bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistance in Enterobacteriaceae: Results of a Multicenter Surveillance Study, 1995-2000
Authors: Friedland Ian , Stinson Lue , Ikaiddi Margaretmary , Harm Sandra , Woods Gail L.
Published: March 2006

Objectives:

To assess changes over time in susceptibility of Enterobacteriaceae from patients in ICUs, compare susceptibility rates of isolates from patients in ICUs with those from inpatients outside ICUs, and explore phenotypic patterns of cross-resistance and co-resistance.

Design:

From 1995 to 2000, centers participating in the ICU Surveillance Study tested 100 to 200 consecutive nosocomial gram-negative bacilli by broth microdilution.

Setting:

Each year, 42 to 97 U.S. hospitals tested isolates.

Results:

In all years, imipenem was the most potent agent tested, followed by amikacin and ertapenem. Extended-spectrum beta-lactam and monobactam agents had good activity against Escherichia coli and Klebsiella species, but limited activity against Enterobacter species. Susceptibility to imipenem and amikacin did not fluctuate during the analysis period, whereas susceptibility to ceftazidime, ceftriaxone, and ciprofloxacin decreased 2% to 5%. The decline was most pronounced for susceptibility of Escherichia coli to ciprofloxacin: 98.7% of ICU isolates were susceptible in 1995 versus 93.2% in 2000. Susceptibility of ICU isolates was lower than that of non-ICU isolates, except for ciprofloxacin, for which the reverse was true. Cross-resistance was common among extended-spectrum cephalosporins and penicillins, but uncommon between imipenem and ertapenem. Only imipenem and ertapenem remained highly active against Enterobacteriaceae with a phenotype suggesting possible production of an extended-spectrum beta-lactamase and those with a phenotype suggesting possible Amp C hyperproduction.

Conclusions:

Imipenem was the most active agent against nosocomial Enterobacteriaceae. Susceptibility to ciprofloxacin decreased from 1995 to 2000, particularly in Escherichia coli, and, in contrast to other agents, was lower among non-ICU isolates.
Attributable Costs and Length of Stay of an Extended-Spectrum Beta-Lactamase-ProducingKlebsiella pneumoniaeOutbreak in a Neonatal Intensive Care Unit
Authors: Stone Patricia W. , Gupta Archana , Loughrey Maureen , Della-Latta Phyllis , Cimiotti Jeannie , Larson Elaine , Rubenstein David , Saiman Lisa
Published: March 2006

Objectives:

To determine the costs of the interventions aimed at controlling the 4-month outbreak and to determine the attributable length of stay (LOS) associated with infection and colonization with extended-spectrum beta-lactamase-producingKlebsiella pneumoniae.

Design:

A retrospective cost analysis was conducted from the hospital perspective. A micro-costing approach was employed. The LOS of four groups of hospitalized patients were compared with each other. National Perinatal Information Center criteria were used to stratify infants for severity of risk. The LOS of each group was compared with that of a national sample of similarly stratified infants.

Setting:

A level III-IV, 45-bed neonatal intensive care unit.

Patients:

Infant groups were infected (n = 8), colonized (n = 14), concurrent cohort (n = 54), and prior cohort (n = 486).

Results:

The cost of the outbreak totaled $341,751. The largest proportion of costs was related to healthcare worker time providing direct patient care (2,489 hours at a cost of $146,331). Infected and colonized neonates had longer LOS than either the concurrent cohort or the prior cohort (P< .001). Compared with the national sample, infected infants had a 48.5-day longer mean LOS (95% confidence interval [CI95], 1.7 to 95.2), whereas the prior cohort's mean LOS was 6 days shorter (CI95, -9.4 to -2.9).

Conclusions:

This study increases the understanding of the burden of these multidrug-resistant organisms. Further research is needed to estimate the societal costs of these infections and the cost-effectiveness of preventive interventions.
Ultraviolet Light Disinfection of Hospital Water for Preventing NosocomialLegionellaInfection: A 13-Year Follow-Up
Authors: Hall Keri K. , Giannetta Eve T. , Getchell-White Sandra I. , Durbin Lisa J. , Farr Barry M.
Published: March 2006

Background and Objective:

CDC has estimated that 23% ofLegionellainfections are nosocomial. When a new hospital was being constructed and a substantial increase in transplantation was anticipated, an ultraviolet light apparatus was installed in the water main of the new building because 27% of water samples from taps in the old hospital containedLegionella.This study reports the rate of nosocomialLegionellainfection and water contamination since opening the new hospital.

Methods:

Charts of all patients with positiveLegionellacultures, direct immunofluorescent antibody (DFA), or urine antigen between April 1989 and November 2001 were reviewed. Frequencies of DFAs and urine antigens were obtained from the laboratory.

Results:

None of the 930 cultures of hospital water have been positive since moving into the new building. Fifty-three (0.02%) of 219,521 patients had a positiveLegionellatest; 41 had pneumonia (40 community acquired). One definiteL. pneumophilapneumonia confirmed by culture and DFA in August 1994 was nosocomial (0.0005%) by dates. This patient was transferred after prolonged hospitalization in another country, was transplanted 11 days after admission, and developed symptoms 5 days after liver transplant. However, tap water from the patient's room did not growLegionella.Seventeen (2.5%) of 670 urine antigens were positive forLegionella(none nosocomial). Thirty-three (1.2%) of 2,671 DFAs were positive, including 7 patients (21%) without evidence of pneumonia and 6 (18%) who had an alternative diagnosis.

Conclusion:

Ultraviolet light usage was associated with negative water cultures and lack of clearly documented nosocomialLegionellainfection for 13 years at this hospital.
AChryseobacterium meningosepticumOutbreak in a Neonatal Ward
Authors: Güngör Serdal , Özen Metehan , Akinci Aysehan , Durmaz Riza
Published: March 2006

Objective:

To report epidemiologic, bacteriologic, and clinical features of aChryseobacterium meningosepticumoutbreak.

Design:

Outbreak investigation.

Setting:

A neonatal intensive care unit (NICU) of a referral teaching hospital.

Methods:

During 2 weeks in September 2001, four neonates in the NICU developed sepsis and underwent laboratory investigation. Multiple samples were obtained for cultures from endotracheal tubes, mechanical ventilators and humidifier boxes, infant incubators, parenteral and antiseptic solutions, feeding bottles, sinks, faucets, doors, and healthcare workers.

Results:

C. meningosepticumwas isolated from the blood cultures of four patients. The first isolate was identified 5 days after the death of the index case. Although all isolates were ciprofloxacin susceptible in vitro, the remaining three patients did not respond to ciprofloxacin therapy given for 6 or 7 days. Therapy was switched to vancomycin and rifampin and all three patients survived, with one having a complication (hydrocephalus). Environmental surveillance revealedC. meningosepticumin the stock lipid solution as the source of the epidemic. The outbreak was controlled after discontinuation of intravenous lipid solution, restriction of further neonatal admissions, and thorough disinfection of the unit and its equipment.

Conclusion:

Early identification of an epidemic and its source is important in avoiding morbidity and mortality. A contaminated lipid stock bottle was the source of this outbreak associated with multiple cases and one death.
Vaccination Without Documentation: Influenza Immunization Among Medical Residents at a Tertiary-Care Medical Center
Authors: Bearman Gonzalo , Fuentes Linda , Vorenkamp Jaclyn Van Lieu , Drusin Lewis M.
Published: March 2006

Sixty-four percent of medical residents unimmunized by the Occupational Health Service were immunized elsewhere. Those unvaccinated lacked time to comply. An immune staff is critical to prevent transmission to high-risk patients and limit absenteeism. The hospital is implementing a program to deliver medical care to the house staff.
Effect of Vancomycin Therapy for Osteomyelitis on Colonization by Methicillin-ResistantStaphylococcus aureus: Lack of Emergence of Glycopeptide Resistance
Authors: Bernard Louis , Vaudaux Pierre , Vuagnat Albert , Stern Richard , Rohner Peter , Pittet Didier , Schrenzel Jacques , Hoffmeyer Pierre ,   Osteomyelitis Study Group
Published: March 2006

Background:

In treating orthopedic infections, the long-term impact of vancomycin therapy on colonization by methicillin-resistantStaphylococcus aureus(MRSA) and the emergence of vancomycin-intermediate S.aureusis unknown.

Design:

Prospective surveillance of the effect of long-term vancomycin therapy on colonization by MRSA and the emergence of vancomycin-intermediateS. aureus.

Methods:

Thirty-four patients with MRSA osteomyelitis that was microbiologically documented were longitudinally observed for the emergence of vancomycin-intermediate S.aureusat 3 body sites (wound, anterior nares, and groin) during the initial period of vancomycin therapy and at the 2-month follow-up. Twenty patients received the standard dose (20 mg/kg/d) for 34 ± 6 days and 14 patients received a high dose (40 mg/kg/d) of vancomycin for 37 ± 9 days.

Results:

During vancomycin treatment, global MRSA carriage (all body sites) fell from 100% to 25% in the group of patients receiving the standard dose of vancomycin, and from 100% to 40% in the group receiving the high dose. During the 2-month follow-up period after vancomycin therapy, global MRSA carriage increased from 25% to 55% in the group receiving the standard dose and decreased from 43% to 36% in the group receiving the high dose.

Conclusion:

Therapy with a high dose of vancomycin contributes to the sustained eradication of MRSA carriage without promoting the emergence of glycopeptide resistance.
Additional Costs for Preventing the Spread of Methicillin-Resistant Staphylococcus aureus and a Strategy for Reducing These Costs on a Surgical Ward
Authors: Herr Caroline Eva Wella , Heckrodt Thomas Hilarius , Hofmann Frank Andreas , Schnettler Reinhard , Eikmann Thomas Friedrich
Published: March 2006

Objective:

To determine the added costs of hygienic measures (barrier precautions, isolation, and decontamination) required for MRSA carriers in German hospitals and possible strategies for cost reduction.

Design:

On a septic surgical ward caring for 35% of all MRSA cases in a university hospital (1,182 beds), additional costs for personnel time and materials were calculated and medical charts of all MRSA cases admitted to the ward during 1 year were analyzed retrospectively. Twelve of the ward's 13 beds were located in rooms with at least 2 beds.

Patients:

Four hundred ninety-eight MRSA carrier hospital-days (of 20 MRSA cases) could be assessed. All patients (80% men, 50% older than 74.5 years) had broken skin.

Results:

In 95% of the cases, microbiological findings suggested transmission of MRSA during the current or a previous stay on this ward. The study found total avoidable costs of approximately 142,794.01 euros in 1 year, averaging 371.95 euros for one MRSA patient hospital-day and 9,261.56 euros per MRSA case. The most expensive single measure was blocked beds in multibed rooms (305.75 euros/day), which accounted for 82% of the extra costs. Costs most likely were underestimated.

Conclusions:

Daily additional case costs amounted to 96% of social security payments. Blocked beds in multibed rooms accounted for more than 80% of these excess costs. Isolation has been scientifically validated and is required by law in Germany. Building an adequate number of single-bed rooms should help prevent spread and would greatly lower the added costs of infection.
Role of Healthcare Workers in Outbreaks of Methicillin-ResistantStaphylococcus aureus: A 10-Year Evaluation From a Dutch University Hospital
Authors: Blok Hetty E. M. , Troelstra Annet , Kamp-Hopmans Titia E. M. , Gigengack-Baars Ada C. M. , Vandenbroucke-Grauls Christina M. J. E. , Weersink Annemarie J. L. , Verhoef Jan , Mascini Ellen M.
Published: March 2006

Background and Objective:

The benefit of screening healthcare workers (HCWs) at risk for methicillin-resistantStaphylococcus aureus(MRSA) carriage and furloughing MRSA-positive HCWs to prevent spread to patients is controversial. We evaluated our MRSA program for HCWs between 1992 and 2002.

Setting:

A university medical center in the Netherlands, where methicillin resistance has been kept below 0.5% of all nosocomial S.aureusinfections using active surveillance cultures and isolation of colonized patients.

Design:

HCWs caring for MRSA-positive patients or patients in foreign hospitals were screened for MRSA. MRSA-positive HCWs had additional cultures, temporary exclusion from patient-related work, assessment of risk factors for persisting carriage, decolonization therapy with mupirocin intranasally and chlorhexidine baths for skin and hair, and follow-up cultures.

Results:

Fifty-nine HCWs were colonized with MRSA. Seven of 840 screened employees contracted MRSA in foreign hospitals; 36 acquired MRSA after contact with MRSA-positive patients despite isolation precautions (attack rate per outbreak varied from less than 1% to 15%). Our hospital experienced 17 MRSA outbreaks, including 13 episodes in which HCWs were involved. HCWs were index cases of at least 4 outbreaks. In 8 outbreaks, HCWs acquired MRSA after caring for MRSA-positive patients despite isolation precautions.

Conclusion:

Postexposure screening of HCWs allowed early detection of MRSA carriage and prevention of subsequent transmission to patients. Where the MRSA prevalence is higher, the role of HCWs may be greater. In such settings, an adapted version of our program could help prevent dissemination.
BioHMM: a heterogeneous hidden Markov model for segmenting array CGH data
Authors: Marioni J. C. , Thorne N. P. , Tavaré S.
Published: March 2006

Summary: We have developed a new method (BioHMM) for segmenting array comparative genomic hybridization data into states with the same underlying copy number. By utilizing a heterogeneous hidden Markov model, BioHMM incorporates relevant biological factors (e.g. the distance between adjacent clones) in the segmentation process.

Availability: BioHMM is available as part of the R library snapCGH which can be downloaded from

Contact:  J.Marioni@damtp.cam.ac.uk

Supplementary information: Supplementary information is available at
Ancient duplicated conserved noncoding elements in vertebrates: A genomic and functional analysis
Authors: McEwen Gayle K. , Woolfe Adam , Goode Debbie , Vavouri Tanya , Callaway Heather , Elgar Greg
Published: March 2006

Fish–mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. Although most of these elements share little sequence identity to each other, a small number are remarkably similar and appear to be the product of duplication events. Here, we searched for duplicated conserved noncoding elements in the human genome, using comparisons with Fugu to select putative cis-regulatory sequences. We identified 124 families of duplicated elements, each containing between two and five members, that are highly conserved within and between vertebrate genomes. In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family, thus removing much of the ambiguity in identifying associated genes. We find that duplicate elements have the potential to up-regulate reporter gene expression in a tissue-specific manner and that expression domains often overlap, but are not necessarily identical, between family members. Over two thirds of the families are conserved in duplicate in fish and appear to predate the large-scale duplication events thought to have occurred at the origin of vertebrates. We propose a model whereby gene duplication and the evolution of cis-regulatory elements can be considered in the context of increased morphological diversity and the emergence of the modern vertebrate body plan.
Genome-wide identification of direct targets of the Drosophila retinal determination protein Eyeless
Authors: Ostrin Edwin J. , Li Yumei , Hoffman Kristi , Liu Jing , Wang Keqing , Zhang Li , Mardon Graeme , Chen Rui
Published: March 2006

The discovery of direct downstream targets of transcription factors (TFs) is necessary for understanding the genetic mechanisms underlying complex, highly regulated processes such as development. In this report, we have used a combinatorial strategy to conduct a genome-wide search for novel direct targets of Eyeless (Ey), a key transcription factor controlling early eye development in Drosophila. To overcome the lack of high-quality consensus binding site sequences, phylogenetic shadowing of known Ey binding sites in sine oculis (so) was used to construct a position weight matrix (PWM) of the Ey protein. This PWM was then used for in silico prediction of potential binding sites in the Drosophila melanogaster genome. To reduce the false positive rate, conservation of these potential binding sites was assessed by comparing the genomic sequences from seven Drosophila species. In parallel, microarray analysis of wild-type versus ectopic ey-expressing tissue, followed by microarray-based epistasis experiments in an atonal (ato) mutant background, identified 188 genes induced by ey. Intersection of in silico predicted conserved Ey binding sites with the candidate gene list produced through expression profiling yields a list of 20 putative ey-induced, eye-enriched, ato-independent, direct targets of Ey. The accuracy of this list of genes was confirmed using both in vitro and in vivo methods. Initial analysis reveals three genes, eyes absent, shifted, and Optix, as novel direct targets of Ey. These results suggest that the integrated strategy of computational biology, genomics, and genetics is a powerful approach to identify direct downstream targets for any transcription factor genome-wide.
Genetic variation in the zebrafish
Authors: Guryev Victor , Koudijs Marco J. , Berezikov Eugene , Johnson Stephen L. , Plasterk Ronald H.A. , van Eeden Fredericus J.M. , Cuppen Edwin
Published: March 2006

Although zebrafish was introduced as a laboratory model organism several decades ago and now serves as a primary model for developmental biology, there is only limited data on its genetic variation. An establishment of a dense polymorphism map becomes a requirement for effective linkage analysis and cloning approaches in zebrafish. By comparing ESTs to whole-genome shotgun data, we predicted >50,000 high-quality candidate SNPs covering the zebrafish genome with average resolution of 41 kbp. We experimentally validated ∼65% of a randomly sampled subset by genotyping 16 samples from seven commonly used zebrafish strains. The analysis reveals very high nucleotide diversity between zebrafish isolates. Even with the limited number of samples that we genotyped, zebrafish isolates revealed considerable interstrain variation, ranging from 7% (inbred) to 37% (wild-derived) of polymorphic sites being heterozygous. The increased proportion of polymorphic over monomorphic sites results in five times more frequent observation of a three allelic variant compared with human or mouse. Phylogenetic analysis shows that comparisons between even the least divergent strains used in our analysis may provide one informative marker approximately every 500 nucleotides. Furthermore, the number of haplotypes per locus is relatively large, reflecting independent establishment of the different lines from wild isolates. Finally, our results suggest the presence of prominent C-to-U and A-to-I RNA editing events in zebrafish. Overall, the levels and organization of genetic variation between and within commonly used zebrafish strains are markedly different from other laboratory model organisms, which may affect experimental design and interpretation.
Subsidence in the super‐deep Pattani and Malay basins of Southeast Asia: a coupled model incorporating lower‐crustal flow in response to post‐rift sediment loading
Authors: Morley Christopher K. , Westaway Rob
Published: March 2006

Two Early Cenozoic rifts in Southeast Asia (beneath the Pattani and Malay basins) experienced only limited upper‐crustal extension (β≤1.5); yet very thick post‐rift sequences are present, with 6–12 km of Late Cenozoic terrestrial and shallow‐marine sediment derived from adjacent sources. Conventional post‐rift backstripping requires depth‐dependent lithospheric thinning by β=2–4 to explain these tremendous thicknesses. We assess an alternative explanation for this post‐rift subsidence, involving lower‐crustal flow from beneath these basins in response to lateral pressure‐gradients induced by the sediment loads and the negative loads arising from the erosion of their sediment sources. We calculate that increased rates of erosion in western Thailand in the Early Miocene placed the crust in a non‐steady thermal state, such that the depth (and thus, the pressure) at the base of the brittle upper crust subsequently varied over time. Following such a perturbation, thermal and mass‐flux steady‐state conditions took millions of years to re‐establish. In the meantime, the lateral pressure‐gradient caused net outflow of lower crust, thinning the crust beneath the depocentre by several kilometres (mimicking the isostatic effect of greater crustal extension having occurred beforehand) and thickening it beneath the sediment source region. The local combination of hot crust and high rates of surface processes, causing lower‐crustal flow to be particularly vigorous and thus making its effects more readily identifiable, means that the Pattani and Malay basins represent a set of conditions different from basins in many other regions. However, lower‐crustal flow induced by surface processes will also occur to some extent, but less recognisably, in many other continental crustal provinces, but its effects may be mistaken for those of other processes, such as larger‐magnitude stretching and/or depth‐dependent stretching.
A critical appraisal of the use of recombinant factor VIIa in acquired bleeding conditions
Authors: Mittal Sajjan , Watson Henry G.
Published: March 2006

Recombinant activated factor VII (rVIIa) was initially used for the treatment of inhibitors in patients with haemophilia. However, its localised mode of action at sites of damage to the vessel combined with dramatic clinical observations in exsanguinating patients have resulted in huge interest in its use as a global haemostatic agent. Although it appears safe, with no obvious excess of thrombotic events, its use in assorted acquired bleeding disorders, especially those associated with the development of complex coagulopathies, such as in the post‐trauma state, has proved to be less dramatic than hoped.
Infantile pyknocytosis: a cause of haemolytic anaemia of the newborn
Authors: Eyssette‐Guerreau Stéphanie , Bader‐Meunier Brigitte , Garcon Loïc , Guitton C. , Cynober Thérèse
Published: March 2006

This study defined the incidence, clinical and haematological characteristics of infantile pyknocytosis in a monocentric retrospective study of 149 blood samples referred for unexplained neonatal haemolytic anaemia. Pyknocytosis was diagnosed in 14 patients (9·4%). All patients had neonatal jaundice and severe anaemia (mean nadir haemoglobin: 6·8 g/dl) at a mean age of 21 d. The percentage of pyknocytes was 4–23%. Packed red blood cell transfusions were needed in 11 of 14 patients. Haemoglobin levels reached normal values within a mean time of 4 months. Infantile pyknocytosis is an unusual cause of neonatal haemolytic anaemia, which requires careful examination of blood smears.
Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet
Authors: Brewer Douglas B.
Published: March 2006

Max Schultze published the first accurate and convincing description of platelets as part of a study devoted mainly to the white blood cells in 1865. He recognised them as a normal constituent of the blood and ‘enthusiastically recommended’ them as an object for further study by ‘those concerned with the in‐depth study of the blood of humans’. In 1882, Bizzozero demonstrated the value of this recommendation in his much more comprehensive study. He observed them microscopically in the circulating blood of living animals and in the blood removed from the blood vessels. In well‐planned experiments, he showed that they were the first component of the blood to adhere to damaged blood vessel walls in vivo and, in vitro, that they were the first components of the blood to adhere to threads that subsequently became covered with fibrin.
Impact of age on survival after intensive therapy for multiple myeloma: a population‐based study by the Nordic Myeloma Study Group
Authors: Lenhoff Stig , Hjorth Martin , Westin Jan , Brinch Lorentz , Bäckström Bengt , Carlson Kristina , Christiansen Ilse , Dahl Inger Marie , Gimsing Peter , Hammerström Jens , Johnsen Hans E , Juliusson Gunnar , Linder Olle , Mellqvist Ulf‐Henrik , Nesthus Ingerid , Nielsen Johan Lanng , Tangen Jon Magnus , Turesson Ingemar ,   Nordic Myeloma Study Group
Published: March 2006

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60–64 years) on survival in a prospective, population‐based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population‐based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta‐2‐microglobulin and age <60 years vs. 60–64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0·001) and 60–64 years (median 50 months vs. 27 months; P = 0·001). We conclude that in a population‐based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60–64 years but with less superiority than in younger patients.
Sulphydryl modifications alter scramblase activity in murine sickle cell disease
Authors: de Jong Kitty , Kuypers Frans A.
Published: March 2006

Increased oxidant stress has been suggested to play a role in the process of phosphatidylserine (PS) externalisation in the red blood cells of sickle cell patients. Inhibition of the ATP‐driven translocation from outer to inner monolayer (flippase) by sulphydryl modification has been established. The present study showed that phospholipid scrambling was also sensitive to protein sulphydryl modification. Treatment with N‐ethylmaleimide lead to enhanced PS exposure and a lower Ca++ requirement for scrambling. In contrast, pyridyldithioethylamine treatment inhibited PS exposure. Red blood cells from a murine model for sickle cell disease exhibited a reduced response to both reagents, suggestive of previous sulphydryl modifications to the protein(s) involved in phospholipid scrambling. We conclude that sulphydryl modifications to both scramblase and flippase underlie the enhanced formation of PS‐exposing cells in sickle cell disease.
Fixed‐dose single agent pegfilgrastim for peripheral blood progenitor cell mobilisation in patients with multiple myeloma
Authors: Hosing Chitra , Qazilbash Muzaffar H. , Kebriaei Partow , Giralt Sergio , Davis Marilyn S. , Popat Uday , Anderlini Paolo , Shpall Elizabeth J. , McMannis John , Körbling Martin , Champlin Richard E.
Published: March 2006

High‐dose chemotherapy and autologous peripheral blood progenitor cell transplantation is an effective treatment for multiple myeloma. Progenitor cells are generally mobilised into the peripheral blood by administration of filgrastim. Pegfilgrastim is a covalent conjugate of filgrastim with a longer half‐life. The results of a phase II study of pegfilgrastim, administered as a single injection to mobilise autologous peripheral blood progenitor cells in patients with multiple myeloma, is reported. All patients (n = 19) received 12 mg of pegfilgrastim. Leukaphaeresis was started when the peripheral blood CD34+ count was >0·015 × 109/l. Daily, leukaphaeresis was performed until the target progenitor cell dose was obtained. The median number of leukaphaeresis procedures required to collect the target CD34+ cell dose was 2 (range 1–5). A median of 8·4 × 106 CD34+ cells/kg (range 4·1–15·8) was collected. The most common toxicity was bone pain/myalgia. Sustained haematological recovery occurred in all the patients who underwent high‐dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation with pegfilgrastim‐mobilised cells. A single fixed dose of pegfilgrastim was effective in mobilising adequate peripheral blood progenitor cells in patients with multiple myeloma. The efficacy and toxicity profile was similar to that described with filgrastim treatment.
Mechanisms of immune suppression by interleukin‐10 and transforming growth factor‐β: the role of T regulatory cells
Authors: Taylor Alison , Verhagen Johan , Blaser Kurt , Akdis Mübeccel , Akdis Cezmi A.
Published: March 2006

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen‐specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen‐specific interleukin‐4 (IL‐4)‐secreting T cells in allergic individuals. Allergen‐specific immunotherapy can induce specific Tr1 cells that abolish allergen‐induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL‐10 and transforming growth factor‐β (TGF‐β) as secreted cytokines and various surface molecules, such as cytotoxic T‐lymphocyte antigen 4 and programmed death‐1. IL‐10 only inhibits T cells stimulated by low numbers of triggered T‐cell receptors, which depend on CD28 costimulation. IL‐10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3‐kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL‐10 and TGF‐β secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non‐inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen‐specific Tr1 cells can thus re‐direct an inappropriate immune response against allergens or auto‐antigens using a broad range of suppressor mechanisms.
Histamine and prostaglandin E2up‐regulate the production of Th2‐attracting chemokines (CCL17 and CCL22) and down‐regulate IFN‐γ‐induced CXCL10 production by immature human dendritic cells
Authors: McIlroy Anne , Caron Gersende , Blanchard Simon , Frémaux Isabelle , Duluc Dorothée , Delneste Yves , Chevailler Alain , Jeannin Pascale
Published: March 2006

Effector memory T helper 2 (Th2) cells that accumulate in target organs (i.e. skin or bronchial mucosa) have a central role in the pathogenesis of allergic disorders. To date, the factors that selectively trigger local production of Th2‐attracting chemokines remain poorly understood. In mucosa, at the sites of allergen entry, immature dendritic cells (DC) are in close contact with mast cells. Histamine and prostaglandin E2(PGE2) are two mediators released by allergen‐activated mast cells that favour the polarization of maturing DC into Th2‐polarizing cells. We analysed here the effects of histamine and PGE2on the prototypic, Th2‐(CCL17, CCL22) versus Th1‐(CXCL10) chemokine production by human DC. We report that histamine and PGE2dose‐dependently up‐regulate CCL17 and CCL22 by monocyte‐derived immature DC. These effects were potentiated by tumour necrosis factor‐α, still observed in the presence of the Th1‐cytokine interferon‐γ (IFN‐γ) and abolished by the immunomodulatory cytokine interleukin‐10. In addition, histamine and PGE2down‐regulated IFN‐γ‐induced CXCL10 production by monocyte‐derived DC. These properties of histamine and PGE2were observed at the transcriptional level and were mediated mainly through H2 receptors for histamine and through EP2 and EP4 receptors for PGE2. Finally, histamine and PGE2also up‐regulated CCL17 and CCL22 and decreased IFN‐γ‐induced CXCL10 production by purified human myeloid DC. In conclusion, these data show that, in addition to polarizing DC into mature cells that promote naïve T‐cell differentiation into Th2 cells, histamine and PGE2may act on immature DC to trigger local Th2 cell recruitment through a selective control of Th1/Th2‐attracting chemokine production, thereby contributing to maintain a microenvironment favourable to persistent immunoglobulin E synthesis.
Phenotypic and immunoregulatory characteristics of monocytic iris cells
Authors: Li Xingya , Shen Shujing , Urso David , Kalique Samara , Park Song Hee , Sharafieh Roshanak , O'Rourke James , Cone Robert E.
Published: March 2006

The introduction of antigen into the anterior chamber of an eye induces the antigen‐specific suppression of cell‐mediated immunity and the antigen‐induced production of immunoglobulin G2 antibodies. To define further the role of iris monocytic cells in the systemic suppression of cell‐mediated immunity that follows the entry of foreign antigen into the anterior chamber, murine iris wholemounts or cell suspensions of iris cells were stained with fluorescent anti‐F4/80 and/or anti‐CD11c, anti‐CD11b antibodies and examined by confocal microscopy or flow cytometry, respectively. Monocytic cells in iris cell suspensions were recovered from mice receiving an injection of trinitrophenylated bovine serum albumin (TNP‐BSA) into an anterior chamber and Percoll‐enriched iris cells separated into cells expressing F4/80 or CD11c were injected intravenously into TNP‐BSA‐immunized or naive recipients. The recipients were challenged to induce delayed‐type hypersensitivity (DTH) or were provided with splenocytes or thymocytes that transfer the suppression of DTH. The homing of monocytic bone marrow cells to the iris was determined by the intravenous injection of bone marrow cells from green fluorescent protein (GFP)‐transgenic donors into C57 mice, and the staining of recipient iris wholemounts with anti‐F4/80 antibodies. Iris cells with a dendritic morphology expressing both F4/80 and/or CD11c and CD11b, some cells expressing only F4/80 or CD11c, were detected. The irides of irradiated GFP– mice that received intravenous GFP+ bone marrow cells contained GFP+ F4/80+ cells. F4/80+ and CD11c+ cells from the irides of donors that received intracameral TNP‐BSA transferred the suppression of DTH when injected intravenously into TNP‐BSA‐immunized recipients, activated immunoregulatory thymocytes and activated antigen‐specific splenic regulatory effector cells. These results support the hypothesis that iris monocytic cells may participate in the systemic induction of regulatory T cells.
Putative virulence‐related genes in Vibrio anguillarum identified by random genome sequencing
Authors: Rodkhum C , Hirono I , Stork M , Di Lorenzo M , Crosa J H , Aoki T
Published: March 2006

The genome of Vibrio anguillarum strain H775‐3 was partially determined by a random sequencing procedure. A total of 2300 clones, 2100 from a plasmid library and 200 from a cosmid library, were sequenced and subjected to homology search by the BLAST algorithm. The total length of the sequenced clones is 1.5 Mbp. The nucleotide sequences were classified into 17 broad functional categories. Forty putative virulence‐related genes were identified, 36 of which are novel in V. anguillarum, including a repeat in toxin gene cluster, haemolysin genes, enterobactin gene, protease genes, lipopolysaccharide biosynthesis genes, capsule biosynthesis gene, flagellar genes and pilus genes.
Interaction of water temperature and challenge model on xenoma development rates for Loma salmonae (Microspora) in rainbow trout, Oncorhynchus mykiss (Walbaum)
Authors: Becker J A , Speare D J , Dohoo I R
Published: March 2006

This study evaluated the regulatory effects of water temperature on the development of branchial xenomas caused by Loma salmonae using a high‐dose per os‐challenge model compared with a low‐dose cohabitation‐challenge model. Approximately 275 juvenile rainbow trout (RBT), Oncorhynchus mykiss, were randomly distributed to six tanks with two tanks each maintained at 11, 15 and 19 °C. Fish in one tank from each temperature setting were exposed per os to macerated L. salmonae‐infected gill material and fish in the other tank from each temperature setting were exposed to L. salmonae using the cohabitation‐challenge model. Fish were monitored for the development of branchial xenomas beginning at day 21 post‐exposure. Survival analyses were used to evaluate the effect of water temperature and challenge model on the number of days until the first visible branchial xenoma was detected. The survivor curves for the per os‐challenge model revealed that there was at least one significant difference, whereas the cohabitation challenge did not reveal any significant differences amongst the temperature settings. The proportional hazards model revealed a significant interaction between the challenge model used and water temperature. This indicated that the effect of water temperature was different depending on challenge model. Additionally, from the mean xenoma intensities, on average, the per os‐challenged fish showed higher xenoma intensity compared with the cohabitation‐challenged fish. Overall, the impact of water temperature on disease pathogenesis was greater when the RBT were per os challenged compared with using the cohabitation model.
Induced cross‐protection in channel catfish, Ictalurus punctatus (Rafinesque), against different immobilization serotypes of Ichthyophthirius multifiliis
Authors: Xu D‐H , Klesius P H , Panangala V S
Published: March 2006

Channel catfish, Ictalurus punctatus (Rafinesque), were immunized with Ichthyophthirius multifiliis (Ich) theronts and trophonts, and the immune response and host protection against both homologous and heterologous serotypes of Ich were evaluated. Immunizations were done with two immobilization serotypes (ARS4 and ARS6) of live theronts by bath immersion (trial I) and with sonicated trophonts by intraperitoneal (i.p.) injection (trial II). Cutaneous and serum antibody titres against Ich following immunization were measured and survival of catfish was determined after theront challenge. Theronts were immobilized by the antiserum from fish immunized with homologous theronts or trophonts, but not by the serum of fish immunized with the heterologous serotype. Serum from fish immunized by immersion with live theronts showed higher enzyme‐linked immunosorbent assay titres against both homologous and heterologous serotypes than fish immunized by i.p. injection of trophonts. Channel catfish immunized by immersion with live theronts or by i.p. injection with sonicated trophonts developed an immune response against Ich and provided cross‐protection against challenge from both serotypes (ARS4 and ARS6) of the parasite. Sonicated trophont antigens in aqueous solution by i.p. injection could stimulate an immune response in fish, but the immunity was of short duration.
Host preference of adult Caligus elongatus Nordmann in the laboratory and its implications for Atlantic cod aquaculture
Authors: Øines Ø , Simonsen J H , Knutsen J A , Heuch P A
Published: March 2006

The sea louse Caligus elongatus utilizes a range of marine fish species as hosts, and it has been suggested that fish farms are infected with adult C. elongatus from wild fish hosts. We assessed experimentally whether dislodged lice return to their original host species. Adult lice from wild lumpfish and saithe were presented to lumpfish, sea trout, Atlantic cod, saithe and European plaice. All fish species became infected. Lumpfish and cod were strongly preferred, followed by saithe, trout and plaice. Lice from wild saithe showed a preference for saithe and lumpfish, followed by cod, sea trout and plaice. The mtCO1 gene was used to determine the genotypes of the lice. Lice from lumpfish were genotype 1. Lice from saithe were mainly genotype 2. The two genotypes of C. elongatus differed slightly in their host preferences: lice from saithe were less discriminating. The data support the hypothesis that adult C. elongatus may transfer between different host species. Cod is an attractive host for lice from both lumpfish and saithe, which suggests that C. elongatus may become a serious pest of farmed cod.
Dietary habits of the Somali population in Liverpool, with respect to foods containing calcium and vitamin D: a cause for concern?
Authors: Maxwell S. M. , Salah S. M. , Bunn J. E. G.
Published: March 2006

Background  A large percentage of Liverpool Somalis have vitamin D deficiency and low calcium excretion. The dietary habits of Liverpool Somalis were investigated with respect to food items containing calcium and vitamin D.

Methods  A questionnaire, administered by a Somali field worker, assessed the intake of food of 60 adult (45 females and 15 males; mean age 42 years) and 10 child (seven females and three males; mean age 10 years) Somali volunteers. Questions concerned personal details, health (bone and muscle problems) and dietary habits including the frequency of consumption of food items containing substantial amounts of calcium and vitamin D.

Results  Most subjects reported bone and muscle pain. Eating habits reflected traditional customs. Foods containing substantial amounts of calcium and vitamin D were consumed infrequently. Milk was only consumed in tea. Those self‐reporting bone pain consumed eggs, cheese and beans rarely.

Conclusion  The food choices of these individuals with regard to bone health is a cause for concern and indicates a likelihood of low calcium and vitamin D intake.
Serum homocysteine concentration as a marker of nutritional status of healthy subjects in Crete, Greece
Authors: Vrentzos G. E. , Papadakis J. A. , Malliaraki N. , Bampalis D. E. , Repa A. , Lemonomichelaki V. , Petinellis E. G. , Ganotakis E. S.
Published: March 2006

Background  Dietary habits are an important determinant of serum homocysteine (tHcy), which may be a marker rather than a cause of progression of the atherosclerotic process. The aim of the present study was to evaluate the nutritional status, and to determine the serum tHcy concentrations in healthy subjects who live in rural areas of Crete, and who theoretically follow a contemporary Mediterranean‐style diet.

Methods  Serum tHcy, folate, vitamin B12, creatinine, glucose, and the lipid profile, were measured in 203 (141 men and 62 women) healthy subjects, aged 33–78 years. The major risk factors for cardiovascular disease such as age, gender, cigarette smoking, obesity were recorded and dietary data were assessed using a 3‐day weighed food intake record.

Results  Our population had high serum tHcy, low serum folate concentrations and lower than the traditional Cretan dietary folate intake [median (range): 12.0 (3.6–44.7) μmol L−1, 7.9 (1.9–15.5) ng mL−1 and 241 (68–1106) μg, respectively]. Dietary intake of fibre, omega‐3, and mono‐ or/ polyunsaturated fatty acids was also low. An inverse relation was observed between serum tHcy concentrations and serum folate (r = −0.28; P < 0.01) and vitamin B12 levels (r = −0.33; P < 0.001).

Conclusions  Nowadays, the Cretan diet has changed towards a more westernized eating pattern. Given the analytic difficulties in determining the amount of folate in food and the inverse correlation between serum tHcy and folate levels, serum tHcy concentrations may be a useful marker for nutritional status, especially folate deficiency, in healthy subjects.
Cold Stress Induces Metabolic Activation of Thyrotrophin‐Releasing Hormone‐Synthesising Neurones in the Magnocellular Division of the Hypothalamic Paraventricular Nucleus and Concomitantly Changes Ovarian Sympathetic Activity Parameters
Authors: Fiedler J. , Jara P. , Luza S. , Dorfman M. , Grouselle D. , Rage F. , Lara H. E. , Arancibia S.
Published: March 2006

Recent studies suggest thyrotrophin‐releasing hormone (TRH) serves as a neurotransmitter and thereby provides a functional vegetative connection between the brain and the ovary. In the present study, magnocellular neurones of the paraventricular nucleus (PVN) in animals subjected to cold exposure were studied to determine the hypothalamic origin of the TRH involved in this pathway. In situ hybridisation analysis of hypothalamic tissue showed that cold exposure causes a two‐fold increase in the total number of neurones expressing TRH mRNA in the PVN. Immunohistochemical studies showed that TRH peptide is localised to the magnocellular PVN and that the number of TRH immunoreactive cells increases two‐fold following 64 h of cold exposure. Double‐immunostaining for MAP‐2 and TRH revealed that TRH peptide is localised in the perikarya of the magnocellular neurones. TRH release was measured in vivo from the magnocellular portion of the PVN using push–pull perfusion. Although controls exhibited a very low level of TRH release, animals subjected to cold showed a pulsatile‐like TRH release profile with two different patterns of release: (i) low basal level with small bursts of TRH release and (ii) a profile with an up to seven‐fold increase in TRH release compared to controls. The colocalisation of TRH with the specific somato‐dendritic marker MAP‐2 in processes of the magnocellular neurones suggested a local release of TRH. Additional studies demonstrated a reduction in ovarian noradrenaline content after 48 h of cold exposure, a feature indicative of nerve activation at the terminal organ. After 64 h of cold exposure, the ovarian noradrenaline returned to control values but the noradrenaline content of the coeliac ganglia was increased, suggesting a compensatory effect originating in the cell bodies of the sympathetic neurones that innervate the ovary. The correlation between the local release of TRH from dendrites within the magnocellular PVN in conditions of cold and the activation of the sympathetic nerves supplying the ovary raises the possibility that TRH contributes to the processing regulating sympathetic outflow and may thereby impact on the functional activity of the ovary.