bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Molecular‐Targeted Therapy for Chronic Myelogenous Leukemia
Authors: Ault Patricia , Kaled Suzan , Rios Mary Beth
Published: February 2008

Purpose

To provide primary care providers with guidelines on the evaluation and management of treatment for patients with chronic myelogenous leukemia (CML) with emphasis on the molecular‐targeted therapy imatinib mesylate.

Data Sources

Research‐based articles in the medical literature, review articles, and clinical practice guidelines.

Conclusions

CML is a clonal stem cell disorder causing 5,000 new cases annually. Research on molecular‐targeted therapy confirms that specific protein kinases have broad consequences for the development of hture drugs to treat CML. The most recent discovery is a new compound, imatinib mesylate, which has become commercially available. Currently, the standard of care for CML is this agent. This therapy has changed management strategies for treatment of patients with the diagnosis of CML.

lmpilcatlons for Practice

Long‐term observations and evaluations are needed for final determination of treatment effectiveness; thus, primary care providers will follow patients with CML in the community. Unforeseen toxicity may surface, requiring accurate assessment and evaluation. Primary care providers will be actively involved with providing symptom management for these patients.

A new compound has been developed that targets the diseased cells in CML and appears to spare normal cells (Savage & Antman, 2002). This selective‐targeted therapy has the ability to inhibit the BCR‐ABL tyrosine kinase enzyme, resulting in complete hemato‐logic responses in 95% and major cytogenetic responses in 60% of the study subject patients with CML after a median follow‐up of 18 months (see Table 1; Kantarjian et al., 2002).

It is not yet known whether this new agent will kill the progenitor bone marrow stem cells that originally carry the Ph+ chromosome. Although a number of study subject patients obtained a complete remission, it is too early to determine whether the patients will ever be able to completely discontinue treatment. Patients may need to take the drug for the rest of their lives. A life‐long commitment to a pill may be inconvenient, but the minimal side effects and lack of severe toxicities seen present a feasible option of treatment. Even though imatinib mesylate holds promise for the treatment of CML, several unanswered question remain: What is the optimal dose and length of therapy? How durable is the response? What are the late side effects or cumulative toxicities? When should patients use it, and should they use it alone or in combination with another agent. The final question remains: Can CML be cured with molecular‐targeted therapy? All of these questions require further research. A randomized trial comparing imatinib mesylate to an interfer‐on‐based regimen in patients with newly diagnosed CML is ongoing, with early data suggesting the superiority of imatinib rnesylate to interferon therapy (Cortes et al., 2002).
Husbandry and breeding of the Alaotran gentle lemur: Hapalemur griseus alaotrensis at Jersey Wildlife Preservation Trust
Authors: BEATTIE J. C. , FEISTNER A. T. C.
Published: February 2008

The Alaotran gentle lemur Hupuletnur griseus ahotrensis is currently classified as Critically Endangered (IUCN, 1996). In 1988 a captive‐breeding programme was considered of highest priority and in November 1990 Jersey Wildlife Preservation Trust. under its accord with the government of Madagascar, imported 6.4 animals. The first captive birth for the species occurred in 1993 and in April 1997 a further 6.4 were imported. As at 1 March 1998 14.8 animals were maintained at Jersey. This paper describes husbandry, enclosure design, diet, reproduction and infant development in H. g. aluotrensis.
Management of the Grey gentle or Eastern lesser bamboo lemur Hapaletnur griseus griseus at Duke University Primate Center, Durham
Authors: HARING D. , DAVIS K.
Published: February 2008

Since 1970 Duke University Primate Center, Durham. has maintained Grey gentle lemurs Hapalemur griseus griseus. This paper gives an overview of the status of Hapalemur spp in captivity and provides an introduction to their conservation status and natural history in Madagascar. Husbandry techniques developed at the Primate Center, with emphasis on the special needs of ♀♀ and infants, are discussed. Scent marking, vocalizations. ♀ dominance, breeding. infant development and hand‐rearing are described. Information on natural‐habitat enclosures. diet and health concerns is also given.
Developing a husbandry manual to facilitate the distribution and presentation of information: with special reference to Slender loris Loris tardigradus nordicus at Ruhr University, Bochum
Authors: SCHULZE H.
Published: February 2008

Generally the practical information required for husbandry of wild species in captivity is not readily available in a single comprehensive source. This paper describes the sort of information which would be most useful for species management, using the Slender loris Loris tardigradus nordicus as an example, and provides a practical model of the possible form and content of a husbandry manual. A single, easily available source of husbandry data would be a valuable tool for all institutions and individuals which are willing to participate in coordinated breeding programmes, helping to maintain genetic diversity and increase the size of captive populations. It would be of particular interest to small institutions, such as zoos with limited staff, breeding colonies in scientific institutions, veterinarians and private breeders. Husbandry manuals which are updated at intervals using, for example, a subscription‐based amendment service or a database of husbandry information which can be accessed using a computer are both reasonable possibilities. Some existing sources of information for the management of Asian loris species and details about on‐line World Wide Web services, for accessing conservation information and species‐management data, which are in the development stages are described. This paper also presents some general information on minimum necessary requirements for successful husbandry of Slender lorises which, in captivity, are cautious but curious animals that become extremely familiar with their environment and react with excitement to novel stimuli. They are prone to both environmental and social stress, and stress‐related symptoms observed in the species, such as slow movements, freezing to motionless or apparent loss of fear in stressful situations, may be based on earlier learning and are sometimes difficult to gauge unless keepers are familiar with the habits of each individual. Enclosure design, lighting and temperature are all significant to the well‐being of the species. Slender lorises prefer to use the upper part of the enclosure, although they will use the lower area to avoid aggressive confrontations with conspecifics, and a system of branches and wiremesh which allows continuous locomotion with no ‘dead ends’ and furnishings that encourage locomotor activity should be provided. Because the species has a tendency towards adiposity and diabetes diet is a serious consideration. A comprehensive husbandry manual for Asian prosimians has been developed (Fitch‐Snyder et al., in press).
Behavioural studies of guenons Cercopithecus spp at Edinburgh Zoo
Authors: YOUNG R. J.
Published: February 2008

Several species of guenon Cercopithecus are threatened in the wild and European Endangered Species Programmes (EEPs) have been established for the Diana monkey Cercopithecus diana diana, Roloway monkey Cercopithecus diana roloway, L'Hoest's monkey Cercopithecus lhoesti, Hamlyn's or Owlfaced monkey Cercopithecus hamlyni and Allen's swamp monkey Allenopithecus nigroviridis. There is limited published information on the behaviour of guenons and at Edinburgh Zoo a number of studies have been carried out on these species and the less threatened De Brazza's monkey Cercopithecus neglectus. This paper presents a review of the studies on the social behaviour, hand‐rearing, feeding and enclosure use of guenons and describes a range of environmental and behavioural enrichment devices which have been developed and assessed at the Zoo.
Redevelopment of a disused enclosure for housing Sulawesi crested macaques Macaca nigra at Newquay Zoo
Authors: BLOUNT J. D.
Published: February 2008

In 1995 at Newquay Zoo a bear pit was redeveloped for Sulawesi crested macaques Macaca nigra. Visual screening and foraging enrichment were used to improve tolerance between ♂♂ and to increase mating opportunities for sub‐dominant ♂♂. To further improve opportunities for avoidance of of seclusion from conspecifics the outdoor area was equipped with a complex climbing apparatus and environmental enrichment, such as a puzzle feeder, sand pit and waterfall, was also provided. The indoor areas were refurbished, heated and fitted with new lighting. The circular shape of the enclosure and improved spatial complexity provides continuity of space, which may reduce the likelihood of physical harm during aggressive encounters. After the death of the dominant ♂ a new adult ♂ was introduced to the established group without difficulty and he has since adopted the dominant position.
The status of Gelada baboon Theropithecus gelada: breeding a neglected species
Authors: JOHANN A.
Published: February 2008

The Gelada baboon Theropithecus gelada has been kept regularly in zoos although it has never been as popular or numerous as other baboon species. In 1989 Rheine Zoo proposed the establishment of an EEP (European Endangered Species Programme) for the species and in 1990 an international studbook was endorsed. As at 31 December 1996 242 animals were listed in the studbook, with 15 institutions holding 52.64 living individuals. The establishment of the breeding programme has facilitated research into the management of the species in captivity which, combined with studies on the behaviour of social‐group structure, housing and diet, has enabled husbandry recommendations to be developed.
Mixed‐species exhibit for Eastern black‐and‐white colobus and Patas monkeys Colobus guereza and Erythrocebus patas at CERZA, Lisieux
Authors: POCHON V.
Published: February 2008

In 1995 a mixed‐species exhibit for Eastern black‐and‐white colobus Colobus guereza and Patas monkeys Erythrocebus patas was developed at CERZA (Centre d'Etude et de Recherche Zoologique Augeron), Lisieux, in an attempt to provide a social and physical environment which promotes the expression of diverse and spontaneous behaviours. Colobus guereza is an arboreal species while E. patas inhabits the savannahs of Equatorial Africa. The centre of the enclosure is naturally forested and is surrounded by a clearing which blends into a strip of low vegetation around the perimeter, providing the monkeys with spatial heterogeneity over the vertical plane, thus accommodating the different habitat niches of the two species. General observations on the territorial, mother‐infant and play behaviours of each group are presented here.
Husbandry and breeding of Douc langurs Pygathrix nemaeus nemaeus at Cologne Zoo
Authors: RUEMPLER U.
Published: February 2008

In 1968 Cologne Zoo obtained 2.1 Douc langurs Pygathrix nemaeus nemaeus. In 1969 an additional 0.2 animals were imported and in 1990 a ♂ from Bekesbourne UK was introduced to infuse new genetic material into the collection. Since 1970 24 Douc langurs have been born at the Zoo where, at time of writing, 5.6 animals are maintained. Details on husbandry, feeding, health, social behaviour and reproduction are given. The hand‐rearing of 1.1 and reintroduction of 0.1 Douc langurs into a social group are described.
Behavioural response of a Western lowland gorilla Gorilla gorilla gorilla group to the loss of the silverback male at Zoo Atlanta
Authors: HOFF M. P. , HOFF K. T. , MAPLE T. L.
Published: February 2008

At Zoo Atlanta in December 1994 a silverback ♂ Western lowland gorilla Gorilla gorilla gorilla group leader died of cardiovascular disease. The behavioural responses of the remaining members of the group were studied and a variety of individual and social behaviours was recorded. For 3 months following the death of the ♂ there was a significant increase in aggressive display behaviours, such as lunge, quadrupedal stiff stance, displace and head divert, and the mother‐offspring relationship intensified. An understanding of the ‘control role’ of the silverback ♂ and the behaviour of group members following changes in social group structure can help zoo managers plan their management strategy when periods of social change are unavoidable.
Conservation and management of orang‐utans Pongo pygmaeus ssp1
Authors: PERKINS L.
Published: February 2008

The orang‐utan Pongo pygmaeus ssp is an Asian great ape which is now only found on the islands of Borneo and Sumatra. In North America in 1982 a Species Survival Plan (SSP) programme was initiated which, over the next 100 years, aims to maintain c. 91% of the original genetic diversity of the captive populations of Bornean Pongo pygmaeus pygmaeus and c. 94% of Sumatran Pongo pygmaeus abelii orang‐utans. There is some controversy over the genetic evidence of distinct subspeciation but in 1985 the SSP adopted a moratorium on the reproduction of subspecific hybrids. The SSP has encouraged various initiatives in North American zoos which house orang‐utans to provide direct support to in situ field conservation and research projects in Indonesia and Malaysia, including a fund‐raising programme at Zoo Atlanta and a Population and Habitat Viability Analysis (PHVA) in Sumatra.
Status of orang‐utans Pongo pygrnaeus ssp in Taiwan
Authors: AGORAMOORTHY G.
Published: February 2008

Since 1989 the orang‐utan Pongo pygmaeus has been a protected species in Taiwan. Between July 1995 and September 1996 a survey was carried out of 16 facilities maintaining orang‐utans in Taiwan. Data on the management, age, sex and life history were collected for 72 orang‐utans housed at three public zoos, nine private parks, two animal breeding farms, one rescue centre and a temple. Information on animals registered as privately owned was also examined. This paper presents data on the status of orang‐utans maintained in Taiwan and gives recommendations for their future management.

Reintroduction strategies, developed at a workshop organized by the Pingtung Rescue Center for Endangered Wild Animals, are also presented.
Environmental enrichment for Old World primates with reference to the primate collection at Edinburgh Zoo
Authors: DICKIE L.
Published: February 2008

Concern over the welfare of captive animals has resulted in the development of environmental enrichment procedures and studies into their effectiveness. Psychological and behavioural problems associated with captive primates, such as increased aggression and stereotypies, and physical problems, such as obesity and lack of muscle tone, need to be addressed if zoos are to maintain self‐sustaining populations which exhibit the same behaviour patterns as those of wild conspecifics. Environmental enrichment should be a routine part of the daily husbandry schedules and all parameters which affect the primates should be enriched. Enclosure design, substrates and furnishings, social groupings, diet, novel objects, mixed‐species exhibits and free‐ranging areas are all discussed in this paper. Often, quick and easy forms of enrichment are the most effective, for example, filling a strong paper sack with straw and food treats can provide both a novel object and a food puzzle. Zoos should strive to carry out environmental enrichment, providing an interesting, stimulating and varying environment for their primates which. in turn. will enable zoos to fulfil their conservation, research, education and entertainment aims.
Towards best practice in the zoo industry: developing key performance indicators as bench‐marks for progress
Authors: BARTOS J. M. , KELLY J. D.
Published: February 2008

The Zoological Parks Board of New South Wales has developed innovative procedures for performance measurement in key operational areas as one of a series of methodologies to improve overall organizational management. The key operational areas identified are conservation, education, research, environment, business operations and commercial aspects. Identifying the desired outcomes in these areas has made it possible to create key performance indicators. This paper describes the development of the methodology and provides examples of how it is used to improve the chances of achieving agreed outcomes.
The Ladybird spider Erews cinnaberinus rearing project
Authors: WISNIEWSKI P. J. , HUGHES I.
Published: February 2008

The Ladybird spider Eresus cinnahrrinus was considered to be extinct in the United Kingdom until 1979, when it was rediscovered at one heathland site in Dorset. The species is listed on Schedule 5 of the Wildlife and Countryside Act and is strictly protected. By 1992 the population had reduced to between 15 and 40 breeding individuals and English Nature, the statutory wildlife conservation body in England, proposed a Species Recovery Plan which included the protection and enhancement of the wild population, the establishment of new colonies and an assessment of the taxonomic status and viability of the population. In 1994 the Federation of Zoological Gardens of Great Britain and Ireland, via the Terrestrial Invertebrate Taxon Advisory Group (TITAG), was contracted to establish a captive‐rearing project for the species. Because it was important that the British population was not further depleted by the collection of specimens until maintenance and breeding protocols had been developed, an experimental captive population was established with 1.10 specimens imported from Denmark, which were considered to be geographically and morphologically most similar to the British specimens. This paper details the maintenance, rearing and breeding protocols developed for the species at the Endangered Species Breeding Unit, Wildfowl and Wetlands Trust. Martin Mere.
Breeding and nesting behaviour of d'orbigny‘s slider turtle Trachemys dorbignyi at Sao Paulo Zoo
Authors: MOLINA F. B. , GOMES N.
Published: February 2008

From 1985 to 1994 the reproductive biology and nesting behaviour of d'orbigny's slider turtle Trachemys clorbignyi were studied at Sao Paulo Zoo. The mating season was from April to July and the egglaying season was from mid‐August to mid‐January. Nesting activity, which was similar to that reported for other species in the Chrysemys complex, was more frequent in the morning and could be divided into five distinct stages: nest‐site selection, nest excavation, egg laying, nest covering and return to water. Nests comprised a cylindrical neck and an oval incubation chamber, the dimensions of which were related to the type of substrate being excavated. Mean clutch size was 8.86 eggs (range = 1–18; n = 530 clutches). Eggs were ellipsoidal and were a mean 3.90 cm long, 2.54 cm wide and 14.07 g. Some ♀♀ laid at least two clutches in a season. The eggs were artificially incubated and mean incubation time was between 55.2 days at 31.5°C and 104.2 days at 25°C. Hatchlings had a mean carapace length of 3.55 cm, maximum carapace width of 3.34 cm and weight of 10.73 g.
Hand‐rearing the Eastern or Great white pelican Pelecanus onocrotalus at Vogelpark Avifauna, Alphen
Authors: OBER S. H. , VERKADE R.
Published: February 2008

The Eastern or Great white pelican Pelecanus onocrotalus is rarely bred in captivity and eggs are often infertile, or are broken or disappear during nesting. At Vogelpark Avifauna, Alphen, mortality of parent‐reared young has been high and some chicks have drowned because they could not climb out of the pond in the outdoor enclosure. Between 26 January and 26 April 1996 52 eggs were laid, only four (8%) of which were fertile. The eggs were removed from the nests and placed in an incubator which was maintained at 37.6°C. The eggs hatched on 26 April, 1, 18 and 19 May. This paper describes incubation, hand‐rearing, diet and development of the hatchlings.
Breeding and rearing the Oriental white stork Ciconia buyciuna at Shanghai Zoological Gardens
Authors: BAOQING H. , YUNSHUANG C.
Published: February 2008

The Oriental white stork Ciconia boyciuna is classified as Endangered by IUCN (IUCN, 1996) and is of highest conservation priority in China. There are c. 2500 storks in the wild and as at 31 December 1995 there were 112.107.56 in captivity. Difficulties in establishing compatible breeding pairs has inhibited breeding in captivity. Because Oriental white storks replace eggs that are lost during the laying period it is possible that the reproductive potential of pairs could be increased by removing the eggs and incubating them artificially. In 1991 a pair of storks at Shanghai Zoological Gardens produced 13 eggs in three clutches, from which nine young were raised. This paper describes the incubation, hand‐rearing, diet and development of Oriental white storks. Information on veterinary treatment is also provided.
Breeding the Red and blue lorry Eos histrio at Loro Parque, Puerto de la Cruz
Authors: SWEENEY R. G.
Published: February 2008

The Red and blue lory Eos histrio is endemic to the Sangihe island group, north of Sulawesi, Indonesia. In 1995 a European studbook was approved and as at 31 December 1996 11.13.1 birds were housed at two European institutions (Loro Parque and Walsrode) and an additional 12.11.4 birds were maintained by six private aviculturists. In 1994 3.3 immature Ens histrio talautensis were imported to Loro Parque. This paper details the husbandry guidelines developed for the species including diet, health care and enclosure design. The artificial incubation, hand‐rearing and development of seven chicks hatched in 1996 are also described.
Management of the Amazon River dolphin Inia geoffrensis at Valencia Aquarium, Venezuela
Authors: BOEDE E. O. , MUJICA‐JORQUERA E. , BOEDE N. DE
Published: February 2008

The Amazon River dolphin Inia geoffensis is distributed throughout the Amazon and Orinoco River basins. The species is rare in captivity and as at 31 December 1996 there were only 3.0 reported to ISlS and 1.4 maintained at Valencia Aquarium, Venezuela. This paper describes the husbandry, diet and veterinary care of 14 dolphins maintained at Valencia Aquarium between 1975 and 1995, and the rearing and development of a ♀ born at the institution in 1994.
A preliminary study of sex ratios in captive‐born ruminants
Authors: BENT N. , REASON R.
Published: February 2008

There are a number of studies reported in the literature which suggest that in the wild, body size and condition of ♀ ruminants can affect the sex ratio of offspring. The physical condition of a ♀ can be affected by factors such as nutrition, age, stress, population density and social status. This paper describes a preliminary study of sex ratios in the offspring of 17 species/subspecies of ruminant, using data obtained from regional and international stud‐books. The total number of ♂ and ♀ offspring were compared with the expected equal sex ratio via Chi‐square analysis for each species/subspecies. The overall sex ratios of 16 specieshbspecies studied did not significantly differ from50:50, which indicates that any effects of maternal condition may cancel each other out at the population level. Kirk's dikdik Mudoyua kirkii was the only species found to have a skewed sex ratio, with more ♂♂ born than ♀♀. The results of this preliminary study are welcome in light of attempts to maintain genetically viable and demographically stable populations in captivity.
Gazelle husbandry at King Khalid Wildlife Research Center, Riyadh: with special reference to capture and handling
Authors: KICHENSIDE T. B.
Published: February 2008

In 1987 King Khalid Wildlife Research Center was founded to breed native Arabian species for reintro‐duction into the wild. Husbandry and management problems at the Center necessitated the development of effective capture and restraint techniques so that TB testing, transfer of animals between enclosures and routine veterinary procedures could be carried out. The majority of captures involved gazelle species. such as Saudi goitered or Sand gazelle Gazelh subgutturosa marica, Mountain gazelle Gazella gazella and Thomson's gazelle Gazella thom‐sonii, which are susceptible to stress and can injure themselves during flight response. A number of restraint procedures were used, including chemical immobilization, a drive‐in boma and a trap‐boma, with varying degrees of success. This paper describes the development of an effective drop‐door trap‐boma which could be built in the enclosures. Techniques for handling gazelles, husbandry, enclosure design and diet are also discussed.
Distribution and abundance of the dugong in New Caledonia, southwest Pacific
Authors: Garrigue Claire , Patenaude Nathalie , Marsh Helene
Published: February 2008

Abstract

New Caledonia is at the eastern limit of the dugong's range. In June 2003 standardized dugong aerial survey methodology was used to estimate the abundance and distribution of dugongs in the coastal waters of New Caledonia, resulting in a population estimate of 1,814 ± SE 332. This represents the largest concentration of dugongs in Melanesia and one of the largest populations in the world, outside Australia and the Arabian region. Calves comprised 7.2% of the population. The observed density of dugongs was highest in the center and southern part of the west coast of the island but not significantly different from the density on the north west and north east. In the central west region, sightings were associated with a pass in the barrier reef and up to a third of the on‐survey sightings were outside of the barrier reef. The dugong distribution we observed during June 2003 differs from the reported locations of historical hunts in several respects.
Determining spatial and temporal scales for management: lessons from whaling
Authors: Clapham Phillip J. , Aguilar Alex , Hatch Leila T.
Published: February 2008

Abstract

Selection of the appropriate management unit is critical to the conservation of animal populations. Defining such units depends upon knowledge of population structure and upon the timescale being considered. Here, we examine the trajectory of eleven subpopulations of five species of baleen whales to investigate temporal and spatial scales in management. These subpopulations were all extirpated by commercial whaling, and no recovery or repopulation has occurred since. In these cases, time elapsed since commercial extinction ranges from four decades to almost four centuries. We propose that these subpopulations did not recover either because cultural memory of the habitat has been lost, because widespread whaling among adjacent stocks eliminated these as sources for repopulation, and/or because segregation following exploitation produced the abandonment of certain areas. Spatial scales associated with the extirpated subpopulations are frcequently smaller than those typically employed in management. Overall, the evidence indicates that: (1) the time frame for management should be at most decadal in scope (i.e., <100 yr) and based on both genetic and nongenetic evidence of population substructure, and (2) at least some stocks should be defined on a smaller spatial scale than they currently are.
Photo‐ID‐based estimates of reproductive patterns in female harbor seals
Authors: Thompson Paul M. , Wheeler Helen
Published: February 2008

Abstract

Variations in reproductive patterns offer important insights into the dynamics of pinniped populations, but collecting data on reproduction for species that spend much of the breeding season in the water is problematic. We used land‐based photo‐identification techniques to collect individual‐based data on the timing of pupping, total pup production, and lactation duration in a population of harbor seals in NE Scotland. Capture–Mark–Recapture (CMR) techniques were used to overcome potential biases due to changes in probability of capture, and provide estimates of lactation duration based upon changes in the “survival” of mother–pup bonds. A mean birth date of 20 June is the first direct estimate of parturition date for UK harbor seals. Information on cumulative births indicated that the peak daily haul‐out count accounted for 77% of total pup production. CMR‐based estimates of lactation duration suggest that 50% of mothers had weaned their pups, when pups were 21‐d old. These results highlight the potential for using photo‐ID techniques to study harbor seal reproductive patterns at sites where intensive capture and marking is not possible for logistic, legislative, or ethical reasons.
Evaluation of a 2-Pyridone, KRQ-10018, against
Mycobacterium tuberculosis
In Vitro and In Vivo
Authors: Lenaerts Anne J. , Bitting Casey , Woolhiser Lisa , Gruppo Veronica , Marietta Karen S. , Johnson Christine M. , Orme Ian M.
Published: February 2008

A novel subclass of quinolones, 2-pyridones, showed potent activity against
Mycobacterium tuberculosis
, with KRQ-10018 being an early lead. KRQ-10018 showed better activity in vitro against
M. tuberculosis
versus moxifloxacin. In vivo efficacy of KRQ-10018 at 300 mg/kg of body weight was similar to that of isoniazid at 25 mg/kg, but showed less activity than moxifloxacin at 300 mg/kg.
Transcriptional Activation and Increased mRNA Stability Contribute to Overexpression of
CDR1
in Azole-Resistant
Candida albicans
Authors: Manoharlal Raman , Gaur Naseem Akhtar , Panwar Sneh Lata , Morschhäuser Joachim , Prasad Rajendra
Published: February 2008

Many azole-resistant (AR) clinical isolates of
Candida albicans
display increased expression of the drug transporters
CDR1
and
CDR2
. In this study, we evaluate the molecular mechanisms that contribute to the maintenance of constitutively high
CDR1
transcript levels in two matched pairs of azole-susceptible (AS) and AR clinical isolates of
C. albicans
. To address this, we use reporter constructs of
GFP
and
lacZ
fused either to the
CDR1
promoter (P

CDR1

-
GFP
/
lacZ
; transcriptional fusion) or to the
CDR1
open reading frame (P

CDR1

-
CDR1
-
GFP
/
lacZ
; translational fusion) integrated at the native
CDR1
locus. It is observed that expression of the two reporter genes as a transcriptional fusion in the AR isolates is higher than that in matched AS isolates. However, the difference in the reporter activity between the AS and AR isolates is even greater for the translational fusions, indicating that the sequences within the
CDR1
coding region also contribute to its increased expression in AR isolates. Further analysis of these observations by transcription run-on assays demonstrated a ∼5- to 7-fold difference in the transcription initiation rates for the AR isolates from those for their respective matched AS isolates. Measurement of mRNA stability showed that the half-life of
CDR1
mRNA in the AR isolates was threefold higher than that in the corresponding AS isolates. Our results demonstrate that both increased
CDR1
transcription and enhanced
CDR1
mRNA stability contribute to the overexpression of
CDR1
in AR
C. albicans
isolates.
Potential Basis for Amphotericin B Resistance in
Aspergillus terreus
Authors: Blum Gerhard , Perkhofer Susanne , Haas Hubertus , Schrettl Markus , Würzner Reinhard , Dierich Manfred P. , Lass-Flörl Cornelia
Published: February 2008

This study investigated the basis for intrinsic amphotericin B (AMB) resistance in
Aspergillus terreus
. The ergosterol content, cell wall composition, and lipid peroxidation level had no influence on AMB resistance. The level of catalase production in
A. terreus
was significantly higher than that in
A. fumigatus
(
P
< 0.05). This higher-level production may contribute to AMB resistance in
A. terreus
since oxidative damage has been implicated in AMB action.
DNA Gyrase from the Albicidin Producer
Xanthomonas albilineans
Has Multiple-Antibiotic-Resistance and Unusual Enzymatic Properties
Authors: Hashimi Saeed M. , Huang Guozhong , Maxwell Anthony , Birch Robert G.
Published: February 2008

The sugarcane pathogen
Xanthomonas albilineans
produces a family of antibiotics and phytotoxins termed albicidins, which inhibit plant and bacterial DNA gyrase supercoiling activity, with a 50% inhibitory concentration (50 nM) comparable to those of coumarins and quinolones. Here we show that
X. albilineans
has an unusual, antibiotic-resistant DNA gyrase. The
X. albilineans gyrA
and
gyrB
genes are not clustered with previously described albicidin biosynthesis and self-protection genes. The GyrA and GyrB products differ from
Escherichia coli
homologues through several insertions and through changes in several amino acid residues implicated in quinolone and coumarin resistance. Reconstituted
X. albilineans
DNA gyrase showed 20- to 25-fold-higher resistance than
E. coli
DNA gyrase to albicidin and ciprofloxacin and 8-fold-higher resistance to novobiocin in the supercoiling assay. The
X. albilineans
DNA gyrase is unusual in showing a high degree of distributive supercoiling and little DNA relaxation activity.
X. albilineans
GyrA (XaA) forms a functional gyrase heterotetramer with
E. coli
GyrB (EcB) and can account for albicidin and quinolone resistance and low levels of relaxation activity. XaB probably contributes to both coumarin resistance and the distributive supercoiling pattern. Although XaB shows fewer apparent changes relative to EcB, the EcA·XaB hybrid relaxed DNA in the presence or absence of ATP and was unable to supercoil. A fuller understanding of structural differences between albicidin-sensitive and -resistant gyrases may provide new clues into features of the enzyme amenable to interference by novel antibiotics.
Stimulation of Inducible Nitric Oxide Synthase Expression by Beta Interferon Increases Necrotic Death of Macrophages uponListeria monocytogenesInfection
Authors: Zwaferink Heather , Stockinger Silvia , Reipert Siegfried , Decker Thomas
Published: February 2008

Murine macrophage death upon infection withListeria monocytogeneswas previously shown to be increased by beta interferon, produced by the infected cells. We saw that interferon-upregulated caspase activation or other interferon-inducible, death-associated proteins, including TRAIL, protein kinase R, and p53, were not necessary for cell death. Macrophage death was reduced when inducible nitric oxide synthase (iNOS) was inhibited during infection, and iNOS-deficient macrophages were less susceptible to death upon infection than wild-type cells. The production of nitric oxide correlated with increased death, while no role was seen for iNOS in control ofListerianumbers during infection of resting macrophages. This indicates that the induction of iNOS by beta interferon in cells infected withL. monocytogenescontributes to cell death. Based on morphology, the maintenance of mitochondrial membrane potential, and a lack of dependence on caspase 1, we characterize the type of cell death occurring and show that infected macrophages die by interferon-upregulated necrosis.
Subcutaneous Vaccination with Attenuated
Salmonella enterica
Serovar Choleraesuis C500 Expressing Recombinant Filamentous Hemagglutinin and Pertactin Antigens Protects Mice against Fatal Infections with both
S. enterica
Serovar Choleraesuis and
Bordetella bronchiseptica
Authors: Zhao Zhanqin , Xue Yun , Wu Bin , Tang Xibiao , Hu Ruiming , Xu Yindi , Guo Aizhen , Chen Huanchun
Published: February 2008

Salmonella enterica
serovar Choleraesuis strain C500 is a live, attenuated vaccine that has been used in China for over 40 years to prevent piglet paratyphoid. We compared the protective efficacies of subcutaneous (s.c.) and oral vaccination of BALB/c mice with C500 expressing the recombinant filamentous hemagglutinin type I domain and pertactin region 2 domain antigen (rF1P2) of
Bordetella bronchiseptica
. Protective efficacy against both
S. enterica
serovar Choleraesuis infection in an oral fatal challenge model and
B. bronchiseptica
infection in a model of fatal acute pneumonia was evaluated. Both the s.c. and oral vaccines conferred complete protection against fatal infection with the virulent parent
S. enterica
serovar Choleraesuis strain (C78-1). All 20 mice vaccinated s.c. survived intranasal challenge with four times the 50% lethal dose of virulent
B. bronchiseptica
(HH0809) compared with 4 of 20 vector-treated controls and 1 of 18 phosphate-buffered saline-treated controls that survived, but no significant protection against HH0809 was observed in orally vaccinated animals. Both the s.c. and oral vaccines elicited rF1P2-specific serum immunoglobulin G (IgG) and IgA antibodies. However, lung homogenates from s.c. vaccinated animals had detectably high levels of rF1P2-specific IgG and IgA; a much lower level of rF1P2-specific IgG was detected in samples from orally vaccinated mice, and the latter showed no evidence of local IgA. Furthermore, a more abundant and longer persistence of vaccine organisms was observed in the lungs of mice immunized s.c. than in those of mice immunized orally. Our results suggest that s.c. rather than oral vaccination is more efficacious in protecting mice from fatal challenge with
B. bronchiseptica
.
Combined Inactivation of the
Candida albicans GPR1
and
TPS2
Genes Results in Avirulence in a Mouse Model for Systemic Infection
Authors: Maidan Mykola M. , De Rop Larissa , Relloso Miguel , Diez-Orejas Rosalia , Thevelein Johan M. , Van Dijck Patrick
Published: February 2008

Inhibition of the biosynthesis of trehalose, a well-known stress protectant in pathogens, is an interesting approach for antifungal or antibacterial therapy. Deletion of
TPS2
, encoding trehalose-6-phosphate (T6P) phosphatase, results in strongly reduced virulence of
Candida albicans
due to accumulation of T6P instead of trehalose in response to stress. To further aggravate the deregulation in the pathogen, we have additionally deleted the
GPR1
gene, encoding the nutrient receptor that activates the cyclic AMP-protein kinase A signaling pathway, which negatively regulates trehalose accumulation in yeasts. A
gpr1
mutant is strongly affected in morphogenesis on solid media as well as in vivo in a mouse model but has only a slightly decreased virulence. The
gpr1 tps2
double mutant, on the other hand, is completely avirulent in a mouse model for systemic infection. This strain accumulates very high T6P levels under stress conditions and has a growth defect at higher temperatures. We also show that a
tps2
mutant is more sensitive to being killed by macrophages than the wild type or the
gpr1
mutant. A double mutant has susceptibility similar to that of the single
tps2
mutant. For morphogenesis on solid media, on the other hand, the
gpr1 tps2
mutant shows a phenotype similar to that of the single
gpr1
mutant. Taken together these results show that there is synergism between Gpr1 and Tps2 and that their combined inactivation results in complete avirulence. Combination therapy targeting both proteins may prove highly effective against pathogenic fungi with increased resistance to the currently used antifungal drugs.
Candida albicans
Uses Multiple Mechanisms To Acquire the Essential Metabolite Inositol during Infection
Authors: Chen Ying-Lien , Kauffman Sarah , Reynolds Todd B.
Published: February 2008

Candida albicans
is an important cause of life-threatening systemic bloodstream infections in immunocompromised patients. In order to cause infections,
C. albicans
must be able to synthesize the essential metabolite inositol or acquire it from the host. Based on the similarity of
C. albicans
to
Saccharomyces cerevisiae
, it was predicted that
C. albicans
may generate inositol de novo, import it from the environment, or both. The
C. albicans
inositol synthesis gene
INO1
(
orf19.7585
) and inositol transporter gene
ITR1
(
orf19.3526
) were each disrupted. The
ino1
Δ/
ino1
Δ mutant was an inositol auxotroph, and the
itr1
Δ/
itr1
Δ mutant was unable to import inositol from the medium. Each of these mutants was fully virulent in a mouse model of systemic infection. It was not possible to generate an
ino1
Δ/
ino1
Δ
itr1
Δ/
itr1
Δ double mutant, suggesting that in the absence of these two genes,
C. albicans
could not acquire inositol and was nonviable. A conditional double mutant was created by replacing the remaining wild-type allele of
ITR1
in an
ino1
Δ/
ino1
Δ
itr1
Δ/
ITR1
strain with a conditionally expressed allele of
ITR1
driven by the repressible
MET3
promoter. The resulting
ino1
Δ/
ino1
Δ
itr1
Δ/

P
MET3

::
ITR1
strain was found to be nonviable in medium containing methionine and cysteine (which represses the

P
MET3

promoter), and it was avirulent in the mouse model of systemic candidiasis. These results suggest a model in which
C. albicans
has two equally effective mechanisms for obtaining inositol while in the host. It can either generate inositol de novo through Ino1p, or it can import it from the host through Itr1p.
Wheat Germ Cell-Free System-Based Production of Malaria Proteins for Discovery of Novel Vaccine Candidates
Authors: Tsuboi Takafumi , Takeo Satoru , Iriko Hideyuki , Jin Ling , Tsuchimochi Masateru , Matsuda Shusaku , Han Eun-Taek , Otsuki Hitoshi , Kaneko Osamu , Sattabongkot Jetsumon , Udomsangpetch Rachanee , Sawasaki Tatsuya , Torii Motomi , Endo Yaeta
Published: February 2008

One of the major bottlenecks in malaria research has been the difficulty in recombinant protein expression. Here, we report the application of the wheat germ cell-free system for the successful production of malaria proteins. For proof of principle, the Pfs25, PfCSP, and PfAMA1 proteins were chosen. These genes contain very high A/T sequences and are also difficult to express as recombinant proteins. In our wheat germ cell-free system, native and codon-optimized versions of the Pfs25 genes produced equal amounts of proteins. PfCSP and PfAMA1 genes without any codon optimization were also expressed. The products were soluble, with yields between 50 and 200 μg/ml of the translation mixture, indicating that the cell-free system can be used to produce malaria proteins without any prior optimization of their biased codon usage. Biochemical and immunocytochemical analyses of antibodies raised in mice against each protein revealed that every antibody retained its high specificity to the parasite protein in question. The development of parasites in mosquitoes fed patient blood carrying
Plasmodium falciparum
gametocytes and supplemented with our mouse anti-Pfs25 sera was strongly inhibited, indicating that both Pfs25-3D7/WG and Pfs25-TBV/WG retained their immunogenicity. Lastly, we carried out a parallel expression assay of proteins of blood-stage
P. falciparum
. The PCR products of 124
P. falciparum
genes chosen from the available database were used directly in a small-scale format of transcription and translation reactions. Autoradiogram testing revealed the production of 93 proteins. The application of this new cell-free system-based protocol for the discovery of malaria vaccine candidates will be discussed.
RECONSTRUCTING GENERALIZED GHOST CONDENSATE MODEL WITH DYNAMICAL DARK ENERGY PARAMETRIZATIONS AND OBSERVATIONAL DATASETS
Authors: ZHANG JINGFEI , ZHANG XIN , LIU HONGYA
Published: February 2008

Observations of high-redshift supernovae indicate that the universe is accelerating at the present stage, and we refer to the cause for this cosmic acceleration as "dark energy". In particular, the analysis of current data of type Ia supernovae (SNIa), cosmic large-scale structure (LSS), and the cosmic microwave background (CMB) anisotropy implies that, with some possibility, the equation-of-state parameter of dark energy may cross the cosmological-constant boundary (w = -1) during the recent evolution stage. The model of "quintom" has been proposed to describe this w = -1 crossing behavior for dark energy. As a single-real-scalar-field model of dark energy, the generalized ghost condensate model provides us with a successful mechanism for realizing the quintom-like behavior. In this paper, we reconstruct the generalized ghost condensate model in the light of three forms of parametrization for dynamical dark energy, with the best-fit results of up-to-date observational data.
ON THE NONRELATIVISTIC LIMIT OF LINEAR WAVE EQUATIONS FOR ZERO AND UNITY SPIN PARTICLES
Authors: MOSHIN P. YU. , TOMAZELLI J. L.
Published: February 2008

The nonrelativistic limit of the linear wave equation for zero and unity spin bosons of mass m in the Duffin–Kemmer–Petiau representation is investigated by means of a unitary transformation, analogous to the Foldy–Wouthuysen canonical transformation for a relativistic electron. The interacting case is also analyzed, by considering a power series expansion of the transformed Hamiltonian, thus demonstrating that all features of particle dynamics can be recovered if corrections of order 1/m2 are taken into account through a recursive iteration procedure.
DARBOUX TRANSFORMATION AND MULTI-SOLITON SOLUTIONS OF A NONCOMMUTATIVE SINE–GORDON SYSTEM
Authors: SIDDIQ M. , SALEEM U. , HASSAN M.
Published: February 2008

We present a Darboux transformation of a noncommutative sine–Gordon system and obtain exact multi-soliton solutions of the system in terms of quasi-determinants.
THERMODYNAMIC DUALITY BETWEEN RN BLACK HOLE AND 2D DILATON GRAVITY
Authors: MYUNG YUN SOO , KIM YONG-WAN , PARK YOUNG-JAI
Published: February 2008

All thermodynamic quantities of the Reissner–Nordström (RN) black hole can be obtained from the dilaton and its potential of two-dimensional (2D) dilaton gravity. The dual relations of four thermodynamic laws are also established. Furthermore, the near-horizon thermodynamics of the extremal RN black hole is completely described by the Jackiw–Teitelboim theory which is obtained by perturbing around the AdS2-horizon.
AN AXIOMATIC DEFINITION OF FUZZY DIVERGENCE MEASURES
Authors: COUSO INÉS , MONTES SUSANA
Published: February 2008

The representation of the degree of difference between two fuzzy subsets by means of a real number has been proposed in previous papers, and it seems to be useful in some situations. However, the requirement of assigning a precise number may lead us to the loss of essential information about this difference. Thus, (crisp) divergence measures studied in previous papers may not distinguish whether the differences between two fuzzy subsets are in low or high membership degrees. In this paper we propose a way of measuring these differences by means of a fuzzy valued function which we will call fuzzy divergence measure. We formulate a list of natural axioms that these measures should satisfy. We derive additional properties from these axioms, some of them are related to the properties required to crisp divergence measures. We finish the paper by establishing a one-to-one correspondence between families of crisp and fuzzy divergence measures. This result provides us with a method to build a fuzzy divergence measure from a crisp valued one.
A FUZZY-NEURAL SYSTEM INCORPORATING UNEQUALLY IMPORTANT EXPERT OPINIONS FOR SEMICONDUCTOR YIELD FORECASTING
Authors: CHEN TOLY , LIN YU-CHENG
Published: February 2008

Yield forecasting is a very important task to a semiconductor manufacturing factory. To enhance both the precision and accuracy of semiconductor yield forecasting, a fuzzy-neural system incorporating unequally important expert opinions is constructed in this study. In the proposed methodology, multiple experts construct their own fuzzy yield learning models from various viewpoints to predict the yield of a product. Besides, these expert opinions can also be considered unequally important. To aggregate these fuzzy yield forecasts, a two-step aggregation mechanism is applied. At the first step, fuzzy intersection is applied to aggregate the fuzzy yield forecasts into a polygon-shaped fuzzy yield forecast, in order to improve the precision of yield forecasting. After that, a back propagation network is constructed to defuzzify the polygon-shaped fuzzy yield forecast and to generate a representative/crisp value, so as to enhance the accuracy. For evaluating the effectiveness of the proposed methodology and to make comparison with some existing approaches, all approaches were applied to the practical data of three products in a real semiconductor manufacturing factory. According to experimental results, the proposed methodology improved both the precision and accuracy of semiconductor yield forecasting by 48% and 38%, respectively.