bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone H3 variants and their potential role in indexing mammalian genomes: The “H3 barcode hypothesis”
Authors: Hake Sandra B. , Allis C. David
Published: March 2006

In the history of science, provocative but, at times, controversial ideas have been put forward to explain basic problems that confront and intrigue the scientific community. These hypotheses, although often not correct in every detail, lead to increased discussion that ultimately guides experimental tests of the principal concepts and produce valuable insights into long-standing questions. Here, we present a hypothesis, the “H3 barcode hypothesis.” Hopefully, our ideas will evoke critical discussion and new experimental approaches that bear on general topics, such as nuclear architecture, epigenetic memory, and cell-fate choice. Our hypothesis rests on the central concept that mammalian histone H3 variants (H3.1, H3.2, and H3.3), although remarkably similar in amino acid sequence, exhibit distinct posttranslational “signatures” that create different chromosomal domains or territories, which, in turn, influence epigenetic states during cellular differentiation and development. Although we restrict our comments to H3 variants in mammals, we expect that the more general concepts presented here will apply to other histone variant families in organisms that employ them.
A role of the double-stranded RNA-binding protein PACT in mouse ear development and hearing
Authors: Rowe Theresa M. , Rizzi Mark , Hirose Keiko , Peters Gregory A. , Sen Ganes C.
Published: March 2006

To determine the physiological functions of the mammalian double-stranded RNA-binding protein PACT, the single-copy mouse Pact gene was disrupted and expression of the protein was completely ablated. The most notable phenotypes of the Pact
−/−
mouse were reduced size and severe microtia. As a result of the congenital abnormality of both outer and middle ears, these mice were hearing impaired.
In situ
hybridization revealed that PACT mRNA was expressed in specific regions of all three parts of the ear in adult and embryonic wild-type mice. Our study demonstrated an essential role of PACT in mammalian ear development and produced the first animal model for studying human microtia.
Recurrence of brain tumours in patients treated with growth hormone: Analysis of KIGS (Pfizer International Growth Database)
Authors: Darendeliler Feyza , Karagiannis Georgios , Wilton Patrick , Ranke Michael B. , Albertsson‐Wikland Kerstin , Price David Anthony ,   On Behalf Of The Kigs International Board
Published: March 2006

Background: Growth hormone (GH) has been used successfully in the treatment of short stature secondary to GH deficiency in survivors of childhood brain tumours. There has been concern that GH might increase the risk of recurrence. Aim: To analyse KIGS (Pfizer International Growth Database) with respect to tumour recurrence in patients with brain tumours. Methods: Data for tumour recurrence were analysed retrospectively in 1038 patients with craniopharyngiomas, 655 with medulloblastomas, 113 with ependymomas, 297 with germinomas, and 400 with astrocytomas or gliomas. All patients had received recombinant human GH (Genotropin®, Pfizer Inc.). Results: Recurrence‐free survival rates were 63% at a follow‐up of 10.3 y in craniopharyngioma, 69% in 9.1 y in the glial tumours, 71% in 7.4 y in germinomas, 92% in 4.6 y in medulloblastomas and 89% in 2.5 y in ependymomas. Dose of GH and treatment modalities did not differ significantly between patients with and without recurrence.

Conclusion: Tumour recurrence rates in surviving patients with brain tumours receiving GH treatment do not appear to be increased compared with published reports. However, longer follow‐up regarding recurrences and secondary neoplasms remains essential.
Cathepsin K expression is diminished in infants with bronchopulmonary dysplasia
Authors: Knaapi Jonni , Lukkarinen Heikki , Kiviranta Riku , Steiner Aida , Lassus Patrick , Andersson Sture , Kääpä Pekka
Published: March 2006

The expression of a potent collagenolytic enzyme, cathepsin K, was measured in repeated tracheal aspirate samples from premature infants with and without a chronic lung disorder, bronchopulmonary dysplasia (BPD). At 9–13 d, but not before, cathepsin K expression was significantly lower in the lungs of premature infants developing BPD. Conclusion: Insufficient pulmonary cathepsin K in BPD may predispose premature lungs to pulmonary fibrosis.
Gender differences in neurodevelopmental outcomes among extremely preterm, extremely‐low‐birthweight infants
Authors: Hintz Susan R. , Kendrick Douglas E. , Vohr Betty R. , Poole W. Kenneth , Higgins Rosemary D. ,   For The Nichd Neonatal Research Network
Published: March 2006

Aim: To determine whether gender‐specific responses to perinatal and neonatal events and exposures explain the male disadvantage in early childhood outcomes. Methods: Infants were in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, born 1/1/1997–12/31/2000, <28 wk, with neurodevelopmental follow‐up at 18–22 mo corrected age. We evaluated and compared univariate and multivariate associations of risk factors with neurodevelopmental outcomes for girls and boys. Neurodevelopmental impairment (NDI) was one or more of the following: moderate–severe cerebral palsy (CP), Bayley Mental (MDI) or Psychomotor (PDI) Development Indices <70, deafness or blindness. Results: Boys (n=1216) were more likely than girls (n=1337) to have adverse outcomes (moderate–severe CP: 10.7% vs 7.3%; MDI<70: 41.9% vs 27.1%; NDI: 48.1% vs 34.1%). Major risk factors were also more common in boys. Independent multivariate associations of risk factors with outcome differed by gender, but not consistently in favor of girls. In multivariate models including both girls and boys, male gender remained an independent risk factor for MDI<70 (2.0, 95% CI 1.6–2.5) and NDI (1.8, 95% CI 1.5–2.2).

Conclusion: Perinatal, neonatal and early childhood factors confer similar incremental risk or protection to boys and girls, but boys appear to have inherently greater baseline risk. Unmeasured biological variables likely contribute to the preterm male neurodevelopmental outcome disadvantage.
Intimal thickness of the coronary arteries in low‐birthweight infants
Authors: Pesonen Erkki , Johnsson Jesper , Berg Ansgar
Published: March 2006

Background: Intimal thickening is considered to be an early manifestation of developing atherosclerosis in healthy young adults and children. Low birthweight correlates with increased incidence of cardiovascular diseases. Aim: To test the hypothesis that low birthweight is associated with relatively thickened intima at birth. Methods: The coronary arteries of 175 children were screened from serial cross‐sections for maximal intimal thickening and measured morphometrically. The area of intima and media and the length of internal elastic lamina were measured. The intimal to medial area ratio and calculated thicknesses of intima were used in statistical comparisons. Only children who died within 30 d after birth (n=111) were included. Results: There was a significant positive correlation between intimal thickness and birthweight in low‐birthweight children (p <0.006). Neither the relative thickness of the intima nor the ratio of intimal to medial area increased with increasing growth restriction. The sum of the thicknesses of arterial media and intima had a significant positive correlation with birthweight in these infants.

Conclusion: Intimal thickness present at birth in small‐for‐date children does not seem to be an aetiological factor for the increased risk of coronary heart disease later in life.
Effect of indomethacin on closure of ductus arteriosus in very‐low‐birthweight neonates 1
Authors: Godambe Sunit , Newby Brandi , Shah Vibhuti , Shah Prakesh S.
Published: March 2006

Aim: To identify factors related to indomethacin non‐responsiveness for patent ductus arteriosus (PDA) closure in very‐low‐birthweight (VLBW) neonates. Methods: A chart review of 107 VLBW neonates with a clinical diagnosis of PDA who received indomethacin, admitted to a tertiary neonatal intensive care unit in Toronto, Canada, was conducted (study period November 2001 to October 2003). Positive responders were those with no clinical evidence of PDA for 72 h after indomethacin. Results: Response to the first course of indomethacin was 75%, and to the second course 67% among initial responders. Higher CRIB score (OR 1.15, 95% CI 1.02–1.31) and early surfactant administration (OR 3.74, 95% CI 1.04–13.47) were associated with non‐responsiveness to indomethacin.

Conclusion: Indomethacin is effective for PDA closure. The response rate diminished with subsequent courses. Early surfactant and severity of illness at admission were associated with non‐responsiveness to indomethacin.
Orthographic Influences on Phoneme Deletion Response Times
Authors: Tyler Michael D. , Burnham Denis K.
Published: March 2006

The aim of this paper is to provide further evidence that orthography plays a central role in phonemic awareness, by demonstrating an orthographic congruency effect in phoneme deletion. In four initial phoneme deletion experiments, adult participants produced the correct response more slowly with orthographically mismatched stimulus–response pairs (e.g., worth–earth) than with matched pairs (e.g., wage–age). This orthographic effect occurred with or without specific instructions to ignore spelling and when stimuli were presented with or without the to-be-deleted sound. In a final experiment, participants made more errors on complex than simple onset items, but there was no interaction with orthographic mismatch. The repeated observation of this robust orthographic effect suggests that participants are at least aware of orthography during phonemic awareness tasks, and it supports the view that phonemic awareness is directly subserved by orthography.
An Insidious Nosocomial Outbreak Due toSalmonella enteritidis
Authors: Guallar Cristina , Ariza Javier , Dominguez Angeles , Peña Carmen , Grau Imma , Verdaguer R. , Torrens LLum , Gudiol Francisco
Published: March 2006

Objectives:

To investigate an increase in the number ofSalmonella enteritidisisolates detected in a large hospital to ascertain whether it was due to a nosocomial source, to identify the mechanisms of transmission, and to institute effective control measures to prevent future episodes.

Design:

Observational study, survey of all microbiological samples positive forS. enteritidisdetected in the hospital, outbreak investigation, and review of the literature.

Setting:

A tertiary-care teaching hospital for adults in Barcelona, Spain.

Results:

During a 7-month period from May to November 1998, we identified 22 inpatients withS. enteritidisinfection for whom nosocomial acquisition was strongly suspected. The attack rate was 0.138 per 1,000 patient-days. All affected patients were immunosuppressed and overall mortality was 41% (9 of 22). A sample of a meal cooked in the kitchen was culture positive forS. enteritidis.All isolates shared the same antibiotic susceptibility pattern and all except one shared the same pulsed-field gel electrophoresis (PFGE) pattern, but PFGE could not differentiate between outbreak-related and control strains. After compliance with kitchen hygiene procedures was emphasized and cleansing was intensified, no more cases were detected.

Conclusions:

Apparently, sporadic cases ofS. enteritidismay be part of an outbreak with a low attack rate. A small but persistent inoculum affecting only individuals with special predisposition forSalmonellainfection might account for this. Suspicion should be raised in hospitals and institutions with a highly susceptible population.
Knowledge, Attitudes, and Practices of Food Service Staff Regarding Food Hygiene in Shiraz, Iran
Authors: Askarian Mehrdad , Kabir Gholamhosein , Aminbaig Maria , Memish Ziad A. , Jafari Peyman
Published: March 2006

Background:

The practice of safety measures by the food service staff in hospitals is necessary for the prevention of food-borne outbreaks. Hospitalized patients are more vulnerable to potential hazards, and neglecting these principles can lead to increased morbidity and mortality.

Methods:

We assessed the knowledge, attitudes, and practices of food service staff regarding food hygiene in government and private hospitals in Shiraz, Iran. Two questionnaires were designed, one for food service staff and the ofher for supervisors. Thirty-one hospitals were approached, and the response rate was 99.5%. Four models were developed regarding knowledge, attitudes, and practices, and a multiple logistic regression analysis was performed. Comparison among the government and private hospitals was done.

Results:

This study showed that personnel had little knowledge regarding the pathogens that cause food-borne diseases and the correct temperature for the storage of hot or cold ready-to-eat foods. Older personnel had better attitudes and practices. Females practiced safety measures less often than did males. Personnel working in hospitals with fewer than 300 beds also had better practices. Most of the personnel had positive attitudes, but disparity between attitude and practice was noted.

Conclusion:

There is a dire need for education and increased awareness among food service staff regarding safe food handling practices.
Does the Architecture of Hospital Facilities Influence Nosocomial Infection Rates? A Systematic Review
Authors: Dettenkofer M. , Seegers S. , Antes G. , Motschall E. , Schumacher M. , Daschner F. D.
Published: March 2006

Objective:

To review the evidence regarding the effects of interventions to improve hospital design and construction on the occurrence of nosocomial infections.

Methods:

Systematic review of experimental and non-experimental, architectural intervention studies in intensive care units (ICUs), surgical departments, isolation units, and hospitals in general. The studies dated from 1975, and were in English, French, German, Italian, and Spanish. Regardless of format, the studies were identified through seven medical databases, reference lists, and expert consultation.

Results:

One hundred seventy-eight scientific articles were identified; however, none of these described a meta-analy-sis, systematic review, or randomized, controlled trial. Most of the articles were categorized at the lowest level of evidence (expert judgment or consensus statements). Only 17 described completed concurrent or historical cohort studies matching the inclusion criteria (ICUs, 9; surgical departments, 4; isolation units, 2; hospitals in generai, 2). The interventions generally included a move to other premises or renovation. However, in many studies, the staff-to-patient ratio was also improved. Some studies showed lower infection rates after intervention, but this finding cannot be generalized because of confounding and fre-quently small study populations.

Conclusions:

The lack of stringent evidence linking hospital design and construction with the prevention of nosocomial infection is partly attributable to the multifactorial nature of these infections, and some improvement will be seen if basic conditions such as the availability of sufficient space, isolation capac-ity, and facilities for handwashing are met. However, to our knowledge, other factors, especially the improper hand hygiene of medical staff, have greater impact.
Infection Control Programs in Italian Hospitals
Authors: Moro Maria Luisa , Petrosillo Nicola , Gandin Claudia , Bella Antonino
Published: March 2006

Objective:

To quantify the frequency and features of infection control programs implemented in Italian public hospitals.

Methods:

In 2000, a questionnaire was mailed targeting all teaching and research hospitals and those with more than 300 beds, and a random sample of 50% of the district hospitals with fewer than 300 beds.

Results:

The overall response rate was 80%. Fifty percent of the 428 respondent hospitals claimed to have an infection control committee, 43% an infection control physician (average, 1 infection control physician per 2,963 beds), and 33% an infection control nurse (average, I infection control nurse per 572 beds). Having an infection control committee, nurse, and physician occurred significantly more frequently in Northern and Central Italy, where the Regional Authority had implemented a regional infection control policy, and in larger hospitals. Thirty-nine percent of the hospitals claimed to have ongoing surveillance in place, mostly based on laboratory results. Eighty percent of the hospitals had defined at least one written protocol related to infection control policies, mostly for housekeeping, cleaning, disinfecting and sterilizing patient equipment, or standard precautions; on the contrary, policies aimed at preventing specifie infections were less frequent.

Conclusion:

This national representative survey showed that the infrastructure for infection control is suboptimal when compared with the guidelines and surveys published in other countries.
Effect of Education and Performance Feedback on Rates of Catheter-Associated Urinary Tract Infection in Intensive Care Units in Argentina
Authors: Rosenthal Victor Daniel , Guzman Sandra , Safdar Nasia
Published: March 2006

Objective:

To evaluate the effect of education and performance feedback regarding compliance with catheter care and handwashing on rates of catheter-associated urinary tract infection (UTI) in intensive care units (ICUs).

Setting:

Two level III adult ICUs in a private healthcare facility in Argentina.

Patients:

All adult patients admitted to the study units who had a urinary catheter in place for at least 24 hours.

Methods:

A prospective, open trial in which rates of catheter-associated UTI determined during a baseline period of active surveillance without education and performance feedback were compared with rates of catheter-associated UTI after imple-menting education and performance feedback.

Results:

There were 1,779 catheter-days during the baseline period and 5,568 catheter-days during the intervention period. Compliance regarding prevention of compression of the tubing by a leg improved (from 83% to 96%; relative risk [RR], 1.15; 95% confidence interval [CI95], 1.03 to 1.28; P = .01) and so did compliance with handwashing (from 23.1% to 65.2%; RR, 2.82; CI95, 2.49 to 3.20; P<.0001). Catheter-associated UTI rates decreased significantly from 21.3 to 12.39 per 1,000 catheter-days (RR, 0.58; CI95, 0.39 to 0.86; P = .006).

Conclusion:

Implementing education and performance feedback regarding catheter care measures and handwashing compliance was associated with a significant reduction in catheter-associated UTI rates. Similar programs may help reduce catheter-associated UTI rates in other Latin American hospitals.
Genetic Analysis ofPseudomonas aeruginosaby Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (PCR) and Arbitrarily Primed PCR: Gel Analysis Compared with Microchip Gel Electrophoresis
Authors: Jamasbi Roudabeh J. , Kennel Stephen J. , Waters Larry C. , Foote Linda J. , Ramsey J. Michael
Published: March 2006

Objectives:

To assess the applicability of a newly emerging microchip gel electrophoresis for rapid strain differentiation among clinical isolates ofPseudomonas aeruginosa,and to compare this technique with the traditional gel method for DNA separation.

Methods:

One hundred clinical strains ofP. aeruginosaobtained from a hospital in northwestern Ohio were tested for reactivity to 3 serotype-specific monoclonal antibodies by enzyme-linked immunosorbent assay. Twelve strains (4 from each serogroup) were selected for DNA analysis by polymerase chain reaction (PCR)-based, single primer DNA fingerprinting methods with 3 different primers: 1 enterobacterial repetitive intergenic consensus PCR and 2 arbitrarily primed PCRs. The PCR products were analyzed by agarose slab gel and microchip gel electrophoresis.

Results:

Of the 100 clinical isolates tested, 39% (4%, 14%, and 21%) were found to be serotypes 0:3, 0:6, and 0:11, respectively. Twelve strains were chosen for DNA analysis by PCR. The PCR products were analyzed by agarose slab gel electrophoresis and on microchips to determine interspecies diversity. Both methods demonstrated that different serotypes exhibited different electrophoretic patterns. Two strains (clinical strains 6 and 7, serotype 0:6) showed identical patterns, indicating a high degree of relatedness.

Conclusion:

In all cases, there was concordance between the electrophoretic patterns detected by the two methods. The capability of conducting both PCR and microchip gel electrophoresis offers an opportunity for an automated and rapid method for genetic analysis and differentiation among strains ofP. aeruginosaand other microorganisms.
Clinical and Microbiological Profile of Urinary Tract Infection at a Tertiary-Care Center in Lebanon
Authors: Fadel Roula , Dakdouki Ghenwa K. , Kanafani Zeina A. , Araj George F. , Kanj Souha S.
Published: March 2006

We compared community-acquired urinary tract infection (UTI) with hospital-acquired UTI at the American University of Beirut Medical Center. Escherichia coli was the most frequently isolated organism. Hospital-acquired E. coli isolates were often rnultidrug resistant. These results can be used to improve empiric treatment of UTI.
Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans
Authors: Mahoney Timothy R. , Liu Qiang , Itoh Takashi , Luo Shuo , Hadwiger Gayla , Vincent Rose , Wang Zhao-Wen , Fukuda Mitsunori , Nonet Michael L.
Published: March 2006

Rab small GTPases are involved in the transport of vesicles between different membranous organelles. RAB-3 is an exocytic Rab that plays a modulatory role in synaptic transmission. Unexpectedly, mutations in the Caenorhabditis elegans RAB-3 exchange factor homologue, aex-3, cause a more severe synaptic transmission defect as well as a defecation defect not seen in rab-3 mutants. We hypothesized that AEX-3 may regulate a second Rab that regulates these processes with RAB-3. We found that AEX-3 regulates another exocytic Rab, RAB-27. Here, we show that C. elegans RAB-27 is localized to synapse-rich regions pan-neuronally and is also expressed in intestinal cells. We identify aex-6 alleles as containing mutations in rab-27. Interestingly, aex-6 mutants exhibit the same defecation defect as aex-3 mutants. aex-6; rab-3 double mutants have behavioral and pharmacological defects similar to aex-3 mutants. In addition, we demonstrate that RBF-1 (rabphilin) is an effector of RAB-27. Therefore, our work demonstrates that AEX-3 regulates both RAB-3 and RAB-27, that both RAB-3 and RAB-27 regulate synaptic transmission, and that RAB-27 potentially acts through its effector RBF-1 to promote soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) function.
Negotiorum Gestio: A Civilian Concept in the Common Law?
Authors: Sheehan Duncan
Published: March 2006

This paper assesses whether English law recognizes a concept of negotiorum gestio. Claimants intervening in other' affairs and seeking restitution or reimbursement of expenses are often labeled ‘officious’, and disallowed relief. That, however, gives a misleading impression of English law. English law does recognize a concept of negotiorum gestio, which while very different to that found in German law, has parallels to versions found in other Civilian systems. It provides a cause of action to recover the intervenor's expenses, and any loss suffered during the intervention. It also provides a defence to the intervenor's intentional torts, although negligent intervenors will remain liable for their negligence
The 2005 UN Convention on State Immunity in Perspective
Authors: Denza Eileen
Published: March 2006

State immunity is highly unusual among established areas of public international law in that it has been created and developed largely through cases in national courts and through national legislation. In sharp contrast to diplomatic and consular privileges and immunities, the role of reciprocity and of diplomatic negotiation in shaping the rules of state immunity has been rather limited. While national courts have purported to apply these rules as international law, they have inevitably viewed them within the frame-work of the constitutional approach taken by the particular national legal order to rules of international law and they have looked to earlier national precedents rather than to cases in other jurisdictions. In consequence, cross-fertilization has been rather limited and the process of response by national courts to the changing functions of States in the modern world has been painfully slow. Over the past 30 years, the uncertainties and inadequacies of leaving state immunity rules to national courts has been addressed mainly through national statutes—but while the draftsmen and legislators have paid careful attention to other statutes and tried to follow their best features, this process has compounded the perception of the courts that state immunity is an area of national law, to be interpreted and refined at national level.
Status of Forces under the UN Convention on State Immunity
Authors: Dickinson Andrew
Published: March 2006

The United Nations Convention on Jurisdictional Immunities of States and Their Property was adopted by the UN General Assembly on 2 December 2004.1The General Assembly recorded, in the first paragraph of its resolution adopting the Convention, its ‘deep appreciation to the International Law Commission and the Ad Hoc Committee on jurisdictional Immunities of States and their Property for their valuable work on the law of jurisdictional immunities of States and their property’. Whatever view one takes as to the merits of the Convention text or the prospects of its success,2it cannot be doubted that this acknowledgment was well deserved—it is, if anything, an understatement to describe the conclusion of a detailed international instrument on state immunity, embodying the restrictive theory of immunity, as a ‘diplomatic triumph’.
I. The 20th Session Of The Hague Conference: A New Choice Of Court Convention And The Issue Of Ec Memebership
Authors: Kruger Thalia
Published: March 2006

On 30 June 2005 a Convention to respect choice of court agreements was finally born. The Hague Convention on Choice of Court Agreements aspires to be parallel to the New York Convention on the Recognition and Enforcement of Foreign Arbitral Awards (1958) (‘New York Convention’). The exception is that if an equally broadly accepted convention exists with respect to choice of court agreements,1 business parties will have an alternative to choosing arbitration in their contracts. If they have the assurance that a judgement will be recognized and enforced in a large number of States, some might be more inclined to insert a choice of court clause instead of an arbitration clause. This assumption has been confirmed by ICC research.2
Expression of vanilloid receptor 1 in cultured fibroblast
Authors: Kim Seong‐Jin , Lee Su‐A , Yun Sook Jung , Kim Jong‐Keun , Park Jong‐Seong , Jeong Han‐Seong , Lee Jeung‐Hoon , Moon Seong‐Joon , Won Young‐Ho
Published: March 2006

Abstract:  Although the vanilloid receptor 1 (VR1) was originally discovered on primary sensory neurons, its broad tissue expression in non‐neuronal cells has been reported on. Recently, VR1 expression was clearly demonstrated in a variety of cutaneous components, such as keratinocytes, glandular epithelium, mast cells and sebocytes, except for melanocytes and fibroblasts. However, we demonstrated the VR1 expression in the cultured human skin fibroblasts as follows. Previously cloned human VR1 primers that corresponded to the expected size of 680 bp by reverse transcriptase polymerase chain reaction were identified on the fibroblasts, the same as was noted for the positive control, the HaCaT cells. A positive immunoreactivity of the VR1 was observed both on fibroblasts and on HaCaT cells by Western blotting analysis. Fibroblasts treated with capsaicin, an agonist to the VR1, induced significant changes of the membrane current and the intracellular calcium level, and these changes were antagonized by capsazepin. Capsaicin treatment also showed a positive immunocytochemistry result. Our results suggest the existence of VR1 on fibroblasts; this receptor is likely to be influenced by ligand‐dependent activation.
Pathogenesis and therapy of cutaneous lymphomas – Progress or impasse?
Authors: Dummer Reinhard , Cozzio Antonio , Urosevic Mirjana
Published: March 2006

Abstract:  The cutaneous environment hosts a number of hematopoietic neoplasms that are dominated by primary cutaneous (PC) T‐cell lymphomas. Recent progress in molecular biology and immunology has provided tools to investigate the pathogenesis and the biology of these neoplasms. This review highlights newest findings concerning the immune biology of CD4+CD56+ hematodermic neoplasms, and PC T‐cell and B‐cell lymphomas, speculating how these can be translated into more sophisticated, biology‐based treatment approaches in the near future.
Mechanical stretch induces clustering of β1‐integrins and facilitates adhesion
Authors: Knies Yvonne , Bernd August , Kaufmann Roland , Bereiter‐Hahn Jürgen , Kippenberger Stefan
Published: March 2006

Abstract:  Human epithelial cells are permanently stimulated by external mechanical forces. The present in vitro study suggests that keratinocytes respond to mechanical strain by a coordinated spatial and functional utilization of β1‐integrins and the epidermal growth factor receptor (EGFR) with impact to the adhesion properties. It was found that a single mechanical stretch applied to HaCaT keratinocytes elevates the substrate adhesion, in particular to fibronectin and collagen type IV but not to laminin indicating the relevance of β1‐integrins in this process. This was confirmed using a functional blocking antibody directed against β1‐integrins which reversed the stretch‐induced adhesion. Furthermore, mechanical stretch gives rise to a rapid redistribution of β1‐integrins in clusters on the basal cell membrane, without changing the overall amount of this particular integrin subset. Concomitantly, the EGFR co‐localizes with β1‐integrin suggesting a functional cooperation of both membrane proteins in mechano‐signaling. This is corroborated by data showing that stretch‐induced activation of the EGFR and the downstream element extracellular regulated kinase 1/2 (ERK1/2) is reversed by preincubation with β1‐integrin antibodies. Vice versa, blocking the EGFR using a specific inhibitor abrogates stretch‐induced ERK1/2 activation. In summary, these results show a functional cooperation of β1‐integrins and EGFR in the adhesion complex supporting the transmission of stretch‐induced signals.
Association study between catalase gene polymorphisms and the susceptibility to vitiligo in Korean population
Authors: Park Hyun‐Ho , Ha Eunyoung , Uhm Yoon Kyung , Jin Sheng‐Yu , Kim Youn‐Jung , Chung Joo‐Ho , Lee Mu‐Hyoung
Published: March 2006

Abstract:  Vitiligo is an acquired pigmentary disorder characterized by well‐circumscribed depigmented patches. Autoimmune, self‐destruction, neural, and genetic theories have been proposed for the pathogenesis of vitiligo. Reactive oxygen species play an important role in the physiology of cell damage, and catalase is known to regulate oxidative stress. Reduced catalase enzyme activity and accumulation of excessive hydrogen peroxide were observed in vitiligo. To examine whether catalase gene polymorphisms are associated with vitiligo patients in Korean population, we investigated two CAT gene polymorphisms including (T/C) BstX I (A/T) Hinf I in 118 vitiligo patients and 200 healthy volunteers. The CAT gene genotype distribution and allele frequency were not significantly different between vitiligo patients and healthy controls. But, the haplotype of two polymorphisms was associated with vitiligo. This study suggests possible association between the CAT gene and the vitiligo susceptibility.
Skin immunoglobulin deposition following intravenous immunoglobulin therapy in toxic epidermal necrolysis
Authors: Paquet P. , Kaveri S. , Jacob E. , Pirson J. , Quatresooz P. , Piérard G. E.
Published: March 2006

Abstract:  Human intravenous immunoglobulins (IVIg) which contain anti‐CD95 antibodies have been proposed to treat toxic epidermal necrolysis (TEN). Presently, there is no evidence that IVIg reach the keratinocytes in TEN patients. The aim of this study was to assess the Ig distribution in the serum, blister fluid and skin of six consecutive TEN patients treated with IVIg (1 g/kg/day) for 3 days. They were compared with five TEN patients who only received supportive therapy. In all patients, IgA, IgM and IgG concentrations were measured in the serum and blister fluid using an immuno‐nephelometric method. Immunohistochemistry was performed on skin biopsies taken from both TEN clinically involved and uninvolved skin to search for IgG deposits. On admission, the IgG concentrations were significantly higher in both TEN serum and TEN blister fluid compared with their respective IgA and IgM contents. The IgG, IgA and IgM concentrations in blister fluid were significantly lower than their respective serum concentrations. The serum and blister fluid IgG concentrations, but not that of IgA and IgM, were markedly increased at the completion of the IVIg treatment. By contrast, they remained unchanged in the TEN patients that were untreated with IVIg. In the IVIg‐treated patients, the IgG intraepidermal deposits raised markedly in both TEN‐involved and uninvolved skin. This was not the case in patients who did not receive IVIg. These results suggest that IVIg perfusions brought a prominent increase in IgG concentration in the serum, blister fluid and epidermis of both TEN‐involved and clinically uninvolved skin. The presence of potentially protective IgG in TEN epidermis following IVIg treatment could help limiting the disease progression.
Inhibition of intestinal carcinogenesis by a new flavone derivative, chafuroside, in oolong tea
Authors: Niho Naoko , Mutoh Michihiro , Sakano Katsuhisa , Takahashi Mami , Hirano Sachiko , Nukaya Haruo , Sugimura Takashi , Wakabayashi Keiji
Published: March 2006

A new flavone derivative, chafuroside, has been isolated as a strong anti‐inflammatory compound from oolong tea leaves, and its structure determined to be (2R,3S,4S,4aS,11bS)‐3,4,11‐trihydroxy‐2‐(hydroxymethyl)‐8‐(4‐hydroxyphenyl)‐3,4,4a,11b‐tetrahydro‐2H,10H‐pyrano[2′,3′:4,5]furo[3,2‐g]chromen‐10‐one. To assess its potential to inhibit intestinal carcinogenesis, 2.5, 5 and 10 p.p.m. chafuroside was given in the diet to Apc‐deficient Min mice for 14 weeks from 6 weeks of age. Total numbers of polyps were reduced to 83, 73 and 56% of the control value, respectively. Moreover, dietary administration at 10 and 20 p.p.m. reduced azoxymethane (AOM)‐induced colon aberrant crypt foci (ACF) development in rats to 69% of the AOM‐treated control value with the higher dose. Chafuroside‐associated toxicity was not observed at 2.5–10 p.p.m. in Min mice and 10–20 p.p.m. in AOM‐treated rats. These results suggest that chafuroside might be a good chemopreventive agent for colon cancer. (Cancer Sci 2006; 97: 248–251)
Expression patterns of polo‐like kinase 1 in human gastric cancer
Authors: Weichert Wilko , Ullrich Andrea , Schmidt Mathias , Gekeler Volker , Noske Aurelia , Niesporek Silvia , Buckendahl Ann‐Christin , Dietel Manfred , Denkert Carsten
Published: March 2006

Polo‐like kinase 1 (PLK1) is centrally involved in the regulation of mitosis in normal and malignant cells. It is known that inhibition of PLK1 expression in vitro and in vivo leads to mitotic arrest, induction of apoptosis and suppression of tumor growth. In the present study, expression of PLK1 was investigated in paraffin tissue of 135 cases of gastric adenocarcinoma and in 46 corresponding lymph node metastases by immunohistochemistry. Expression data were correlated with clinicopathological parameters and patient survival. Seventy‐three (54.1%) of 135 carcinomas showed an overexpression of PLK1 compared to normal gastric mucosa. Overexpression of PLK1 correlated positively with tumor stage, nodal status and diffuse growth pattern. PLK1 expression in the primary tumor did not differ from PLK1 expression in the corresponding lymph node metastases. PLK1 expression was a significant prognostic factor in univariate but not in multivariate survival analysis. As a conclusion, upregulated PLK1 expression in gastric cancer correlates with a malignant tumor phenotype and has impact on patient prognosis. These data underscore the importance of PLK1 in gastric carcinogenesis and present a translational link for functional data into potential clinical use by defining PLK1 as an attractive protein for novel targeted chemotherapeutic approaches in gastric cancer. (Cancer Sci 2006; 97: 271 –276)
Randomized phase II study of concurrent and sequential rituximab and CHOP chemotherapy in untreated indolent B‐cell lymphoma
Authors: Ogura Michinori , Morishima Yasuo , Kagami Yoshitoyo , Watanabe Takashi , Itoh Kuniaki , Igarashi Tadahiko , Hotta Tomomitsu , Kinoshita Tomohiro , Ohashi Yasuo , Mori Shigeo , Terauchi Takashi , Tobinai Kensei
Published: March 2006

CHOP combined with rituximab (R‐CHOP) is regarded as one of the most effective treatments for indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B‐NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n = 34) or sequential (n = 35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85–100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non‐hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow‐up of 28.2 months, the median progression‐free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R‐CHOP is highly effective in untreated indolent B‐NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation. (Cancer Sci 2006; 97: 305 – 312)
Cationized gelatin delivery of a plasmid DNA expressing small interference RNA for VEGF inhibits murine squamous cell carcinoma
Authors: Matsumoto Goichi , Kushibiki Toshihiro , Kinoshita Yukihiko , Lee Ushaku , Omi Yasushi , Kubota Eiro , Tabata Yasuhiko
Published: March 2006

Double‐stranded RNA (dsRNA) plays a major role in RNA interference (RNAi), a process in which segments of dsRNA are initially cleaved by the Dicer into shorter segments (21–23 nt) called small interfering RNA (siRNA). These siRNA then specifically target homologous mRNA molecules causing them to be degraded by cellular ribonucleases. RNAi downregulates endogenous gene expression in mammalian cells. Vascular endothelial growth factor (VEGF) is a key molecule in vasculogenesis as well as in angiogenesis. Tumor growth is an angiogenesis‐dependent process, and therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. To investigate the feasibility of using siRNA for VEGF in the specific knockdown of VEGF mRNA, thereby inhibiting angiogenesis, we have performed experiments with a DNA vector based on a siRNA system that targets VEGF (siVEGF). It almost completely inhibited the expression of three different isoforms (VEGF120, VEGF164 and VEGF188) of VEGF mRNA and the secretion of VEGF protein in mouse squamous cell carcinoma NRS‐1 cells. The siVEGF released from cationized gelatin microspheres suppressed tumor growth in vivo. A marked reduction in vascularity accompanied the inhibition of a siVEGF‐transfected tumor. Fluorescent microscopic study showed that the complex of siVEGF with cationized gelatin microspheres was still present around the tumor 10 days after injection, while free siVEGF had vanished by that time. siVEGF gene therapy increased the fraction of vessels covered by pericytes and induced expression of angiopoietin‐1 by pericytes. These data suggest that cationized‐gelatin microspheres containing siVEGF can be used to normalize tumor vasculature and inhibit tumor growth in a NRS‐1 squamous cell carcinoma xenograft model. (Cancer Sci 2006; 97: 313 – 321)
Review article: hepatitis B and liver transplantation
Authors: MUTIMER D.
Published: March 2006

Liver transplantation is an excellent treatment for hepatitis B virus infected patients who have acute or chronic liver failure and/or primary liver cancer. Advances in antiviral prophylaxis prevent clinically significant graft re‐infection for the majority of patients. Graft and patient survival has improved significantly during the past decade, and results of transplantation for hepatitis B virus are now superior to those achieved for most other indications. In particular, the availability of lamivudine and adefovir have transformed outcome.

The addition of lamivudine to passive immunoprophylaxis with hepatitis B virus immunoglobulin prevents re‐infection in most cases. Adefovir should be added to this combination when the patient develops lamivudine resistance before transplantation. The significance of serum hepatitis B virus DNA positivity in the absence of circulating hepatitis B surface antigen is uncertain. Hepatitis B virus infection of the graft can be observed when prophylaxis is inadequate, when the donor liver contains latent hepatitis B virus infection (so‐called de novo infection from the hepatitis B virus core antibody positive donor), and when the donor is exposed to third party infection (sexual or nosocomial transmission).

Established hepatitis B virus graft infection is a good indication for combination nucleoside analogue therapy. Combination therapy can achieve sustained suppression of viral replication, and hepatitis B e antigen and hepatitis B surface antigen clearance can also be observed.
Pancreatic cancer in England and Wales 1975–2000: patterns and trends in incidence, survival and mortality
Authors: WOOD H. E. , GUPTA S. , KANG J. Y. , QUINN M. J. , MAXWELL J. D. , MUDAN S. , MAJEED A.
Published: March 2006

Background Rates and time trends in mortality from pancreatic cancer vary considerably between countries.

Aim To examine trends and patterns in the incidence of, and the survival and mortality from, pancreatic cancer in England and Wales from 1975 to 2000; in particular, whether incidence and survival rates are related to socio‐economic deprivation.

Methods We calculated annual age‐specific and overall age‐standardized incidence and mortality rates by sex for pancreatic cancer in total, and by subsite. We also estimated survival by sex and age group and by subsite.

Results In males, the age‐standardized rate fluctuated in the late 1970s, to peak at 13.0 per 100 000 in 1979, declined steadily by an average of 1.3% per year to around 10.3 per 100 000 in the mid‐1990s and then levelled off. For females, the rate peaked at 8.4 per 100 000 in the late 1980s before declining and fluctuating around 7.7 per 100 000 in the late 1990s. Patterns and trends in mortality rates were closely similar to those in incidence, due to the very low survival rates: only 2–3% at 5 years from diagnosis. Survival rates improved only minimally over the period 1971–99. Incidence and mortality rates were slightly higher in both males and females living in the most deprived areas, but survival was not consistently related to socio‐economic deprivation.

Conclusions The incidence of, and mortality from, pancreatic cancer in England and Wales have fallen from peak levels observed in the 1970s and 1980s, and levelled off in the 1990s for both sexes; survival rates remain very low.
Review article: predicting response in hepatitis C virus therapy
Authors: MIHM U. , HERRMANN E. , SARRAZIN C. , ZEUZEM S.
Published: March 2006

The introduction of combination therapy with ribavirin and of pegylated interferons has improved treatment results in patients with chronic hepatitis C. However, overall rates of sustained virologic response following antiviral therapy of chronic hepatitis C still do not exceed 54–63%. Because of several virus‐ and patient‐related factors, treatment is even less successful in some patient subpopulations.

The major viral factors associated with impaired response are hepatitis C virus genotype 1 infection and a high viral load. Among patient‐related factors cirrhosis is of special importance. Baseline predictive factors for sustained virologic response become less important for prediction of treatment outcome when quantifications of hepatitis C virus RNA during early therapy are taken into account.

This article provides a summary of virus‐ and patient‐related parameters, which are prognostic for response to antiviral therapy in chronic hepatitis C and focuses on the prediction of treatment response by quantification of hepatitis C virus RNA concentration during therapy.
Intragastric acid control in non‐steroidal anti‐inflammatory drug users: comparison of esomeprazole, lansoprazole and pantoprazole
Authors: GOLDSTEIN J. L. , MINER P. B. , SCHLESINGER P. K. , LIU S. , SILBERG D. G.
Published: March 2006

Background  Studies to date have not directly compared the pharmacodynamic efficacies of different proton pump inhibitors in controlling intragastric acidity in patients treated with non‐steroidal anti‐inflammatory drugs.

Aim  To compare acid suppression with once‐daily esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg in patients receiving non‐selective or cyclo‐oxygenase‐2–selective non‐steroidal anti‐inflammatory drug therapy.

Methods  In this multicentre, open‐label, comparative, three‐way crossover study, adult patients (n = 90) receiving non‐steroidal anti‐inflammatory drugs were randomized to one of six treatment sequences. At the study site, patients were administered esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for 5 days each, with a washout period of ≥10 days between each treatment. Twenty‐four–hour pH testing was performed on day 5 of each dosing period.

Results  The mean percentage of time during the 24‐h pH monitoring period that gastric pH was >4.0 was significantly greater with esomeprazole (74.2%) compared with lansoprazole (66.5%; P < 0.001) and pantoprazole (60.8%; P < 0.001), and significantly greater with esomeprazole (P < 0.05) than with the comparators regardless of whether using non‐selective vs. cyclo‐oxygenase‐2–selective non‐steroidal anti‐inflammatory drugs.

Conclusions  At the doses studied, esomeprazole treatment provides significantly greater gastric acid suppression than lansoprazole or pantoprazole in patients receiving non‐selective or cyclo‐oxygenase‐2–selective non‐steroidal anti‐inflammatory drugs.