtHMA3, a plant P1B‐ATPase, functions as a Cd/Pb transporter in yeast
Authors: Gravot Antoine , Lieutaud Aurélie , Verret Frédéric , Auroy Pascaline , Vavasseur Alain , Richaud Pierre
Published: March 2004

The Arabidopsis thaliana AtHMA3 protein belongs to the P1B‐adenosine triphosphatase (ATPase) transporter family, involved in heavy metal transport. Functional expression of AtHMA3 phenotypically complements the Cd/Pb‐hypersensitive yeast strain Δycf1, but not the Zn‐hypersensitive mutant Δzrc1. AtHMA3‐complemented Δycf1 cells accumulate the same amount of cadmium as YCF1‐complemented Δycf1 cells or wild‐type cells, suggesting that AtHMA3 carries out an intracellular sequestration of Cd. A mutant of AtHMA3 altered in the P‐ATPase phosphorylation domain did not complement Δycf1, suggesting that metal transport rather than chelation is involved. The fusion protein AtHMA3::green fluorescent protein (GFP) is localized at the vacuole, consistent with a role in the influx of cadmium into the vacuolar compartment. In A. thaliana, the mRNA of AtHMA3 was detected mainly in roots, old rosette leaves and cauline leaves. The expression levels were not affected by cadmium or zinc treatments.
Ca2+ binding sites in calmodulin and troponin C alter interhelical angle movements
Authors: Goto Kunihiko , Toyama Akira , Takeuchi Hideo , Takayama Kazuyoshi , Saito Tsutomu , Iwamoto Masatoshi , Yeh Jay Z , Narahashi Toshio
Published: March 2004

Molecular dynamics analyses were performed to examine conformational changes in the C‐domain of calmodulin and the N‐domain of troponin C induced by binding of Ca2+ ions. Analyses of conformational changes in calmodulin and troponin C indicated that the shortening of the distance between Ca2+ ions and Ca2+ binding sites of helices caused widening of the distance between Ca2+ binding sites of helices on opposite sides, while the hydrophobic side chains in the center of helices hardly moved due to their steric hindrance. This conformational change acts as the clothespin mechanism.
L‐Arginine inhibits xanthine oxidase‐dependent endothelial dysfunction in hypercholesterolemia
Authors: White C.Roger , Parks Dale A. , Patel Rakesh P. , Shelton Jonathan , Tarpey Margaret M. , Freeman Bruce A. , Darley-Usmar Victor M.
Published: March 2004

Xanthine oxidase (XO)‐derived superoxide contributes to endothelial dysfunction in humans and animal models of hypercholesterolemia (HC). SinceL‐arginine supplementation prevents defects in NO signaling, we tested the hypothesis thatL‐arginine blunts the inhibitory effect of XO on vascular function. Acetylcholine‐mediated relaxation was significantly impaired in ring segments of HC rabbits, a response that was associated with an increase in plasma XO activity.L‐Arginine treatment of HC rabbits reduced plasma XO and improved endothelial function.L‐Arginine also modestly prolonged the lag time for oxidation in isolated lipoprotein samples. These results reveal that the principal action ofL‐arginine is to protect against the XO‐dependent inactivation of NO in arteries of HC rabbits.
MEF up‐regulates human β‐defensin 2 expression in epithelial cells
Authors: Lu Zhuo , Kim Kyoung-Ah , Suico Mary Ann , Shuto Tsuyoshi , Li Jian-Dong , Kai Hirofumi
Published: March 2004

Human β‐defensin 2 (HBD2), an antimicrobial peptide, is widely expressed in epithelial tissues and displays a potent killing activity in response to the invasiveness of a wide range of microorganisms and the stimulation of various molecules. Myeloid ELF‐1‐like factor (MEF) has been reported to be involved in innate immunity responses, such as activation of perforin and lysozyme transcription. The role of MEF in the transcription regulation of HBD2, however, is unknown. Here, we show that MEF not only activated HBD2 promoter activity, but also increased the endogenous HBD2 transcription level. Moreover, the activated HBD2 promoter activity was attenuated by the antisense MEF RNA input and the loss of the ETS binding site (EBS: GGAA core sequence) in the HBD2 promoter. The interaction between the EBS and MEF protein was further confirmed by electrophoretic mobility shift assay. Thus, our data indicate that MEF may play an important role in regulating HBD2 expression in epithelial cells.
Degadration of mismatch repair hMutSα heterodimer by the ubiquitin‐proteasome pathway
Authors: Hernandez-Pigeon Hélène , Laurent Guy , Humbert Odile , Salles Bernard , Lautier Dominique
Published: March 2004

Mismatch repair plays a critical role in genome stability. This process requires several proteins including hMSH2/hMSH6 (hMutSα) heterodimer involved in the first stage of the process, the mispair recognition. We previously reported that in U937 and HL‐60 cell lines, hMSH2 and hMSH6 protein expression was much lower than that in HeLa and KG1a cells. Here, we showed that the decreased expression of hMutSα results from differences in the degradation rate of both proteins by the ubiquitin‐proteasome pathway. Our data suggest that in human cell lines, ubiquitin‐proteasome could play an important role in the regulation of hMutSα protein expression, thereby regulating mismatch repair activity.
Killing of target cells by redirected granzyme B in the absence of perforin
Authors: Kurschus Florian C. , Kleinschmidt Martin , Fellows Edward , Dornmair Klaus , Rudolph Rainer , Lilie Hauke , Jenne Dieter E.
Published: March 2004

Granzyme B (GzmB) is a potent apoptosis‐inducing serine protease of cytotoxic lymphocytes. Following receptor‐mediated endocytosis, GzmB is supposed to enter the cytosol through perforin‐mediated membrane disruption. We investigated whether retargeting of GzmB to Lewis Y positive surface receptors could lead to perforin‐independent target cell death. We coupled recombinant GzmB to the Lewis Y‐binding antibody dsFv‐B3. Targeting of GzmB to Lewis Y positive cells triggered cell death with similar efficacy as dsFv‐B3 targeted Pseudomonas exotoxin fragment 38 (PE38). Since GzmB was only weakly inhibited by plasma proteins, GzmB‐based immunoconjugates should be useful as a new class of immunotoxins with low immunogenicity utilizing programmed cell death for therapeutic purposes.
On the mechanism of SPP‐catalysed intramembrane proteolysis; conformational control of peptide bond hydrolysis in the plane of the membrane
Authors: Lemberg Marius K , Martoglio Bruno
Published: March 2004

Intramembrane‐cleaving proteases are members of a novel type of enzyme that hydrolyse substrate proteins within transmembrane regions. The presently known proteases that catalyse such cleavage reactions are membrane proteins of high hydrophobicity and multiple predicted transmembrane regions. A key feature is the positioning of active site residues in hydrophobic segments implying that the catalytic centre is assembled within the plane of the membrane. Nevertheless, all these proteases appear to utilise catalytic mechanisms similar to classic proteases that expose their active site domains in aqueous compartments. In the present review, we will address the mechanism of intramembrane proteolysis on the example of the signal peptide peptidase, and discuss how enzyme‐catalysed hydrolysis of peptide bonds within the plane of a cellular membrane might occur.
Crystal structures of bR(D85S) favor a model of bacteriorhodopsin as a hydroxyl‐ion pump
Authors: Facciotti Marc T , Rouhani Shahab , Glaeser Robert M
Published: March 2004

Structural features on the extracellular side of the D85S mutant of bacteriorhodopsin (bR) suggest that wild‐type bR could be a hydroxyl‐ion pump. A position between the protonated Schiff base and residue 85 serves as an anion‐binding site in the mutant protein, and hydroxyl ions should have access to this site during the O‐intermediate of the wild‐type bR photocycle. The guanidinium group of R82 is proposed (1) to serve as a shuttle that eliminates the Born energy penalty for entry of an anion into this binding pocket, and conversely, (2) to block the exit of a proton or a related proton carrier.
Crystal structure of human monoamine oxidase B, a drug target enzyme monotopically inserted into the mitochondrial outer membrane
Authors: Binda Claudia , Hubálek Frantisek , Li Min , Edmondson Dale E. , Mattevi Andrea
Published: March 2004

Monoamine oxidase B (MAO B) is an outer mitochondrial membrane protein that oxidizes arylalkylamine neurotransmitters and has been a valuable drug target for many neurological disorders. The 1.7 Å resolution structure of human MAO B shows the enzyme is dimeric with a C‐terminal transmembrane helix protruding from each monomer and anchoring the protein to the membrane. This helix departs perpendicularly from the base of the structure in a different way with respect to other monotopic membrane proteins. Several apolar loops exposed on the protein surface are located in proximity of the C‐terminal helix, providing additional membrane‐binding interactions. One of these loops (residues 99–112) also functions in opening and closing the MAO B active site cavity, which suggests that the membrane may have a role in controlling substrate binding.
Structural basis for ion conduction and gating in ClC chloride channels
Authors: Dutzler Raimund
Published: March 2004

Members of the ClC family of voltage‐gated chloride channels are found from bacteria to mammals with a considerable degree of conservation in the membrane‐inserted, pore‐forming region. The crystal structures of the ClC channels of Escherichia coli and Salmonella typhimurium provide a structural framework for the entire family. The ClC channels are homodimeric proteins with an overall rhombus‐like shape. Each ClC dimer has two pores each contained within a single subunit. The ClC subunit consists of two roughly repeated halves that span the membrane with opposite orientations. This antiparallel architecture defines a chloride selectivity filter within the 15‐Å neck of a hourglass‐shaped pore. Three Cl− binding sites within the selectivity filter stabilize ions by interactions with α‐helix dipoles and by chemical interactions with nitrogen atoms and hydroxyl groups of residues in the protein. The Cl− binding site nearest the extracellular solution can be occupied either by a Cl− ion or by a glutamate carboxyl group. Mutations of this glutamate residue in Torpedo ray ClC channels alter gating in electrophysiological assays. These findings reveal a form of gating in which the glutamate carboxyl group closes the pore by mimicking a Cl− ion.
A new approach that allows identification of intron‐split peptides from mass spectrometric data in genomic databases
Authors: Allmer Jens , Markert Christine , Stauber Einar J. , Hippler Michael
Published: March 2004

We present a new approach that allows the identification of intron‐split peptides from mass spectrometric data in genomic databases. Our algorithm uses small regions of peptide sequence information which are automatically deduced from de novo amino acid sequence predictions together with the molecular mass information of the precursor ion. The sequence predictions are based on selected collision‐induced mass spectrometric fragmentation spectra. Fragments of the predicted amino acid sequence are aligned with each of the six frames of the translated genome and the precursor mass information is used to assemble the corresponding tryptic peptides using the sequence as a matrix. Hereby, intron‐split peptides can be gathered and in turn verified by mass spectrometric data interpretation tools such as Sequest.
Molecular cloning and characterization of β1,4‐N‐acetylgalactosaminyltransferases IV synthesizing N,N′‐diacetyllactosediamine1
Authors: Gotoh Masanori , Sato Takashi , Kiyohara Katsue , Kameyama Akihiko , Kikuchi Norihiro , Kwon Yeon-Dae , Ishizuka Yasuko , Iwai Toshie , Nakanishi Hiroshi , Narimatsu Hisashi
Published: March 2004

A sequence highly homologous to β1,4‐N‐acetylgalactosaminyltransferase III (β4GalNAc‐T3) was found in a database of human expressed sequence tags. The full‐length open reading frame of the gene, β4GalNAc‐T4 (GenBank accession number AB089939), was cloned using the 5′ rapid amplification of cDNA ends method. It encodes a typical type II transmembrane protein of 1039 amino acids having 42.6% identity with β4GalNAc‐T3. The recombinant enzyme transferred N‐acetylgalactosamine to N‐acetylglucosamine‐β‐benzyl with a β1,4‐linkage to form N,N′‐diacetyllactosediamine as did β4GalNAc‐T3. In specificity toward oligosaccharide acceptor substrates, it was quite similar to β4GalNAc‐T3 in vitro, however, the tissue distributions of the two enzymes were quite different. These results indicated that the two enzymes have similar roles in different tissues.
Analysis of GT‐3a identifies a distinct subgroup of trihelix DNA‐binding transcription factors in Arabidopsis
Authors: Ayadi Mira , Delaporte Virginie , Li You-Fang , Zhou Dao-Xiu
Published: March 2004

Trihelix DNA‐binding factors (or GT factors) bind to GT elements found in the promoters of many plant genes. Although the binding specificity and the transcriptional activity of some members (e.g. GT‐1 and GT‐2) have been studied, the regulatory function of this family of transcription factors remains largely unknown. In this work, we have characterised a new GT factor, namely GT‐3a, and a closely related member, GT‐3b. We show that (1) they can form either homo‐ or heterodimers but do not interact with GT‐1; (2) they are predominantly expressed in floral buds and roots; (3) GT‐3a cannot bind to the binding sites of GT‐1 or GT‐2, but binds to the cab2 and rbcS‐1A gene promoters via the 5′‐GTTAC sequence, which has been previously shown to be the core of the Site 1 type of GT elements. These results suggest that GT‐3a and GT‐3b belong to a distinct subgroup of GT factors and that each subgroup of GT factors binds to a functionally distinct type of cis‐acting GT elements.
The islet‐specific glucose‐6‐phosphatase‐related protein, implicated in diabetes, is a glycoprotein embedded in the endoplasmic reticulum membrane
Authors: Shieh Jeng-Jer , Pan Chi-Jiunn , Mansfield Brian C. , Chou Janice Yang
Published: March 2004

The islet‐specific glucose‐6‐phosphatase‐related protein (IGRP) has no known catalytic activity, but is of interest because it is the source of the peptide autoantigen targeted by a prevalent population of pathogenic CD8+ T cells in non‐obese diabetic mice. To better understand the potential roles of this protein in diabetes mellitus, we examine the subcellular localization and membrane topography of human IGRP. We show that IGRP is a glycoprotein, held in the endoplasmic reticulum by nine transmembrane domains, which is degraded in cells predominantly through the proteasome pathway that generates the major histocompatibility complex class I‐presented peptides.
HBZ interacts with JunD and stimulates its transcriptional activity
Authors: Thébault Sabine , Basbous Jihane , Hivin Patrick , Devaux Christian , Mesnard Jean-Michel
Published: March 2004

Human T‐cell leukemia virus type I (HTLV‐I) bZIP factor (HBZ) is a viral basic leucine zipper protein that was originally described as a partner of cAMP response element binding protein‐2 and as a repressor of HTLV‐I viral transcription. In addition, HBZ is able to interact with the activator protein‐1 (AP‐1) transcription factors c‐Jun and JunB, the interaction with c‐Jun leading to a transcriptional repression of AP‐1‐regulated genes. Here we show that HBZ also interacts with JunD in vitro and in vivo, and that this association occurs via the bZIP domain of the two proteins. Moreover, we show that HBZ can activate JunD‐dependent transcription and that its amino‐terminus is required.
Conditioned stress‐induced analgesia in humans
Authors: Flor Herta , Grösser Sabine M.
Published: March 2004

The purpose of this experiment was the demonstration of conditioned stress‐induced analgesia in humans. Following a baseline day (day 1), two groups of 10 subjects were each exposed to green light as the conditioned stimulus (CS) and mental arithmetic plus noise as the unconditioned stimulus (US) for 5 days (days 2–6), a third group of 10 subjects was only exposed to the US. On the test day (day 7), pain threshold and pain tolerance were tested, while groups 1 and 3 received the green light CS and group 2 received no CS. Group 1 showed a significantly higher pain threshold and higher pain tolerance on the test day, whereas the two control groups did not have altered pain perception. Heart rate data confirmed successful stress induction. Heart rate and blood pressure were unaltered on the test day, thus making cardiovascular mediation of the conditioning effect unlikely. Conditioned stress analgesia might be useful in the understanding of chronic pain‐syndromes.
The lifetime occurrence of Herpes zoster and prevalence of post‐herpetic neuralgia: A retrospective survey in an elderly population
Authors: Bowsher David
Published: March 2004

One‐thousand‐and‐seventy‐one randomly chosen elderly persons (537 women, 534 men; median age 80) were recruited from the Institute of Human Aging (Dept of Psychiatry, University of Liverpool). Almost a quarter (23.8%; equal numbers of both sexes) had had shingles (HZ), at a median age of 60 (for both sexes); 39 subjects (3.6% of all respondents, 15% of those who had had shingles), two thirds of whom were female, developed post‐herpetic neuralgia (PHN), defined as pain persisting for more than 3 months; they acquired HZ at a median age of 70. In 22 of them, pain had resolved by the time they were questioned, but in 17 it was ongoing (from less than 12 to 504 months). Two new independent risk factors for PHN were identified: (1) female gender; and (2) living alone at the time of HZ acquisition (p = 0.009). In addition to confirming the well‐known factor of: (3) age at shingles acquisition (up to the early 90s); and (4) scarring, presumed to be a consequence of rash severity, was significantly commoner in subjects whose HZ was followed by PHN.

Extrapolating the prevalence figures to the whole UK population, of whom 9.28 million were over 64 in 1992, it can be conservatively estimated that at any one time, some 200 000 people in the UK have PHN.
Behavioural effects of LTP‐inducing sciatic nerve stimulation in the rat
Authors: Svendsen Frode , Tjølsen Arne , Rykkja Frøydis , Hole Kjell
Published: March 2004

A short‐lasting tetanic sciatic nerve stimulation that previously has been shown to be nociceptive only during the stimulation, induces long‐term potentiation (LTP) of nociceptive evoked responses in wide dynamic range neurons in the dorsal horn of rats. The LTP may contribute to the process of central sensitization. We have shown that the tetanic conditioning stimulation with muscular contractions induces LTP of both Aβ‐ and C‐fibre evoked responses. However, the same stimulation during muscular paralysis induces LTP only of C‐fibre evoked responses. In the present study, we investigated the effects of this conditioning stimulation with or without muscular paralysis in behavioural tests in rats. Conditioning stimulation with muscular contractions caused a significant reduction of weight borne on the stimulated side, suggesting muscular soreness and peripheral sensitization. Conditioning stimulation during neuromuscular paralysis, which only has given LTP of C‐fibre evoked responses in intact animals, caused no change in the weight borne on the stimulated side, suggesting less or even absence of allodynia. However, in these animals the response temperature in the hot plate test was increased both on the stimulated and on the contralateral side compared to sham‐operated rats. In view of our recent results indicating that a descending inhibition reduces the expression of LTP in dorsal horn cells, and the suggestion by others that long‐term descending inhibition may override a segmental facilitation, it is suggested that an increased long‐lasting endogenous nociceptive inhibition is induced after LTP‐inducing stimulation. This is an interesting parallel to stimulation‐induced analgesia in humans. C 1999 European Federation of Chapters of the International Association for the Study of Pain
Thermal and tactile perception thresholds in acute herpes zoster
Authors: Haanpää Maija L. , Laippala Pekka A. , Nurmikko Turo J.
Published: March 2004

This study was conducted to determine somatosensory perception thresholds in 97 immunocompetent patients with herpes zoster (HZ), and to evaluate their associations with the development of post‐herpetic neuralgia (PHN). Warm, cold and heat pain thresholds were tested by Thermotest (SOMEDIC) and tactile thresholds by Semmes‐Weinstein monofilaments. To establish reference values, 103 healthy subjects underwent somatosensory testing, from which values were calculated for both genders for four age groups (<60, 60–69, 70–79 and ≥ in five dermatomal levels (VI, C3, T3, T10 and S1). Patients with HZ underwent quantitative somatosensory testing within the affected dermatome, its mirror image dermatome and an adjacent dermatome bilaterally. The follow‐up visits with somatosensory testing took place at 2 weeks, 6 weeks, 3 months and 6 months. When evaluated as means of the results, warm and cold thresholds were significantly elevated in the affected dermatome from the initial visit until 3 and 6 months, respectively. By contrast, heat pain thresholds were lowered at the initial visit but normalized by 2 weeks, and tactile thresholds remained unchanged. These threshold changes were associated neither with further development of PHN nor each other. It is concluded that measurement of somatosensory perception thresholds in early stages of HZ shows evidence of impaired neural function but is not helpful in predicting which patient will go on to develop PHN.