bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of an Inhibitor of Nitric Oxide Synthesis on Skin Wound Repair
Authors: Amadeu TP , Desmoulière A , Costa AMA
Published: January 2005

Considering that nitric oxide (NO) plays an important role on cutaneous wound repair, but its effects have not been defined, an inhibitor of NO synthesis (LNAME) was used. Control group received free water and LNAME group received LNAME (20 mg/kg/day) in drinking water. A full‐thickness excisional wound was performed (0d), and the animals were sacrificed 7, 14, and 21 days later. Wound contraction was evaluated by lesion surface measurement at 0d, 7d, 14d, and 21d. The blood pressure of all rats was measured in the beginning and at the each time point of the experiment with a plethysmography method. The wound and normal skin surrounding was formol fixed and paraffin embedded. To evaluate the vessels, an immunohistochemistry for α‐smooth muscle actin was done and stereological parameters were estimated in superficial and deep dermis. At 7d, 14d, and 21d the blood pressure of LNAME group was higher compared with control group (p < 0.001 for all). The wound contraction of LNAME group was slower compared with control group at 14d and 21d (p = 0.004 for both). In superficial dermis, vessels were more dilated in control group compared with LNAME group at 14d and 21d (p = 0.02; p < 0.0001, respectively) and longer in control group compared with LNAME group at 7d and 14d (p = 0.043; p = 0.002, respectively). Deep dermal vessels were more prominent and dilated in control group compared with LNAME group at 21d (p = 0.003; p = 0.0007, respectively), but at 7d, vessels were more dilated in LNAME group compared with control group (p = 0.015). In deep dermis, vessels were longer in control group compared with LNAME group at 14d and 21d (p = 0.002; p = 0.046, respectively). Our results show that nitric oxide inhibition affects the wound contraction and the vascularization pattern, mainly in the later phases of skin wound repair.
Increased Smad4‐Mediated Acceleration of TGF‐β1 Signaling and Myofibroblastic Differentiation in Tubulointerstitial Cells in Kidneys of Hereditary Nephrotic Mice
Authors: Goto Y , Anan S , Yamaguchi‐Yamada M , Sakata C , Manabe N
Published: January 2005

ICR‐derived glomerulonephritis (ICGN) mouse is a hereditary model animal for nephrotic syndrome with chronic renal tubulointerstitial fibrosis. In fibrotic disorder, myofibroblastic differentiation plays crucial roles in pathogenesis and is dominantly regulated by the transforming growth factor‐beta1 (TGF‐β1) signaling system. To reveal the relationships between the pathogenic mechanism of the renal fibrosis and TGF‐β1 signaling in ICGN mice, we examined the expression and localization of TGF‐β1 signal transducer proteins, TGF‐β receptor (TGFR)‐I, TGFR‐II, Smad2/3 and Smad4, in kidney sections and in primarily cultured renal tubulointerstitial fibroblasts (TIFs). In kidneys of ICGN mice, many TIFs were differentiated to myofibroblastic cells, confirmed as alpha‐smooth muscle actin (αSMA)‐positive cells, and though no significant increase in production and activation of TGF‐β1 were observed in ICGN‐TIFs as compared with control ICR‐TIFs. The rate of αSMA positive cells in ICGN‐TIFs increased during cell culture but not in those of ICR‐TIFs. In vitro transcriptional reporter assay for TGF‐β1 and Western blotting for TGF‐β1 signal transducers revealed that no notable differences in the expression levels of TGFR‐I, TGFR‐II or Smad2/3 were seen between ICR‐ and ICGN‐TIFs. However, augmented cytoplasmic Smad4 in ICGN‐TIFs was observed, and it may cause hypersensitivity against TGF‐β1. These results indicate that abnormal cytoplasmic augmentation of Smad4 induces acceleration of TGF‐β1 signaling and fibrogenic myofibroblastic differentiation in the renal tubulointerstitial cells of ICGN mice.
Persistent Ischemia Impairs Myofibroblast Development in Wound Granulation Tissue a New Model of Delayed Wound Healing
Authors: Alizadeh N , Pepper MS , Alfo K , Montandon D , Gabbiani G , Bochaton‐Piallat ML , Pittet B
Published: January 2005

We describe here a new animal model designed to assess the impact of ischemia on wound healing. Among eight patterns of arterial lesion, resection of the external iliac artery down to the femoral artery at the level of the knee was chosen as the reference model, and was performed on the left limb in 24 Wistar rats. The right limb was sham operated and was used as a control. Skin wounds measuring 1.2 × 0.8 cm were created bilaterally on the dorsal aspect of the foot. Blood flow, measured by laser Doppler flowmetry, decreased by over 90% in the ischemic limb after arterial lesion. A significant delay in wound closure was observed with a measurable decrease in wound contraction. Quantification of myofibroblasts by means of α‐smooth muscle actin staining showed a significant delay in the appearance and a decrease in the number of myofibroblasts. These findings suggest that decreased wound contraction plays an important role in delayed ischemic wound healing, probably due to reduced myofibroblast development and activity. The model we have developed may also be useful for further investigating other mechanisms of wound healing, for testing pharmaceutical agents and for the study of the impact of pathological conditions such as hypertension or diabetes mellitus.
Contribution of Interstitial Fluid Flow to Fibroblast Alignment and Differentiation
Authors: Ng CP , Hinz B , Swartz M
Published: January 2005

Fibrosis is often seen in tissues following vessel hyperpermeability, interstitial fluid flow, and edema; examples include secondary lymphedema in skin and pulmonary edema. To determine whether the biophysical changes that interstitial flow induces can influence fibroblast behavior, we developed a tissue culture model of interstitial flow that can be chronically applied to 3‐D cultures. We use it to demonstrate that even very low interstitial fluid flows (of 1–10 microns/sec) can induce human dermal and lung fibroblasts embedded in type I collagen to align perpendicular to the direction of flow and align the collagen extracellular matrix fibers. We saw that attachment to collagen is necessary for alignment, since fibroblasts in fibrin gels do not align, and those grown in fibrin‐collagen mixtures align only weakly. Furthermore, fibroblast alignment corresponds to increased expression of alpha‐smooth muscle actin, signaling that the cells are undergoing differentiation to a fibrotic myofibroblast phenotype. Collagen fiber alignment is demonstrated using confocal reflectance microscopy and FFT analysis. Our results indicate that interstitial flow, which is increased in vivo during wound healing and many pulmonary disorders such as edema, may contribute to interstitial fibrosis. The results also suggest that interstitial flow can be used to develop in vitro models of interstitial fibrosis for studies of directed matrix remodeling and cell orientation.
T cell repertoire in patients with stable scleroderma
Authors: Tiev K P , Abriol J , Burland M C , Antonelli D , Klatzmann D , Cabane J , Boyer O
Published: January 2005

At onset of systemic sclerosis (SSc), T cells have been found to oligoclonally expand in the skin, presumably in response to auto-antigens, but the T cell repertoire has not been evaluated at a later stage. To determine whether a perpetuating immune response contributes to the pathogenesis of stable SSc, the T cell repertoire was analysed in patients with diffuse (d) or limited (l) SSc, and compared to patients with primary Raynaud's phenomenon (RP) or healthy volunteers (Ctrl). The T cell repertoire (total, CD4 or CD8 sorted blood T cells) was analysed by qualitative and quantitative immunoscope (14 BV families analysed) in 11 untreated dSSc and 11 untreated lSSc, 10 RP and 11 Ctrl. To better detect in vivo activated cells, repertoire analysis was also performed on sorted CD4 T cells after in vitro culture with IL-2. In parallel, 6 skin biopsies from SSc patients were analysed. After 7–8 years of disease evolution, SSc patients did not show detectable clonal T cell expansions in the skin, even after tentative expansion from the biopsy with IL-2. Total T cell, sorted CD4 and CD8 T cell repertoires from the blood of patients with SSc did not show significant perturbation as compared to patients with RP and Ctrl. After IL-2 culture for 7 days, blood CD4 T cells from the patients did not preferentially expand as compared to RP and Ctrl. These findings suggest that antigen-driven immune responses may play a lesser role in established SSc than at disease onset.
Elevated macrophage migration inhibitory factor (MIF) levels in the urine of patients with focal glomerular sclerosis
Authors: Matsumoto K , Maruyama N , Maruyama T , Ohnishi Y , Nonaka S , Inoshita A , Ito K , Kitajima S , Abe M , Satomura A , Fujita T
Published: January 2005

The pathogenesis of focal glomerular sclerosis (FGS) is poorly understood. Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine released from T cells and macrophages, and is a key molecule in inflammation. To examine further the possible role of MIF in FGS, we measured MIF levels in the urine. The purpose of the present study was to evaluate the involvement of MIF in FGS. Urine samples were obtained from 20 FGS patients. The disease controls included 40 patients with minimal-change nephrotic syndrome (MCNS) and membranous nephropathy (MN). A group of healthy subjects also served as controls. Biopsies were performed in all patients prior to entry to the study. The samples were assayed for MIF protein by a sandwich enzyme-linked immunosorbent assay (ELISA). The levels of MIF in the urine of FGS patients were significantly higher than those of the normal controls and patients with MCNS and MN. In contrast, the levels of urinary MIF (uMIF) in patients with MCNS and MN did not differ significantly from normal values. In the present study, attention also focused on the relationship between uMIF levels and pathological features. Among the patients with FGS, uMIF levels were significantly correlated with the grade of mesangial matrix increase and that of interstitial fibrosis. There was also a significant correlation between uMIF levels and the number of both intraglomerular and interstitial macrophages. Although the underlying mechanisms remain to be determined, our study presents evidence that urinary excretion of MIF is increased in FGS patients with active renal lesions.
A new mouse model of lung allergy induced by the spores ofAlternaria alternataandCladosporium herbarummolds
Authors: Havaux X , Zeine A , Dits A , Denis O
Published: January 2005

Asthma is a serious health problem and during the last decade various experimental models of asthma have been developed to study the pathogenesis of this disease. In this study we describe a new mouse model of asthma that uses the spores of Alternaria alternata and Cladosporium herbarum, two allergenic molds recognized as common inducers of rhinitis and asthma in humans. Here we demonstrate that A. alternata and C. herbarum spores are immunogenic when injected into BALB/c mice, and induce the production of specific IgM and IgG1 antibodies and strongly increase IgE serum levels. To induce the allergic response, mice were sensitized by two intraperitoneal (i.p.) injections and then intranasaly (i.n.) challenged with A. alternata and C. herbarum spores. Bronchoalveolar lavages (BALs) from these mice contained numerous macrophages, neutrophils, eosinophils and lymphocytes whereas neutrophils were the predominant BAL inflammatory cells in nonsensitized mice. Histological studies demonstrated an influx of eosinophils in peri-vascular and peri-bronchial areas and the presence of numerous epithelial goblet cells only in sensitized mice. Increased expression of mRNA specific for various chemokines (eotaxin, MIP-1α, MIP-2) and chemokine receptors (CCR-1, CCR-2 and CCR-5) was observed in the lungs of nonsensitized mice challenged with the spores. Expression of CCR-3 mRNA in the lungs and Th2 cytokine  (IL-4,  IL-5  and  IL-13)  secretion  in  the  BAL  was  additionally observed in sensitized and challenged mice. Finally we demonstrate through whole-body plethysmography that mold spore sensitization and challenge induce the development of an airway hyperreactivity in response to nebulized methacholine.
Mycophenolate mofetil and roscovitine decrease cyclin expression and increase p27kip1 expression in anti Thy1 mesangial proliferative nephritis
Authors: Chiara M , Menegatti E , Di Simone D , Davit A , Bellis D , Sferch D , De Rosa G , Giachino O , Sena L M , Roccatello D
Published: January 2005

The response of mesangial cells to a phlogistic challenge includes cell proliferation and mesangial matrix expansion. Cell proliferation is a highly regulated process which includes enhancing factors such as cyclins, cyclin dependent kinases, and inhibitory proteins, such as p27kip1. The aim of the study was to evaluate the effects of Mycophenolate mofetil (MMF), and roscovitine (R), on the cell cycle regulatory system when administered in the florid phase of the experimental model of mesangial proliferative nephritis induced by the anti Thy-1 antigen monoclonal antibody. Three days after nephritis induction, different groups were given MMF and R. Rats treated with MMF or R showed a slight decrease in mesangial proliferation and matrix expansion. Samples of cortical tissue were tested by ‘real time’ RT-PCR in order to study gene expression of cyclins B, D1, D2, D3, E, and the cyclin inhibitor p27kip1. Localization of mRNA was evaluated by in situ hybridization. Real time RT-PCR analysis showed a significant decrease in cyclins B, D1, D2, and D3 in rats treated with either MMF or R as compared to controls. Both MMF and R treatment induced a significant increase in p27kip1 mRNA expression. In situ hybridization showed a mesangial-endothelial expression pattern in glomeruli. The number of labelled cells per glomerulus, the number of positive glomeruli in each examined slide as well as cyclin D2 and D3 signal intensity was significantly lower in rats treated with MMF or R as compared to controls, whereas MMF or R treatment up-regulated p27kip1 mRNA expression. Immunohistochemical evaluation of p27kip1 aimed to examine the influence of MMF or R on protein expression confirmed up-regulation.
Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behçet's disease
Authors: Imamura Y , Kurokawa M S , Yoshikawa H , Nara K , Takada E , Masuda C , Tsukikawa S , Ozaki S , Matsuda T , Suzuki N
Published: January 2005

Involvement of excessive Th1 cell functions and heat shock protein expression in the pathogenesis of Behçet's disease (BD) has been reported. In this study we have characterized immune responses in intestinal lesions of BD. Peripheral blood lymphocytes (PBL) of BD and healthy controls (HC) and tissue specimens of intestinal Behçet's disease (intestinal BD), Crohn's disease (CD) and ulcerative colitis (UC) were analysed for mRNA and protein expression by reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry, respectively. PBL of BD patients expressed the Th1-related chemokine receptor, CCR5 and CXCR3 preferentially compared with those of healthy controls. Intestinal lesions of BD expressed interferon (IFN)-γ, tumour necrosis factor (TNF)-α and interleukin (IL)-12 mRNA, indicating Th1 skewed responses in vivo. mRNA of Txk, a Tec family tyrosine kinase specific to Th1 cells, was expressed in the lesions, suggesting its contribution to the Th1-dominant responses. In the intestinal samples, CCR5 was detected in all the cases with BD, whereas Th2-related CCR3 and CCR4 were detected randomly, mainly in the cases with inactive BD and those receiving large amounts of prednisolone, indicating the Th1-dominant immune responses in the intestinal lesions. As the ligands of CCR5, MIP1α and MIP1β were detected, whereas RANTES was not. Heat shock protein (HSP) 60 was expressed in PBL and intestinal tissues of BD. Th1-dominant immune responses and HSP60 expression may induce the inflammatory responses and thus be associated with the pathogenesis of intestinal BD.
Generation of Th1 T cell responses directed to a HLA Class II restricted epitope from theAspergillusf16 allergen
Authors: Ramadan G , Davies B , Kurup V P , Keever-Taylor C A
Published: January 2005

The Aspergillus allergen Asp f16 has been shown to confer protective Th1 T cell-mediated immunity against infection with Aspergillus conidia in murine models. Here, we use overlapping (11-aa overlap with preceding peptide) pentadecapeptides spanning the entire 427-aa coding region of Asp f16 presented on autologous dendritic cells (DC) to evaluate the ability of this antigen to induce Th1 responses in humans. Proliferative responses were induced in five out of five donors, and one line with a high frequency of interferon (IFN)-γ-producing CD4+ T cells in response to the complete peptide pool was characterized. This line was cytotoxic to autologous pool-pulsed and Aspergillus culture extract-pulsed targets. Limitation of cytotoxicity to the CD4+ T cell subset was demonstrated by co-expression of the degranulation marker CD107a in response to peptide pool-pulsed targets. Cytotoxic T lymphocytes (CTL) killed Aspergillus hyphae and CTL culture supernatant killed Aspergillus conidia. By screening 21 smaller pools and individual peptides shared by positive pools we identified a single candidate sequence of TWSIDGAVVRT that elicited responses equal to the complete pool. The defined epitope was presented by human leucocyte antigen (HLA)-DRB1-0301. These data identify the first known Aspergillus-specific T cell epitope and support the use of Asp f16 in clinical immunotherapy protocols to prime protective immune responses to prevent or treat Aspergillus infection in immunocompromised patients.
The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma and its precursor lesions and up-regulated by H. pylori
Authors: Schmaußer B , Endrich S , Brändlein S , Schär J , Beier D , Müller-Hermelink H-K , Eck M
Published: January 2005

CCR7 chemokine-receptor expression on tumour cells of gastric carcinoma has been associated with lymph-node metastasis and is thought to play an important role in metastasis. However, so far it is unknown whether CCR7 is newly up-regulated on gastric carcinoma or already expressed in non-neoplastic gastric epithelium. Therefore, epithelial CCR7 expression was investigated in the process of gastric carcinogenesis: non-inflamed mucosa –Helicobacter pylori gastritis – intestinal metaplasia/dysplasia – gastric carcinoma. CCR7 was expressed by gastric epithelium in non-inflamed gastric mucosa (n = 5), H. pylori gastritis (n = 17), intestinal metaplasia (n = 10), dysplasia (n = 3) and on tumour cells in 20 of 24 patients with gastric carcinoma (13/14 intestinal-type; 7/10 diffuse-type) as tested by immunohistochemistry. As CCR7 expression by gastric epithelium was significantly stronger in H. pylori gastritis than in non-infected mucosa, the influence of H. pylori on CCR7 receptor expression of gastric epithelial cells was investigated by fluorescence activated cell sorter analysis. H. pylori strains up-regulated the CCR7 chemokine-receptor in CCR7-positive cell lines. No difference in CCR7 up-regulation between cag+ and cag–H. pylori strains was found. Epithelial CCR7 up-regulation by H. pylori may alter the metastatic fate of gastric carcinoma. Additionally, CCR7 expression not only on gastric carcinoma, but also on non-neoplastic gastric epithelium, suggests a novel biological function.
Reasons for non‐treatment of hepatitis C in veterans in care
Authors: Butt A. A. , Wagener M. , Shakil A. O. , Ahmad J.
Published: January 2005

Summary.  We prospectively studied 354 patients with hepatitis C virus (HCV) infection who were referred to a hepatology specialty clinic to find the reasons for non‐treatment of HCV. The median age was 48 years (range 27–77 years), 98.5% were male and 71% were white. Seventy per cent of the patients were not treated. The most common reasons for non‐treatment were non‐adherence to follow‐up visit (24%), normal liver enzymes (14%), concurrent medical problems (11%), alcohol and drug use (9%), psychiatric problems (7%), advanced liver disease (7%), referral for transplant evaluation (6.4%) and patient refusal, transfer of care to another facility and non‐detectable HCV RNA levels (5% each). The reason was not recorded for 5% of the patients and was treatment deferred in 2.4% while waiting for pegylated interferon approval. Non‐treatment was more likely in patients with less than 12 years of education and a history of incarceration. Patients who were lost to follow‐up and refused treatment were more likely to have current alcohol and drug use and a history of incarceration.
The rate of treatment of chronic hepatitis C in patients co‐infected with HIV in an urban medical centre
Authors: Restrepo A. , Johnson T. C. , Widjaja D. , Yarmus L. , Meyer K. , Clain D. J. , Bodenheimer H. C. , Min A. D.
Published: January 2005

Summary.  Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co‐infection is common. HIV co‐infection results in a higher rate of histologic progression and shorter interval to HCV‐related cirrhosis. Successful treatment of HCV with interferon‐based therapy reduces the morbidity and mortality of patients. Significant factors may limit the availability of treatment in co‐infected patients. The rate of treatment of HCV and limiting factors to treatment in a co‐infected population in an urban setting were determined. A retrospective review of co‐infected patients was conducted at our liver and gastrointestinal (GI) clinics for treatment of HCV from July 2001 to June 2002. Treatment of HCV and reasons for nontreatment were recorded. A total of 104 HCV/HIV co‐infected patients were identified. Seventy‐two per cent were males. Mean age was 47.2 years (32–72). Seventy‐four of the 82 (90%) with identifiable risk factors for HCV infection had a history of intravenous drug use (IVDU). Twenty per cent (21/104) of the total underwent a liver biopsy. Sixty‐seven per cent who had a liver biopsy were treated. Overall, sixteen patients were treated. Eighty‐eight (85%) patients were not treated for the following reasons: 13 refused treatment, and 75 were ineligible. Of the ineligible patients, 40% were noncompliant with visits, 15% were active substance abusers, 13% had decompensated cirrhosis, 8% had significant active psychiatric conditions and 24% had significant co‐morbid disease. A majority of patients co‐infected with HCV/HIV had a IVDU history. Most co‐infected patients were not eligible for HCV treatment. A majority of noncandidates had potentially modifiable psychosocial factors leading to nontreatment.
Usefulness of a new immuno‐radiometric assay to detect hepatitis C core antigen in a community‐based population
Authors: Hayashi K. , Hasuike S. , Kusumoto K. , Ido A. , Uto H. , Kenji N. , Kohara M. , Stuver S. O. , Tsubouchi H.
Published: January 2005

Summary.  A new immuno‐radiometric assay (IRMA) to detect hepatitis C virus (HCV) core antigen (HCVcAg) has been developed. The aim of the present study was to investigate the sensitivity and specificity of this IRMA to measure HCV antigenemia, based on the detection of HCV RNA as the gold standard, and to assess the utility of the IRMA in a community‐based population. Anti‐HCV positive residents in a hyperendemic area of HCV infection in Japan were studied. Serum levels of HCVcAg were measured using IRMA, and the presence of HCV RNA was determined by a qualitative reverse transcription‐polymerase chain reaction (RT‐PCR) assay. The sensitivity and the specificity of the IRMA were 96.4 and 100%, respectively. The sensitivity of the IRMA was similar between serological HCV group I (HCV genotypes 1a and 1b) (97.6%) and group II (HCV genotypes 2a and 2b) (94.0%). There was a strong correlation between serum HCVcAg level and HCV‐RNA measured by a quantitative RT‐PCR (r = 0.832, P < 0.0001). There also was a very strong correlation of HCVcAg level between IRMA measurements performed on serum and those performed on plasma (r = 0.984, P < 0.0001). In conclusion, this new IRMA is useful for the detection of HCV core antigen in a community‐based population.
Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a multicentre randomized controlled trial
Authors: Wright M. , Forton D. , Main J. , Goldin R. , Torok E. , Tedder R. , Grant P. , Thursz M. , Naoumov N. , Millson C. , Mills P. R. , Bassendine M. , Thomas H. C. ,   on behalf of the UK Mild HCV Trial investigators
Published: January 2005

Summary.  Current guidelines advocate no treatment for patients with histologically mild hepatitis C virus (HCV) infection. This was a UK multicentre randomized controlled trial comparing α‐interferon (3 MU thrice weekly) + ribavirin (1000–1200 mg/day) for 48 weeks with no treatment in treatment naïve, adult patients with histologically mild chronic HCV infection. The aim was to compare benefits, safety and efficacy of combination therapy with α‐interferon 2b and ribavirin for 48 weeks with no treatment (current standard management) in this patient group. In the treatment group 32 of 98 (33%) patients achieved a sustained virological response (SVR). Patients infected with genotype 1 had a lower SVR than those infected with genotype non‐1 (18%vs 49%P = 0.02). No patients who failed to achieve a 2‐log drop in viral load at 12 weeks achieved SVR. Improvements in quality of life 24 weeks postcessation of therapy compared with baseline using the SF‐36 questionnaire measures were observed in the treated group. For patients with mild HCV infection with viral genotype non‐1, the results are sufficiently good to suggest that therapeutic decisions should no longer be biopsy‐driven. For patients infected with genotype 1, a liver biopsy is still indicated as the low chance of SVR is outweighed by an unacceptable burden of side‐effects. Patients who fail to respond by 12 weeks of therapy should have their treatment curtailed early.
Activity of adefovir dipivoxil against all patterns of lamivudine‐resistant hepatitis B viruses in patients
Authors: Westland C. E. , Yang H. , Delaney W. E. , Wulfsohn M. , Lama N. , Gibbs C. S. , Miller M. D. , Fry J. , Brosgart C. L. , Schiff E. R. , Xiong S.
Published: January 2005

Summary.  One hundred and thirty‐one post‐liver transplantation patients with chronic hepatitis B and failing lamivudine therapy with detectable serum hepatitis B virus (HBV) deoxyribonucleic acid by hybridization assays or ≥1 × 106 copies/mL by polymerase chain reaction, and elevated alanine transaminase levels despite continuous lamivudine, were enrolled in an open‐label study of adefovir dipivoxil. The B and C domains of HBV polymerase were sequenced for baseline samples to determine the presence of lamivudine resistance mutations. The results showed that 98% of the samples had tyrosine‐methionine‐aspartate‐aspartate (YMDD) mutations, indicating a strong correlation between the above clinical definition of lamivudine treatment failure and the presence of YMDD mutations. In addition to the rtM204V/I and the rtL180M mutations, the mutation rtV173L was identified in 19% of patients. Four major patterns of lamivudine‐resistant HBV were identified: rtL180M + rtM204V (60%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%) and rtL180M + rtM204I (9%). Treatment with adefovir dipivoxil showed similar antiviral efficacy in patients with lamivudine‐resistant virus from all four patterns.
Conditions affecting hydrodynamics‐based gene delivery into mouse liver in vivo
Authors: Feng Deng‐Min , He Chen‐Xia , Miao Chao‐Yu , Lu Bin , Wu Wen‐Jun , Ding You‐Fa , Xue Jing‐Lun
Published: January 2005

1. It has been demonstrated that the hydrodynamics‐based procedure has high efficiency to deliver foreign genes into the liver. The widespread use of this procedure in gene function studies and as a treatment option for liver and other organ diseases puts considerable importance on the investigation of various conditions that affect hydrodynamics‐based gene delivery into mouse liver in vivo.

2. Various conditions, including the volume, speed and solution of the injection and the state, gender and strain of the animal were manipulated to evaluate their effect on the expression levels in mice of human factor IX (hFIX) 8 h after tail vein injection of the plasmid pCMV‐hFIX.

3. It was found that an injection volume of 2–2.5 mL and an injection speed of 5–7 s were very effective in delivering DNA into the mouse liver. Using Ringer's solution as an injection fluid increased the efficiency of hFIX expression.

4. Anaesthetized mice expressed higher hFIX than conscious mice. Males expressed higher hFIX than females. The ICR mouse strain demonstrated higher expression of the foreign gene than did the C57 strain.

5. The effects of these specific factors on hFIX expression may be caused by variations in hydrostatic pressure, the degree of liver damage and liver size.

6. It can be concluded that there are optimal conditions for hFIX expression in the liver. This information may be helpful for the application of hydrodynamics‐based procedures in the investigation of gene expression and gene therapy.
Anti‐infarct effect of magnesium is not mediated by adenosine A1 receptors in rat globally ischaemic isolated hearts
Authors: Ebrahimi S , Faghihi M , Keshavarz M , Kadkhodaee M , Mirershadi F , Asadi B
Published: January 2005

1. The aim of present study was to investigate the effects of magnesium (Mg) on cardiac function and infarct size and to compare it effects with those of adenosine. The mechanism of Mg‐mediated cardioprotection was explored by combined use of Mg and a selective adenosine A1 receptor antagonist.

2. Rat isolated hearts were used for Langendorff perfusion. Hearts were either non‐preconditioned or preconditioned with Mg (6 mmol/L) or adenosine (1 mmol/L) before 30 min sustained ischaemia followed by 120 min reperfusion. Within each of these protocols, hearts were divided into two groups; one group was exposed to the A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX; 200 nmol/L). Infarct size was measured by the triphenyltetrazolium chloride method. Left ventricular function was assessed by left ventricular developed pressure (LVDP), the product of heart rate × LVDP and coronary flow (CF).

3. The administration of Mg had an anti‐infarct effect independent of its effect on postischaemic functional recovery in rats. Both Mg and adenosine equipotently reduced infarct size, but this effect of Mg was not blocked by the simultaneous administration of DPCPX. Cardiac function was improved by both adenosine and Mg and blockade of adenosine A1 receptors attenuated these effects for both agents.

4. In conclusion, the results of the present study indicate that stimulation of adenosine A1 receptors is not responsible for the anti‐infarct effect of Mg in ischaemic myocardium in rats, but that the Mg‐mediated protection of postischaemic functional recovery in rats is mediated by these receptors.
Renal papillae metastasis of sigmoid colon adenocarcinoma
Authors: KİBAR YUSUF , DEVECİ SALİH , SÜMER FAHRİ , SEÇKİN BEDRETTİN
Published: January 2005

Abstract Colonic carcinoma metastatic to the kidney is very rare. The usual anatomical localization for secondary renal neoplasms is the renal cortex. We report a case of sigmoid colon carcinoma with unilateral kidney metastasis localized only in the renal papillae without obvious metastatic disease.
Can epithelized neobladder‐cutaneous fistula provide urinary continence?
Authors: PINTÉR ANDREW , VAJDA PETER , KROOWAND LAWRENCE , FARKAS ANDREW
Published: January 2005

Abstract The paper presents a case of a boy born with a bladder exstrophy, who underwent several surgical procedures, including bladder augmentation. During the last procedure, the patient received a suprapubic catheter that accidentally slipped out. The epithelized neobladder‐cutaneous fistula resulted in a continent and easily catheterizable abdominal stoma.
Splenogonadal fusion: Report of a case and review of the literature
Authors: ALIVIZATOS GERASIMOS , SKOLARIKOS ANDREAS , SOPILIDIS ODYSSEAS , FERAKIS NIKOLAOS , CHORTI MARIA
Published: January 2005

Abstract We report a case of splenogonadal fusion masquerading as a testicular tumor and review the etiology, the pathogenesis and the management of this rare disease.

A 20‐year‐old male patient presented with clinical and radiological findings of a left testicular mass for which he underwent a left radical inguinal orchidectomy. Histopathology of the removed testicle revealed no tumor. The gonad was fused to ectopic splenic tissue, the later forming a distinct encapsulated mass attached to the lower pole of the testicle inside the tunica vaginalis.

Splenogonadal fusion, although a rare condition, may account for a non‐malignant testicular mass and should be suspected in young patients with other congenital anomalies.
Construction of the Mandarin version of the International Prostate Symptom Score inventory in assessing lower urinary tract symptoms in a Malaysian population
Authors: QUEK KIA FATT , CHUA CHONG BENG , RAZACK AZAD HASSAN , LOW WAH YUN , LOH CHIT SIN
Published: January 2005

Abstract Background:  The purpose of the present study was to validate the Mandarin version of the International Prostate Symptom Score (Mand‐IPSS) in a Malaysian population.

Methods:  The validity and reliability were studied in patients with lower urinary tract symptoms (LUTS; benign prostatic hyperplasia [BPH] group) and without LUTS (control group). Test–retest methodology was used to assess the reliability while Cronbach alpha was used to assess the internal consistency. Sensitivity to change was used to express the effect size index in the preintervention versus post‐intervention score in patients with LUTS who underwent transurethral resection of the prostate.

Results:  For the control group and BPH group, the internal consistency was excellent and a high degree of internal consistency was observed for all seven items (Cronbach α = 0.86–0.98 and 0.90–0.98, respectively). Test–retest correlation coefficients for all items were highly significant. Intraclass correlation coefficient (ICC) was high for the control (ICC = 0.93–0.99) and BPH group (ICC = 0.91–0.99). The sensitivity and specificity showed a high degree of sensitivity and specificity to the effects of treatment. A high degree of significance between baseline and post‐treatment scores was observed across all seven items in the BPH group but not in the control group.

Conclusions:  The Mand‐IPSS is a suitable, reliable, valid and sensitive instrument to measure clinical change in the Malaysian population.
Memory for action events: Findings in neurological patients
Authors: KNOPF MONIKA , MACK WOLFGANG , LENEL ALINE , FERRANTE SEBASTIANO
Published: January 2005

Encoding action phrases by enacting leads normally to better memory performance than verbal encoding. In order to gain additional insight into the representational basis of the enactment effect, neurological patients are contrasted with healthy participants. Persons suffering from Parkinson's disease, which primarily impairs the motor system, and patients suffering from Frontal Lobe Syndrome, which primarily affects action‐related planning processes, were involved. We investigated whether the enactment effect would be differentially affected by these disorders. In addition, the characteristics of information processing after encoding by enacting was analyzed by varying memory material (unrelated versus clusterable actions) and by adding an encoding condition that included obligatory action planning (director condition). The findings indicate that the impact of motor information for the enactment effect is not dominant compared to the role of action‐related cognitive and motivational processes, in particular planning processes. The findings of the two experiments are explained within traditional conceptual memory theories.
What's measured is not necessarily managed: Cognitive contingencies of organizational measurement
Authors: ARNULF JAN KETIL
Published: January 2005

Organizational measurement is necessary for managing incremental improvements or change efforts. Some have argued that indicators of financial performance measure the past and should be joined by “lead” measures such as management development and customer relations, assumed to be drivers of performance. Approaches of “lead” measures have met criticism for not contributing to operational management. The present is an empirical case study where measures from a customer satisfaction survey and a management assessment instrument were analyzed and compared to actual measures of financial performance. The effects of measures obtained seem to depend on the interpretations and reflection taking place in the organization. The pursuit of “lead” indicators did not seem to drive results. Counter‐intuitively, higher scores on these measures were related to poorer financial performance. The explication of and reflection on the underlying dynamic seemed to turn the development in a profitable direction.
Significance testing, interval estimation or Bayesian inference: Comments to “Extracting a maximum of useful information from statistical research data” by S. Sohlberg and G. Andersson
Authors: THORBURN DANIEL
Published: January 2005

Statistical inference plays an important part in the formation of scientific knowledge in psychology. Starting from a paper by Sohlberg and Andersson (2005; Scandinavian Journal of Psychology, 46, 69–77) these issues are discussed. It is argued that interval estimates are easy to understand and that they are more suitable than significance testing for most problems. Bayesian inference is a coherent description of the information building process. With some examples it is shown that null hypothesis significance testing is full of contradictions. Finally, some other important issues like convenience sampling and model selection are shortly mentioned.
Creating Visionary and Enhanced Theological Institutions
Authors: Valantasis Richard
Published: January 2005

Abstract.  Theological school faculty at mid‐career often discover a bifurcated work environment in the theological institutions they serve. Scholarly and pedagogical passions can be set in tension with academic administrative responsibilities – each vying for the lion's share of time. In this essay the author plunges into murky vocational waters to explore possible contributing factors for the bifurcated existence mid‐career faculty experience. The essay suggests creative steps toward new visionary paradigms to aid theological institutions in adopting and modeling visionary theological education. This transformative model would strive to enhance community life, nurture leadership, foster intellectual formation, cope with institutional strife, and constructively shape an institution's future.
The Seasons of a Scholar's Calling: Insights from Mid‐Field
Authors: Stortz Martha E.
Published: January 2005

Abstract.  A scholar's calling at mid‐career is latticed with challenges and changing responsibilities. In this essay the author considers faculty role changes during the mid‐career phase of life as a teacher. The essay first addresses issues related to the responsibility of mid‐career faculty to mentor the next generation of scholars/teachers. Keenly aware of stresses under which pre‐tenure faculty labor the author highlights proven strategies and insights for successful mentoring. The last half of the essay offers reflections on life as a scholar, colleague and teacher at mid‐career. With transparent honesty the author scrawls contours of experience, motivations, and challenges for mid‐career faculty and sketches specific strategies for maneuvering through this phase of one's career.
Placebo Effects in Oral Triptan Trials: the Scientific and Ethical Rationale for Continued use of Placebo Controls
Authors: Loder E , Goldstein R , Biondi D
Published: January 2005

The aim of this study was to determine the characteristics of placebo effects in acute migraine treatment trials of triptans performed over 12 years and assess whether the use of placebo controls in trials of acute migraine treatment remains ethically and scientifically appropriate. We conducted a search for all controlled trials published in English between January 1991 and April 2002 in which adult subjects with migraine were randomly assigned to receive an oral triptan or placebo for the acute treatment of a migraine attack. Thirty-one trials met our criteria for inclusion. Placebo results for each study and pooled placebo results were calculated for the endpoints of headache response, pain-free response and adverse events. Heterogeneity was assessed using the Q statistic, and meta-regression using prespecified covariates was performed to investigate heterogeneity. The study results show a significant degree of heterogeneity. Efforts to explain heterogeneity with available data were not successful, with the exception of adverse event rates to placebo, for which study location (Europe vs. North America) partially explained differences in study results. AE rates were lower in European studies than in North American studies. Across all studies, the mean proportion of subjects who experienced a treatment response at two hours to placebo was 28.48 + 8.73% (range 17-50%). The mean proportion of subjects who experienced an adverse event to placebo was 23.40 + 14.05% (range 4.86-74%). The mean proportion of subjects who experienced a pain-free response to placebo at two hours was 6.08 + 4.43% (range 5-17%). Results of studies allowing use of prophylaxis did not differ significantly from those that did not allow prophylaxis. Placebo effects appear to be enhanced in studies involving children and adolescents. In contrast to an earlier, smaller review, our results do not suggest that randomization ratios influence placebo rates. We conclude that placebo effects in published trials of acute migraine medications are highly variable and often substantial. This variability in placebo response means that active control equivalence trials or the use of historical controls will not provide adequate proof of the safety or efficacy of new drugs, and will not differentiate between drugs that are active vs. placebo but of unknown efficacy relative to each other. The potential for approval of ineffective drugs, inability to compare results of studies performed in different locations, and poor characterization of the tolerability and safety profiles of new drugs represent a greater danger to migraineurs than does the limited-duration use of placebo in carefully monitored clinical trials of consenting subjects. These observations support the view that the inclusion of a placebo group remains of major scientific and ethical importance in trials of migraine medications.
Vagus Nerve Stimulation Relieves Chronic Refractory Migraine and Cluster Headaches
Authors: Mauskop A
Published: January 2005

Anticonvulsant and antidepressant medications have demonstrated efficacy in migraine treatment. Vagus nerve stimulation (VNS) is an effective treatment for drug-refractory epilepsy and possibly depression and it also has documented analgesic effects. These observations suggested a possible role for VNS in treating severe refractory headaches, and led to a trial of VNS in patients with such headaches. VNS was implanted in four men and two women with disabling chronic cluster and migraine headaches. In one man and one woman with chronic migraines VNS produced dramatic improvement with restoration of ability to work. Two patients with chronic cluster headaches had significant improvement of their headaches. VNS was well tolerated in five patients, while one developed nausea even at the lowest current strength. In conclusion, VNS may be an effective therapy for intractable chronic migraine and cluster headaches and deserves further trials.
Hyperoxia‐induced arterial compliance decrease in healthy man
Authors: Rossi Pascal , Boussuges Alain
Published: January 2005

Introduction:  Oxygen therapy is commonly used in emergency department and intensive care units without careful evaluation of its effects, especially on the haemodynamics and artery characteristics.

Materials and methods:  A prospective laboratory study evaluated brachial circulatory effects of normobaric hyperoxia using ultrasonography‐Doppler. The study was set in a hospital research laboratory. The subjects were thirteen healthy volunteers. Investigations were performed under normal air ventilation and after 20 min of hyperoxic mixture ventilation using a high concentration mask. Two dimensional images and brachial blood flow velocities were recorded using ultrasonography and pulsed Doppler to study changes in cross sectional area, blood flow, resistance index, and cross‐sectional compliance coefficient.

Results:  During hyperoxic exposure, mean PaO2 was 372 ± 21 mmHg. A significant decrease of heart rate was observed. Arterial pressures (systolic and diastolic arterial pressures) were not modified. A decrease of cross sectional areas at end diastole and end systole was observed. Pulsed Doppler study showed a decrease of brachial artery blood flow and an increase of the resistance index. Furthermore, a decrease of the cross‐sectional compliance coefficient was observed during hyperoxic exposure in all subjects.

Conclusion:  This study using two‐dimensional ultrasonography and pulsed Doppler could demonstrate an increase in brachial arterial tone and a decrease in brachial blood flow under normobaric hyperoxia.
Lower body positive pressure by anti‐G garment inflation: a suitable method to increase pulmonary capillary wedge pressure in healthy elderly subjects
Authors: Remmen J. J. , Aengevaeren W. R. M. , Verheugt F. W. A. , Bos A. , Jansen R. W. M. M.
Published: January 2005

In a study on non‐invasive assessment of pulmonary capillary wedge pressure (PCWP), we sought a method to increase PCWP non‐invasively. We hypothesized that inflation of an anti‐G garment was suitable to increase PCWP non‐invasively in healthy elderly subjects. In 20 subjects, aged 70 ± 4 years (mean ± SD), before, immediately after, and 4 min after anti‐G garment inflation to 52 mmHg, PCWP and mean pulmonary artery pressure (MPAP) were measured with a Swan‐Ganz catheter, and mean arterial blood pressure (MAP) with Finapres, in supine and semi‐recumbent position. Supine, PCWP (mmHg, mean ± SD) increased from 9·9 ± 2·1 to 15·5 ± 3·9** immediately after inflation and 13·4 ± 3·7** at 4 min; semi‐recumbent from 8·9 ± 2·0 to 17·5 ± 3·3** and 14·7 ± 2·9** (*P<0·05, **P< 0·001 versus before inflation). MPAP (mmHg) increased after inflation: supine 16·9 ± 2·3 to 22·3 ± 4·6** and 20·6 ± 3·9** and semi‐recumbent 15·7 ± 2·8 to 24·3 ± 5·1** and 22·5 ± 3·5**, suggesting that increased preload was the primary effect of anti‐G garment inflation. Supine MAP (mmHg) increased from 96·0 ± 11·3 to 101·4 ± 13·4** and 100·5 ± 12·7* and semi‐recumbent from 102·0 ± 8·9 to 108·3 ± 11·4** and 106·0 ± 11·3*, suggesting an effect of increased afterload as well. The latter was supported by an increase in total peripheral resistance (d s cm−5) from 1346 ± 299 to 1441 ± 384 after 4 min (P = 0·057) and from 1461 ± 341 to 1532 ± 406 (P = 0·054), supine and semi‐recumbent respectively, while cardiac output remained unchanged. Complications did not occur. We conclude that in healthy elderly subjects, anti‐G garment inflation is a safe, non‐invasive, method to induce a significant increase in PCWP. Our findings justify its application in future studies in which non‐invasive temporary increase in PCWP is required.