bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C–related fibrosis: A systematic review
Authors: Shaheen Abdel Aziz M. , Myers Robert P.
Published: August 2007

The development of noninvasive markers of liver fibrosis is a clinical and research priority. The aspartate aminotransferase-to-platelet ratio index (APRI) is a promising tool with limited expense and widespread availability. Our objective was to systematically review the performance of the APRI in hepatitis C virus (HCV)–infected patients. Random effects meta-analyses and areas under summary receiver operating characteristic curves (AUC) were examined to characterize APRI accuracy for significant fibrosis (stages 2–4) and cirrhosis. In 22 studies (n = 4,266), the summary AUCs of the APRI for significant fibrosis and cirrhosis were 0.76 [95% confidence interval (CI), 0.74–0.79] and 0.82 (95%CI, 0.79–0.86), respectively. For significant fibrosis, an APRI threshold of 0.5 was 81% sensitive and 50% specific. At a 40% prevalence of significant fibrosis, this threshold had a negative predictive value (NPV) of 80%, but could reduce the necessity of liver biopsy by only 35%. For cirrhosis, a threshold of 1.0 was 76% sensitive and 71% specific. At a 15% cirrhosis prevalence, the NPV of this threshold was 91%. Higher APRI thresholds had suboptimal positive predictive values except in settings with a high prevalence of cirrhosis. APRI accuracy was not affected by the prevalence of advanced fibrosis, or study and biopsy quality. However, the accuracy for cirrhosis was greater in studies including human immunodeficiency virus (HIV)/HCV–co-infected patients.

Conclusion:

The major strength of the APRI is the exclusion of significant HCV-related fibrosis. Future studies of novel markers should demonstrate improved accuracy and cost-effectiveness compared with this economical and widely available index. (Hepatology 2007.)
The impact of ethnicity on the natural history of autoimmune hepatitis
Authors: Verma Sumita , Torbenson Michael , Thuluvath Paul J.
Published: August 2007

The impact of ethnicity on the natural history of autoimmune hepatitis (AIH) has not been well characterized. The aim of this study was to assess the natural history of AIH in blacks in comparison with others (nonblacks). This was a 10-year (June 1996 to June 2006) retrospective analysis of patients with AIH from a single tertiary care center. The diagnosis of AIH was defined by the criteria established by the International Autoimmune Hepatitis Club. A poor outcome was defined as liver failure at presentation, failure to achieve remission, need for liver transplantation, and/or death. One hundred one patients with AIH were eligible for the study. Black patients were more likely to have cirrhosis (56.7% versus 37.5%,

P

= 0.061), have liver failure at the initial presentation (37.8% versus 9.3%,

P

= 0.001), and be referred for liver transplantation (51.3% versus 23.4%,

P

= 0.004). The overall mortality was also significantly higher in black patients (24.3% versus 6.2%,

P

= 0.009). Compared with nonblacks, blacks had more advanced hepatic fibrosis (3.6 ± 2.7 versus 2.1 ± 2.4,

P

= 0.013). A Kaplan-Meier analysis showed that the probability of developing a poor outcome was significantly higher in blacks (

P

= 0.003). Independent predictors of poor outcome were black ethnicity, the presence of cirrhosis, and the fibrosis stage at presentation. Black males were the group most likely to have a poor outcome (85.7%).

Conclusion:

Blacks, especially black men with AIH, have more aggressive disease at the initial presentation, are less likely to respond to conventional immunosuppression, and have a worse outcome than nonblacks. (Hepatology 2007.)
Institutional factors and HIV/AIDS, TB and Malaria
Authors: Simmonds Stephanie
Published: August 2007

This paper outlines the principal institutional factors affecting the slow progress in reaching agreed targets in Africa regarding the prevention and control of HIV/AIDS, TB and Malaria. It focuses on three key factors: political analysis, strategic business approach and international inputs.

Most of the analyses tend to look at the technical aspects of disease prevention and control, of political analysis there is a marked absence. Yet, we know that wider contextual or macro factors such as power and political decision making can make or break a programme.

Many senior managers in public sector institutions are preoccupied with day‐to‐day work. Successful businesses in the private sector have some things in common with each other. Outstanding leadership, a strategic and action orientated culture, highly focused on comparative strengths on priorities and quality being some of the key ones. Adopting such successful business characteristics might make the difference to public institutions.

The move to results based institutions by focussing on outputs and outcomes is for the better. However, we still need to rigorously examine the quality of inputs that the increasing availability of funds is being used on. This is especially so in relation to needing a better balance between aid for health services and that for institutional and health systems development. In addition, technical advisers from development partners need to work more across a ministry of health on institutional and management change to have a greater impact on achieving targets. Copyright © 2007 John Wiley & Sons, Ltd.
Parameterization of azole‐bridged dinuclear platinum anticancer drugs via a QM/MM force matching procedure
Authors: Spiegel Katrin , Magistrato Alessandra , Maurer Patrick , Ruggerone Paolo , Rothlisberger Ursula , Carloni Paolo , Reedijk Jan , Klein Michael L.
Published: August 2007

Azole‐bridged diplatinum compounds are promising new anticancer drugs designed to induce small distortions upon DNA alkylation, able to circumvent resistance problems of existing platinum drugs. Hybrid quantum classical (QM/MM) molecular dynamics (MD) simulations of different azole‐bridged platinum drugs have recently revealed the nature of the local deformations at the DNA binding site. However, the description of global slow converging rearrangements cannot be addressed by QM/MM MD due to the short time scale accessible. Extensive classical MD simulations are therefore mandatory to describe accurately the structural distortions in the DNA double helix. This issue is now addressed by developing a new set of accurate force field parameters of the platinated moiety via a recently proposed force matching procedure of the classical forces to ab initio forces obtained from QM/MM trajectories. The accuracy of our force field parameters is validated by comparison of structural properties from classical MD and hybrid QM/MM simulations. The structural characteristics of the Pt‐lesion are well reproduced during classical MD compared with QM/MM simulations and available experimental data. The global distortions in the DNA duplex upon binding of dinuclear Pt‐compounds are very small and rather opposite to those induced by cisplatin. Thus, the force match approach significantly extends the potentialities of molecular simulations in the study of anticancer drugs and of the interactions with their biological targets. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Modulation of scratching behavior by silencing an endogenous cyclooxygenase‐1 gene in the skin through the administration of siRNA
Authors: Inoue Tomoyuki , Sugimoto Masanori , Sakurai Takanobu , Saito Rie , Futaki Nobuko , Hashimoto Yuki , Honma Yusuke , Arai Iwao , Nakaike Shiro
Published: August 2007

Background

RNA interference (RNAi) is rapidly becoming a major tool that is revolutionizing research in the bioscience and biomedical fields. To apply the RNAi technique in vivo, it is crucial to develop appropriate methods of guiding the short interfering RNA (siRNA) molecules to the right tissues and cells. Here, we demonstrate an efficient method for performing gene knockdown in the body skin using the in vivo electro‐transduction of siRNA. Using this method, we examined whether the targeted silencing of the cyclooxygenase (COX) gene in the skin could modulate the scratching behavior of an atopic dermatitis mouse model.

Methods

NC/Nga mice were used as the atopic dermatitis model. Using our optimized in vivo electroporation conditions, siRNAs were introduced into the skin; the silencing efficiency was then analyzed by Western blotting, measuring the levels of prostaglandins, and immunohistochemistry. The scratching behaviors of the mice were measured using an automatic system.

Results

Targeted silencing of the COX‐1 gene using our in vivo siRNA technique significantly accelerated the scratching behavior of NC/Nga mice, whereas the COX‐2 siRNA showed no effect. In addition, the effect of COX‐1 siRNA was mimicked by treatment with a COX‐1‐selective inhibitor (SC‐560).

Conclusions

We have demonstrated the successful silencing of endogenous gene expression in the skin using the intradermal transfection of unmodified siRNA via electroporation. Using this method, we revealed that COX‐ 1‐mediated prostaglandins may act as endogenous inhibitors of scratching behavior. Copyright © 2007 John Wiley & Sons, Ltd.
Provider response to insulin‐induced hypoglycemia in hospitalized patients
Authors: Garg Rajesh , Bhutani Himanshu , Jarry Amy , Pendergrass Merri
Published: August 2007

BACKGROUND

Risk of hypoglycemia is a major barrier to the implementation of tight blood glucose (BG) control in hospitalized patients. The objective of this study was to evaluate the changes in diabetes treatment after an episode of hypoglycemia.

METHODS

The study was a retrospective data analysis of patients who received 50% dextrose for an episode of hypoglycemia. Data on immediate and subsequent changes in the antidiabetic medications the patients received were collected and evaluated by 2 diabetes specialists.

RESULTS

Data from 52 patients were included in the study. Mean BG at the time of dextrose administration was 52.1 ± 9.3 mg/dL (range 31‐68). Mean BG during the 24 hours before the hypoglycemic episode was 137.5 ± 57.0 mg/dL (range 63‐287). Insulin dose was held at the time of the hypoglycemic episode in all 52 patients. Diabetes specialists agreed with this decision 100% of the time. Changes were subsequently made in the treatment of only 21 patients (40%), and diabetes specialists agreed with the changes made for 11 of these patients (52%). Thirty‐one patients (60%) received no changes in treatment, and diabetes specialists agreed with that decision for 10 patients (32%).

CONCLUSIONS

Provider response in making treatment changes after an episode of hypoglycemia is suboptimal. Standardized protocols to make changes in diabetes treatment after an episode of hypoglycemia need to be tested. Journal of Hospital Medicine 2007;2:258–260. © 2007 Society of Hospital Medicine.
Impact of Society of Hospital Medicine workshops on hospitalists' knowledge and perceptions of health care–associated infections and antimicrobial resistance
Authors: Bush‐Knapp Megan E. , Budnitz Tina , Lawton‐Ciccarone Rachel M. , Sinkowitz‐Cochran Ronda L. , Brinsley‐Rainisch Kristin J. , Dressler Daniel D. , Williams Mark V.
Published: August 2007

BACKGROUND

Health care–associated infections and antimicrobial resistance threaten the safety of hospitalized patients. New prevention strategies are necessary to address these problems. In response, the Society of Hospital Medicine (SHM) in collaboration with the Centers for Disease Control and Prevention developed and conducted workshops to educate hospitalists about conducting quality improvement programs to address antimicrobial resistance and health care–associated infections in hospitalized patients.

METHODS

SHM collected and analyzed data from pretests and posttests administered to physicians who attended SHM workshops in 2005 in 1 of 3 major cities: Denver, Colorado; Boston, Massachusetts; or Portland, Oregon.

RESULTS

A total of 69 SHM members attended the workshops, and 50 completed both a pretest and a posttest. Scores on the knowledge‐based questions increased significantly from pretest to posttest (x̄ = 48% vs. 63%, P < .0001); however, perceptions of the problem of antimicrobial resistance did not change. Most participants (85%) rated the quality of the workshop as “very good” or “excellent” and rated the workshop sessions as “useful” (x̄ = 3.9 on a 5.0 scale).

CONCLUSIONS

Hospitalists who attended the SHM workshop increased their knowledge of health care–associated infections, antimicrobial resistance, and quality improvement programs related to these issues. Similar workshops should be considered in efforts to prevent health care–associated infections and antimicrobial resistance. Journal of Hospital Medicine 2007;2:268–273. © 2007 Society of Hospital Medicine.
Respiratory syncytial virus protects against the subsequent development of Japanese cedar pollen‐induced allergic responses
Authors: Liu Beixing , Kimura Yoshinobu
Published: August 2007

Respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans still remain inconclusive. The association between RSV infection and allergic diseases may be dependent on atopic background and previous history of RSV infection. In this study, the influence of the timing of RSV infection on the development of Japanese cedar pollen (JCP)‐induced allergic responses was examined. BALB/c mice were intranasally infected with RSV before or after sensitization to JCP. Production of cytokines in the culture fluid of lung parenchyma cells and the level of antigen‐specific antibodies in the serum were determined. It became clear that JCP was a strong inducer for the elicitation of Th2‐type responses, characterized by production of interleukin (IL)‐4 and IL‐5 in the lung and JCP‐specific IgE antibody in the serum. RSV infection, however, suppressed JCP‐induced allergic responses by decreasing the production of Th2‐like cytokines and Th2‐type antibodies. This phenomenon was observed more clearly in the groups that were infected with RSV, 2 weeks or 2 days before sensitization to JCP. The inhibitory mechanism of RSV infection seems to be due to RSV‐induced Th1 type dominant environment, which down‐regulated the Th2‐type responses subsequently induced by allergen sensitization. On the other hand, JCP‐inoculation altered RSV‐induced immune responses to shift from Th1‐ to Th2‐type dominance, by inhibiting RSV‐induced Th1‐like cytokine production. These data provide evidence that under a certain condition, RSV infection may play a protective role in JCP‐induced allergic responses. J. Med. Virol. 79:1600–1605, 2007. © Wiley‐Liss, Inc.
High prevalence of amantadine‐resistance influenza a (H3N2) in six prefectures, Japan, in the 2005–2006 Season
Authors: Saito Reiko , Li Danjuan , Suzuki Yasushi , Sato Isamu , Masaki Hironori , Nishimura Hidekazu , Kawashima Takashi , Shirahige Yutaka , Shimomura Chieko , Asoh Norichika , Degawa Satoshi , Ishikawa Hidefumi , Sato Maki , Shobugawa Yugo , Suzuki Hiroshi
Published: August 2007

Substantial increase in amantadine‐resistant influenza A (H3N2) was reported in Asia and North America in 2005. In this study the frequency and genetic characteristics of amantadine‐resistant influenza A, circulated in Japan in 2005–2006 season, were investigated. Isolates were tested by amantadine susceptibility test (TCID50/0.2 ml method), and sequencing of the M2 gene to identify mutations that confer resistance. Additionally, the hemagglutinin (HA) and neuraminidase (NA) genes of the viruses were examined. In total, 415 influenza A isolates from six prefectures were screened, and 231 (65.3%) of 354 influenza A (H3N2) were amantadine‐resistant, with a serine to asparagine (S31N) change in the M2 gene. However, none of 61 A (H1N1) isolates were resistant. In addition, genetic analyses of the HA gene showed all amantadine‐resistant viruses clustered in one (named clade N), possessing specific double mutations at 193, serine to phenylalanine (S193F), and at 225, asparatic acid to asparagine (D225N), and sensitive viruses belonged to another group (clade S). The clinical presentations at the clinical visit did not differ between patients shedding clade N virus and those shedding clade S virus. None of the patients had received previous treatment with amantadine. The results indicate an unusually high prevalence and wide circulation of the amantadine‐resistance influenza A (H3N2) in Japan in the 2005–2006 season. These strains had the characteristic double mutations in the HA, in addition to the M2 mutation responsive for resistance. Antiviral resistance monitoring should be intensified and maintained for rapid feedback into treatment strategies, and selection of alternative therapeutic agents. J. Med. Virol. 79:1569–1576, 2007. © Wiley‐Liss, Inc.
Neuraminidase inhibitor resistance in influenza viruses
Authors: Reece Phillip Andrew
Published: August 2007

Zanamivir and oseltamivir, the currentlymarketed influenza virus neuraminidase inhibitors (NAIs), are prescribed for the treatment and prophylaxis of influenza and are being stockpiled for pandemic influenza. Oseltamivir resistance has been reported in up to 2% of patients in clinical trials of oseltamivir and in up to 18% of treated children. There are also reports in at least three patients treated with oseltamivir for influenza A (H5N1) infections. At this stage, there are no reports of resistance occurring to zanamivir in immunocompetent patients. Zanamivir and oseltamivir bind differently at the neuraminidase catalytic site and this contributes to different drug resistance profiles. The magnitude and duration of NAI concentrations at the site of infection are also expected to be important factors and are determined by route and timing of drug administration, dose, and pharmacokinetic differences between patients. In addition, the type, strain, and virulence of the influenza strain and the nature of the immune response all appear to play a role in determining the likelihood of drug resistance arising. The clinical significance of a particular NAI‐resistant isolate from a patient is often not clear but virus viability and transmissibility are clearly important characteristics. Early initiation of NAI treatment in suspected cases of influenza is important for maximizing efficacy and minimizing the risk of drug resistance. Higher NAI doses and longer periods of treatment may be required for patients with influenza A (H5N1) infections but further work is needed in this area. J. Med. Virol. 79:1577–1586, 2007. © Wiley‐Liss, Inc.
The membrane protein of SARS‐CoV suppresses NF‐κB activation
Authors: Fang Xiaonan , Gao Jinrong , Zheng Hong , Li Baozong , Kong Lingbao , Zhang Yijuan , Wang Wei , Zeng Yingchun , Ye Linbai
Published: August 2007

Severe acute respiratory syndrome coronavirus (SARS‐CoV) infects many organs, such as lung, liver, and immune organs and causes life‐threatening atypical pneumonia, SARS causes high morbidity and mortality rates. The molecular mechanism of SARS pathogenesis remains elusive. Inflammatory stimuli can activate IκB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF‐κB), which influences gene expression of cyclooxygenase‐2 (Cox‐2) along with other transcription factors. In this work, we found that the membrane (M) protein of SARS‐CoV physically interacted with IKKβ using a co‐immunoprecipitation assay (IPA). Expression of M suppressed tumor necrosis factor alpha (TNF‐α) induced NF‐κB activation using a luciferase reporter assay. Further investigation showed M protein suppressed Cox‐2 expression using a luciferase reporter gene assay, RT‐PCR and Western blot analysis. The carboxyl terminal of M protein was sufficient for the M protein function. Together, these results indicate that SARS‐CoV M suppresses NF‐κB activity probably through a direct interaction with IKKβ, resulting in lower Cox‐2 expression. Suppression of NF‐κB activity and Cox‐2 expression may contribute to SARS pathogenesis. J. Med. Virol. 79:1431–1439, 2007. © Wiley‐Liss, Inc.
Molecular epidemiology of HIV‐1 in Santa Catarina State confirms increases of subtype C in Southern Brazil
Authors: Locateli Dayse , Stoco Patrícia H. , de Queiroz Artur T.L. , Alcântara Luiz C.J. , Ferreira Luiz G.E. , Zanetti Carlos R. , Rodrigues Rosângela , Grisard Edmundo C. , Pinto Aguinaldo R.
Published: August 2007

Recent studies have demonstrated an increased prevalence of human immunodeficiency virus type 1 (HIV‐1) subtype C in southern Brazil. Although Santa Catarina State (SC) is located in this area and presents one of the country's highest incidences of HIV/AIDS, knowledge on the molecular epidemiology of HIV‐1 in such State is lacking. The aim of this study was to investigate the HIV‐1 molecular diversity and epidemiological profile of HIV‐1‐infected patients from SC. DNA samples were PCR amplified and HIV‐1 subtypes were determined using both env and gag genes by direct sequencing. Phylogenetic analyses revealed that 48% were subtype C and 23% were subtype B. Possible recombinant forms were observed for both B/C (23%) and B/F (6%) subtypes. Our results, for the first time, identifies HIV‐1 subtype C as a major clade circulating in SC and contributes to the understanding of HIV epidemics in the country by confirming the epidemic spread of the HIV‐1 subtype C in southern Brazil. J. Med. Virol. 79:1455–1463, 2007. © Wiley‐Liss, Inc.
Environmental contamination with rhinovirus and transfer to fingers of healthy individuals by daily life activity
Authors: Winther Birgit , McCue Karen , Ashe Kathleen , Rubino Joseph R. , Hendley J. Owen
Published: August 2007

Rhinovirus infection may be acquired by inoculation of virus on fingertips to conjunctiva or nose (self‐inoculation). The virus contaminating the fingertips may come from hand contact with someone with a cold or from virus in mucus on environmental surfaces. This study was designed to assess rhinovirus contamination of surfaces by adults with colds and rhinovirus transfer from surfaces to fingertips during normal daily activities. Fifteen adults with natural rhinovirus colds stayed overnight in a local hotel. Ten touched sites in each room were tested for rhinovirusRNA using RT‐PCR. Transfer to fingertips of five subjects was examined by drying 10 µl of virus‐containing mucus from each subject onto light switches, telephone dial buttons and telephone handsets. After an interval of 1 or 18 hr the subject flipped the light switch, pressed the button, held the handset. Fingertip rinses were tested for virus. Thirty five percent of the 150 environmental sites in the rooms were contaminated. Common virus‐positive sites were door handles, pens, light switches, TV remote controls, faucets, and telephones. Rhinovirus was transferredfrom surfaces to fingertips in 18/30 (60%) trials 1 hr after contamination and in 10/30 (33%) of trials 18 hr (overnight) after contamination. Adults with colds commonly contaminate environmental surfaces with rhinovirus; virus on surfaces can be transferred to a fingertip during normal daily activities. J. Med. Virol. 79:1606–1610, 2007. © Wiley‐Liss, Inc.
Dengue neurovirulence in mice: Identification of molecular signatures in the E and NS3 helicase domains
Authors: Bordignon Juliano , Strottmann Daisy M. , Mosimann Ana Luiza P. , Probst Christian M. , Stella Vanessa , Noronha Lucia , Zanata Sílvio M. , dos Santos Claudia N. Duarte
Published: August 2007

Recent observations indicate that the clinical profile of dengue virus (DENV) infection is changing, and that neurological manifestations are becoming frequent. The neuro pathogenesis of dengue, and the contribution of viral and host factors to the disease are not well understood. To define the amino acid substitutions in DENV potentially implicated in the acquisition of a neurovirulent phenotype we used a murine model to characterize two neuroadapted strains of DENV‐1, FGA/NA a5c (previously obtained), and FGA/NA P6 (recently obtained). Only three amino acid substitutions were identified in the neurovirulent strains, mapping to the E and NS3 helicase domains. These mutations enhanced the ability of neuroadapted viral strains to replicate in the CNS of infected mice, causing extensive damage with leptomeningitis and encephalitis. J. Med. Virol. 79:1506–1517, 2007. © Wiley‐Liss, Inc.
Prevalence and characterization of enteric adenoviruses in the South of Ireland
Authors: Lennon G. , Cashman O. , Lane K. , Cryan B. , O'Shea H.
Published: August 2007

Enteric adenoviruses have been shown to be a substantial cause of pediatric gastroenteritis in various parts of the world, and are considered to be the second most common cause of viral gastroenteritis, next to rotavirus in young children. Genetic characterization of 95 adenovirus isolates obtained from patients with acute gastroenteritis between 2002 and 2007 from the southern regions of Ireland, were characterized by PCR analysis, restriction endonuclease (RE) analysis and sequencing analysis. All isolates were found to be of adenovirus type 41 origin. Genetic analysis of seven hypervariable regions (HVRs) located within the hexon gene has revealed a high level of amino acid sequence homology in samples over the course of this study, with a very close relationship to the D22 genome type. The D22 genome type has been detected in several other countries, thus suggesting Irish isolates have common genome types with other stains worldwide. This is the first such study undertaken in the south of Ireland, to type and genetically characterize adenoviral gastroenteritis isolates, and has revealed a high level of conservation within the isolated analyzed. J. Med. Virol. 79:1518–1526, 2007. © Wiley‐Liss, Inc.
Loss of hepatitis B surface antigen from the serum of patients with chronic hepatitis treated with lamivudine
Authors: Kobayashi Mariko , Suzuki Fumitaka , Akuta Norio , Hosaka Tetsuya , Sezaki Hitomi , Yatsuji Hiromi , Yatsuji Hiromi , Kobayashi Masahiro , Suzuki Yoshiyuki , Arase Yasuji , Ikeda Kenji , Watahiki Sachiyo , Iwasaki Satomi , Miyakawa Yuzo , Kumada Hiromitsu
Published: August 2007

Although loss of hepatitis B e antigen (HBeAg) from the serum is sought by treatment with lamivudine, clearance of hepatitis B surface antigen (HBsAg) is the eventual goal of any antiviral therapy. In a single hepatology center in the Metropolitan Tokyo, 486 patients with chronic hepatitis B were followed up for longer than 3 years after they started treatment with lamivudine. HBsAg disappeared from the serum in 17 (3.5%). Age ≥50 years and low HBsAg levels (hemagglutination titer ≤27) at the start of lamivudine were significantly more frequent in the patients who did than did not lose HBsAg from the serum. Except for these two factors, there were no differences between the two groups of patients in the prevalence of HBeAg and HBV DNA levels at the baseline, as well as the development of YMDD mutants and breakthrough hepatitis during lamivudine treatment. Using multivariate analysis, age ≥50 years at the start of lamivudine was the only factor predicting the loss of HBsAg (hazard ratio: 2.96 [95% confidence interval: 1.14–7.68], P = 0.028). By the method of Kaplan–Meier performed on the 486 patients, the loss of HBsAg was estimated to occur in 3% and 13% of patients, respectively, who had received lamivudine therapy for 5 and 10 years. These results indicate that loss of HBsAg occurs in a minority (3.5%) of patients with chronic hepatitis B who receive lamivudine therapy and more frequently in those with lower HBsAg titers and older ages at the start of treatment. J. Med. Virol. 79:1472–1477, 2007. © Wiley‐Liss, Inc.
Do G protein‐coupled receptors expressed in human lingual epithelium interact with HPV11?
Authors: Durzyński Lukasz , Gaudin Jean‐Charles , Breuils Laure , Szydłowski Jaroslaw , Goździcka‐Józefiak Anna , Haertlé Thomas
Published: August 2007

Human papillomaviruses infect epithelia but little is known about the nature of cell surface receptors interacting with the viral particles. It has been proposed that glycosaminoglycans and integrins may be involved in the attachment process. In the present study, the putative interactions of virus‐like particles of human papillomavirus type 11 (HPV11), which present a tropism for nasopharyngeal epithelia, with olfactory and taste receptors expressed in the human lingual epithelium were studied. The L1 protein of HPV11 was produced in insect cells. The presence of L1 virus‐like particles was analyzed by ELISA using monoclonal antibodies specific for full‐size particles and by electron microscopy. Using immunofluorescence, it was observed that virus‐like particles interacted with taste buds from murine tongue, with the tagged human olfactory receptor hJCG5 expressed in HEK‐293 but not with the tagged taste receptor hT2R4. This therefore suggests that hJCG5 may be involved in the adsorption process of HPV11 to lingual epithelium serving as a so‐called “adsorption‐adhesive molecule.” J. Med. Virol. 79:1545–1554, 2007. © Wiley‐Liss, Inc.
Polymorphism and drug selected mutations of reverse transcriptase gene in 102 HIV‐1 infected patients living in China
Authors: Liu Li , Lu Hong Zhou , Henry Mireille , Tamalet Catherine
Published: August 2007

Few data are available for genotypic patterns within human immunodeficiency virus‐1 (HIV‐1) reverse transcriptase (RT) in drug‐naive patients and RT inhibitor (RTI) treated patients in China. This study aimed at characterizing the polymorphism of RT HIV‐1 in the absence of drug treatment and to identify known and unknown mutations emerging under RTI selective pressure. The HIV‐1 RT gene from 21 drug‐naive patients and 81 RTI treated patients from three provinces in China was analyzed. Most patients (>80%) received a triple regimen including stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP), or d4T plus lamivudine (3TC) and efavirenz (EFV), or zidovudine (AZT) +ddI + NVP. In untreated patients, four highly polymorphic positions were found (122, 200, 207, and 211). In treated patients, two patterns of resistance associated mutations (RAMs) were observed: (1) K65R (9.8%), L74V (7.4%), M184V (7.4%), Q151M (5%), and thymidine analogue mutations (TAMs) (9.3%) including T215Y (5.5%), in patients who underwent ddI + d4T + NVP. (2) T215Y (23%), M184V (20%), and TAMs (15.4%) in patients receiving d4T + 3TC + EFV. In all cases, a high prevalence of non‐nucleoside RTIs (NNRTI) RAMs (41.9%) was found. Four RTI suspected new RAMs were described at position 142, 221, 224, and 228. An association between H221Y and L228H/R with Y181C was noted. These data highlight the predominant spread of NNRTI RAM in China, depict the specific genotypic pattern of RTI selected mutations in China, and suggest the association of newly described mutations with RTI therapy. J. Med. Virol. 79:1593–1599, 2007. © Wiley‐Liss, Inc.
Strategic tools: an empirical investigation into strategy in practice in the UK
Authors: Gunn Rod , Williams Wil
Published: August 2007

At the core of strategic planning has been the use of strategic tools and frameworks such as the ubiquitous SWOT analysis and a variety of frameworks bearing Michael Porter's moniker. There has been a tendency for generic tools to be developed and disseminated to industry, with a one‐type‐fits‐all approach.

Planning and the use of tools have largely been dismissed in much contemporary, particularly European practice‐based, strategic literature. This paper argues that the use of strategic tools has a place in contemporary strategic management. However, the traditional prescriptive rationale for strategic frameworks is replaced with a practice‐based set of reasons advocating the use of strategic tools.

The paper advocates the use of strategic tools in a variety of strategic contexts including planning. However, it is shown that groupings of strategic tool usage can be identified which might indicate that business and business schools should reconsider how they apply, learn and disseminate strategic framework.

Copyright © 2007 John Wiley & Sons, Ltd.
Poly(vinylidene fluoride)‐graft‐Poly(N‐vinyl‐2‐pyrrolidone) Copolymers Prepared via a RAFT‐Mediated Process and their Use in Antifouling and Antibacterial Membranes
Authors: Peng Qiang , Lu Shiqiang , Chen Dezhi , Wu Xiaoqin , Fan Panfeng , Zhong Rong , Xu Yongwen
Published: August 2007

PNVP‐g‐PVDF copolymers were synthesized and used to produce microfiltration membranes. The pore size and distribution varied with the grafting concentration and the density of graft points. A significant decrease of the amounts of adsorbed BSA indicated improved antifouling properties of PVDF. The MF membranes were further functionalized via surface‐initiated block copolymerization with DMAEMA to obtain (PVDF‐g‐PNVP)‐b‐PDMAEMA MF membranes. Quaternization of the tertiary amine groups of the PDMAEMA brushes gave rise to a high concentration of quaternary ammonium salt on the membrane surfaces. The bactericidal effect of the QAS‐functionalized membranes on E. coli was also demonstrated and discussed.

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Organic Light‐Emitting Diode Application of Fluorescent Cellulose as a Natural Polymer
Authors: Karakawa Makoto , Chikamatsu Masayuki , Nakamoto Chikanobu , Maeda Yasukatsu , Kubota Shizuo , Yase Kiyoshi
Published: August 2007

Fluorescent cellulose derivatives were synthesized by utilizing the carbazole group in order to induce optical and semi‐conducting properties. The PL spectra of these cellulose derivatives exhibit UV‐blue emissions at about 350–450 nm attributed to carbazole groups. Analyses of photoelectron spectra were also performed to determine IP values. The results of IP, UV‐vis and PL analyses were almost the same as those of PVK, while the PL intensity and efficiency of the cellulose derivatives were quite different. These compounds functioned as hole transporting materials of OLEDs. Devices using each of the derivatives showed different electronic behavior (current density‐voltage characteristics, EL spectra, etc.), indicating the importance of regioselectivity of the substituent group.

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Microwave‐Accelerated Polymerization of 2‐Phenoxymethyl‐1,4,6‐trioxaspiro[4,4]nonane with Diglycidyl Ether of Bisphenol A
Authors: Canadell Judit , Mantecón Ana , Cádiz Virginia
Published: August 2007

The cationic copolymerization of 2‐phenoxymethyl‐1,4,6‐trioxaspiro[4,4]nonane with DGEBA under microwave irradiation using ytterbium and lanthanum triflates as initiators is described. A comparison with thermal heating showed a great enhancement in the reaction rates and a higher SOE incorporation in the network. The double ring opening of SOE reduces the usual shrinkage of epoxy resins on curing, and it was lower under microwave irradiation. Moreover, the ytterbium triflate initiator lead to a higher incorporation of linear ester moieties in the network than lanthanum triflate.

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Synthesis of an Acid‐Labile Diacrylate Crosslinker for Cleavable Michael Addition Networks
Authors: Mather Brian D. , Williams Sharlene R. , Long Timothy E.
Published: August 2007

A novel acid‐cleavable diacrylate crosslinker, DCDA, was used as a difunctional Michael acceptor in the synthesis of acid‐cleavable crosslinked networks via base‐catalyzed Michael addition of telechelic poly(ethylene glycol) bis(acetoacetate). Michael addition networks containing DCDA were degraded in the presence of catalytic quantities of acids to form soluble polymeric products. Michael addition networks of non‐degradable diacrylate crosslinkers were chemically unchanged under identical reaction conditions and remained insoluble. Thermal degradation of DCDA‐containing networks was also investigated using TGA, which confirmed the thermal reactivity and concentration of the acid‐labile crosslink points.

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Dipyridamole‐Loaded Poly(L‐lactide) Single Crystals as Drug Delivery Systems
Authors: D'Ilario Lucio , Francolini Iolanda , Martinelli Andrea , Piozzi Antonella
Published: August 2007

Poly(L‐lactide) (PLLA) single crystals grown from dilute solution were employed for the first time in the preparation of drug delivery systems. PLLA single crystals were selectively hydrolyzed with HCl to provide the lamellar surface with carboxylic groups, which were employed to graft Dipyridamole (Dip), chosen as a model drug. The influence of the hydrolysis conditions on the single crystals properties was investigated by FT‐IR, DSC and GPC measurements, while Dip grafting yield and drug release in lipase solution were followed by UV‐vis spectroscopy. Dip was slowly delivered over a few days, suggesting the potential use of PLLA single crystals as controlled drug release carriers for either oral or parenteral injection administration.

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Polycondensation of ‘a − bn’ or ‘a2 + + bn’ Monomers ‐ A Comparison
Authors: Kricheldorf Hans R.
Published: August 2007

Characteristic similarities and differences in polycondensations of ‘a − b’ and ‘a2 + b2’ monomers are described including cyclic ‘a − b’ and cyclic ‘a2’ monomers. Polycondensations of ‘ab3’ monomers that yield (hyper)branched polymers are compared with polycondensations of ‘a2 + b3’ monomers that yield (hyper)branched, multicylic, or crosslinked polymers. In all cases the influence of cyclization reactions on structure and molecular weight of the reaction products is considered. Furthermore, the definitions of polycondensation and condensative chain polymerization are discussed along with a differentiation between kinetically controlled and thermodynamically controlled polycondensations.

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Microwave‐Assisted Controlled Ring‐Closing Cyclopolymerization of Diallyldimethylammonium Chloride Via the RAFT Process
Authors: Assem Yasser , Greiner Andreas , Agarwal Seema
Published: August 2007

The present studies provide the first example of controlled free radical polymerization of a cyclopolymerizing monomer, i.e. diallyldimethylammonium chloride (DADMAC) via reversible addition fragmentation chain transfer (RAFT) chemistry in the presence of trithiocarbonate agent in aqueous solution at 60 °C under microwave irradiation. The polymers [poly(diallyldimethylammonium chloride), PDADMAC] were soluble in water. The structural characterization of the polymers was achieved via NMR spectroscopy. The cyclization reactions during DADMAC polymerization under microwave irradiation attained higher conversions at each time interval as compared to thermal heating. The rate enhancements till around 520% were seen for some reactions. High molecular weight PDADMAC with narrow polydispersities (approaching PDI ≈ 1.05) could be made using microwave irradiation.

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Commentary
Authors: DiMasi Joseph A.
Published: August 2007

The three papers by Scherer (2007), Berndt et al. (2007), and Reiffen and Ward (2007) in this issue cover disparate topics, but together they manage to encompass much of what is important during a drug's lifecycle. Scherer's paper examines pharmaceutical industry R&D productivity and efficacy and safety testing during a new drug's development, Berndt, Danzon and Kruse investigate cross‐national data on utilization, pricing, promotion, and diffusion of brand name drugs after they have been developed for marketing approval, and Reiffen and Ward explore generic competition once a new drug loses patent protection. They add much to our understanding of these topics. Copyright © 2007 John Wiley & Sons, Ltd.
The cost of US pharmaceutical price regulation: a financial simulation model of R&D decisions
Authors: Abbott Thomas A. , Vernon John A.
Published: August 2007

Previous empirical studies that have examined the links between pharmaceutical price controls, profits, cash flows, and investment in research and development (R&D) have been largely based on retrospective statistical analyses of firm‐ and/or industry‐level data. These studies, which have contributed numerous insights and findings to the literature, relied upon ad hoc reduced‐form model specifications. In the current paper we take a very different approach: a prospective micro‐simulation approach. Using Monte Carlo techniques we model how future price controls in the US will impact early‐stage product development decisions in the pharmaceutical industry. This is done within the context of a net present value (NPV) framework that appropriately reflects the uncertainty associated with R&D project technical success, development costs, and future revenues. Using partial‐information estimators calibrated with the most contemporary clinical and economic data available, we demonstrate how pharmaceutical price controls will significantly diminish the incentives to undertake early‐stage R&D investment. For example, we estimate that cutting prices by 40–50% in the US will lead to between 30 and 60% fewer R&D projects being undertaken (in early‐stage development). Given the recent legislative efforts to control prescription drug prices in the US and the likelihood that price controls will prevail as a result, it is important to better understand the firm response to such a regulatory change. Copyright © 2007 John Wiley & Sons, Ltd.
Mergers and acquisitions in the pharmaceutical and biotech industries
Authors: Danzon Patricia M. , Epstein Andrew , Nicholson Sean
Published: August 2007

We examine the determinants and effects of M&A activity in the pharmaceutical/biotechnology industry using SDC data on 383 firms from 1988 to 2001. For large firms, mergers are a response to expected excess capacity due to patent expirations and gaps in a firm's product pipeline. For small firms, mergers are primarily an exit strategy in response to financial trouble (low Tobin's q, few marketed products, low cash–sales ratios). In estimating effects of mergers, we use a propensity score to control for selection based on observed characteristics. Controlling for merger propensity, large firms that merged experienced a similar change in enterprise value, sales, employees, and R&D, and had slower growth in operating profit, compared with similar firms that did not merge. Thus mergers may be a response to trouble, but they are not a solution. Copyright © 2007 John Wiley & Sons, Ltd.
Pharmaceutical‐embodied technical progress, longevity, and quality of life: drugs as ‘Equipment for Your Health’
Authors: Lichtenberg Frank R. , Virabhak Suchin
Published: August 2007

Several econometric studies have concluded that technical progress embodied in equipment is a major source of manufacturing productivity growth. Other research has suggested that, over the long run, growth in the US economy's ‘health output’ has been at least as large as the growth in non‐health goods and services. One important input in the production of health—pharmaceuticals—is even more R&D‐intensive than equipment.

In this paper, we test the pharmaceutical‐embodied technical progress hypothesis—the hypothesis that newer drugs increase the length and quality of life—and estimate the rate of progress. To do this, we estimate health production functions, in which the dependent variables are various indicators of post‐treatment health status (such as survival, perceived health status, and presence of physical or cognitive limitations), and the regressors include drug vintage (the year in which the FDA first approved a drug's active ingredient(s)) and indicators of pre‐treatment health status. We estimate these relationships using extremely disaggregated—prescription‐level—cross‐sectional data derived primarily from the 1997 Medical Expenditure Panel Survey.

We find that people who used newer drugs had better post‐treatment health than people using older drugs for the same condition, controlling for pre‐treatment health, age, sex, race, marital status, education, income, and insurance coverage: they were more likely to survive, their perceived health status was higher, and they experienced fewer activity, social, and physical limitations. The estimated cost of the increase in vintage required to keep a person alive is lower than some estimates of the value of remaining alive for 1 month. One estimate of the cost of preventing an activity limitation is $1745, and the annual rate of technical progress with respect to activity limitations is 8.4%. People consuming newer drugs tend to experience greater increases (or smaller declines) in physical ability than people consuming older drugs.

Most of the health measures indicate that the effect of drug vintage on health is higher for people with low initial health than it is for people with high initial health. Therefore in contrast to equipment‐embodied technical progress, which tends to increase economic inequality, pharmaceutical‐embodied technical progress has a tendency to reduce inequality as well as promote economic growth, broadly defined. Copyright © 2007 John Wiley & Sons, Ltd.
A primer on the economics of re‐importation of prescription drugs
Authors: Berndt Ernst R.
Published: August 2007

Using the basic tools of intermediate microeconomic theory (such as taught at the level of undergraduate or first‐year MBA courses), in this primer I present a framework that helps the reader gain an understanding of economic issues underlying the current political economy debates concerning the impacts on consumers (both US and ex‐US) and on prescription pharmaceutical manufacturers of moving to a world with more uniform pricing across countries than is currently the case. The impact on global revenues and profitability of moving from differential to uniform global pricing is relatively modest if confined to the North American (US and Canadian) market, with only Canadians bearing the brunt of higher prices, a most unlikely political economy outcome. The impacts on global revenues and profitability from global uniform prices become considerably larger, however, when one incorporates the much larger entire ex‐US market, including not only Canada, but also Europe, Asia and other countries. I conclude with some observations on likely longer term outcomes. Copyright © 2007 John Wiley & Sons, Ltd.
Generic competition and market exclusivity periods in pharmaceuticals
Authors: Grabowski Henry G. , Kyle Margaret
Published: August 2007

In this paper we examine generic competition and market exclusivity periods for pharmaceuticals experiencing their initial generic entry between 1995 and 2005. We find that generic competition has increased over several dimensions. First, an increasing number of drugs are subject to generic entry, including drugs with relatively modest annual average sales. Second, drugs with larger sales attract more generic entrants and have shorter market exclusivity periods than smaller selling drugs. Third, blockbuster drugs with annual sales in excess of $1 billion have experienced significant decreases in their market exclusivity periods in recent years. We also find that Hatch‐Waxman Act patent challenges have negatively affected market exclusivity periods over the 1995 to 2005 period. Copyright © 2007 John Wiley & Sons, Ltd.