bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifiable risk factors for impaired fertility in women: What nurse practitioners need to know
Authors: Kelly‐Weeder Susan , O’Connor Alane
Published: May 2006

Purpose: To provide an overview of impaired fertility in childbearing‐aged women, to review the current research on modifiable lifestyle risk factors implicated in its development, and to suggest strategies for nurse practitioners (NPs) to assist women in behavioral changes that will allow them to protect their fertility.

Data sources: Original research articles and comprehensive review articles identified through Medline, CINAHL, and OVID databases.

Conclusions: Research has shown that advancing age, a history of a sexually transmitted infection and/or pelvic inflammatory disease, extremes of body weight, and tobacco and caffeine use are potentially modifiable risk factors in the development of impaired fertility.

Implications for practice: NPs must be aware of the link between these behaviors and the development of impaired fertility in order to assist women in preserving their fertility. Individual counseling, education, and community‐wide education strategies are discussed.
Pilot study: Nurse practitioner communication and the use of recommended clinical preventive services
Authors: Berry Judith A.
Published: May 2006

Purpose:The purpose of the pilot study was to determine the feasibility of investigating nurse practitioners’ (NPs) use of clinical preventive services (CPS) in practice and the influence of provider–patient communication in achieving the CPS outcome. NP–patient communication styles were also explored.

Data sources:Five NPs were audio‐taped each during one patient encounter. Using manifest content analysis, the transcripts were evaluated for the presence of CPS and communication styles.

Conclusion:Because this was a pilot study and the sample size was small, no generalizations could be made. The presence of health promotion and disease prevention activities, as evaluated by the use of recommended CPS, was present in only one NP–patient encounter. NPs did use patient‐centered communication style in all the encounters. No correlations could be made to link communication styles with CPS.

Implications for practice:Further study with a larger sample size needs to be done. NPs may not be using health promotion and disease prevention, as demonstrated by CPS, in actual practice. This may be an area that needs greater emphasis in education and practice.
When I go in to wake them … I wonder: Parental perceptions about congenital long QT syndrome
Authors: Farnsworth Monica M. , Fosyth Diane , Haglund Carla , Ackerman Michael J.
Published: May 2006

Purpose:Congenital long QT syndrome (LQTS) affects an estimated 1 in 5000 persons, is characterized by QT interval prolongation, and has a clinical presentation ranging from asymptomatic longevity to sudden death in the young as the initial event. The purpose of this study was to describe the experiences of parents who have a child or children with LQTS. Information from parents of children with this diagnosis can provide insight to healthcare providers who care for these families.

Data sources:The literature reveals that very little is known about the psychosocial aspects of this potential sudden death syndrome. This was a secondary analysis of a 2002 qualitative phenomenological primary study done to explore fear of death and quality of life for 58 patients with LQTS. The secondary study analyzed responses derived from 31 parents of children with LQTS.

Conclusions:We speculated this far‐reaching clinical spectrum would arouse fear and uncertainty for a parent of a child with LQTS. Results of the study revealed that parents with young children described fear of their children dying and strategies they used to manage their fear, as well as frustrations about lack of knowledge of LQTS among healthcare providers. When the diagnosis of LQTS is established during adolescence, the impact on the lives of children and their families is more significant.

Implications for practice:In order to support families experiencing the stress of living daily with someone with LQTS, healthcare providers including nurse practitioners need a better understanding of the symptoms, diagnosis, management, and lifestyle implications of LQTS. Further studies are needed to understand the long‐term psychosocial effects of children on beta‐blockers, children with implantable cardioverter defibrillators, and children, adolescents, and young adults who survive a sudden death event.
Prescribing trends by nurse practitioners and physician assistants in the United States
Authors: Cipher Daisha J. , Hooker Roderick S. , Guerra Patricia
Published: May 2006

Purpose: As an important step in analyzing the role of nurse practitioners (NPs) and physician assistants (PAs), we examined their prescribing behavior. The intent is to study the characteristics of providers and patients, and the type of prescriptions written by NPs and PAs in primary care and to compare these activities to physicians.

Data sources: The National Ambulatory Medical Care Survey (NAMCS) database was examined for prescriptions written by primary care clinicians (family and general medicine, internal medicine, and general pediatrics). A representative sample of 88,346 primary care visits over a 6‐year period (1997–2002) was analyzed in which a prescription was written by an NP, a PA, or a physician in an urban or rural setting.

Conclusions: The characteristics of all the patients seen were similar for geographical region of visit, age, and gender, but differed by ethnicity and race. An NP or a PA was the provider of record for 5% of the primary care visits in the NAMCS database. The three clinician types were likely to write at least one prescription for 70% of all visits, and the mean number of prescriptions was 1.3–1.5 per visit (range 0–5) depending on the provider. PAs were more likely to prescribe a controlled substance for a visit than a physician or an NP (19.5%, 12.4%, 10.9%, respectively). Only in nonmetropolitan settings did differences emerge. In rural areas, NPs wrote significantly more prescriptions than physicians and PAs.

Implications for practice: We suggest that NPs and PAs may provide a role that is similar to that of physicians in primary care based on prescribing behavior. The prescribing behavior of PAs and NPs parallels that of physicians by the number of medications per visit, the types of therapeutic classes, and the type of patient. However, in nonmetropolitan areas, prescribing differences emerge between the three types of providers that bear further exploration.
Nutritional aspects of non‐alcoholic steatohepatitis treatment
Authors: YUNIANINGTIAS Diah , VOLKER Dianne
Published: May 2006

Objective and design: The aim of the present study is to review literature associated with the nutritional aspect of the treatment of non‐alcoholic steatohepatitis (NASH).

Subjects and setting: The studies reviewed used small numbers of subjects and the majority of the studies were retrospective reviews and case series, not randomised controlled trials. The duration of the studies ranged from seven weeks to two years.

Main outcome measures: Almost all of the studies demonstrate improvement in liver function tests, with weight loss combined with exercise beneficially reversing fatty liver. Omega‐3 fatty acid supplementation suggests positive effects in triglycerides level reduction by its role in suppression of sterol regulatory element binding protein‐1, whereas vitamin E supplementation reduces serum transaminase. Nutritional treatment in NASH is directed at its risk factors. Some studies give useful information regarding the importance of the nutritional aspects of treatment of the NASH patient, and almost all of the studies provide positive results although in some regimens the results are inconsistent.

Conclusion: Well‐designed trials (in terms of numbers of subjects, with valid outcome measures) are needed to determine the efficacy of each strategy.
Post‐migration food habits of sub‐Saharan African migrants in Victoria: A cross‐sectional study
Authors: RENZAHO André M.N. , BURNS Cate
Published: May 2006

Objective:  (i) To describe sub‐Saharan African (SSA) post‐migration food habits and eating patterns; and (ii) to examine how the food habits of SSA households in Victoria reflect post‐migration acculturation.

Design:  A cross‐sectional survey using a snowball sampling technique. Data on food habits and eating patterns were obtained using semi‐structured, face‐to‐face interviews from November 2001 to April 2002.

Subjects:  A total of 139 households of demographically diverse recent migrants from across sub‐Saharan Africa.

Setting:  Melbourne metropolitan and Melbourne fringes.

Analysis:  Data were summarised using descriptive statistics.

Results:  SSA migrants and refugees indicated dietary acculturation characterised by three processes: substitution, supplementation and modification of recipes. They experienced difficulty locating their traditional foods, in particular, African vegetables (34.2%), unprocessed maize meal (29.1%), camel milk (23.1%) and maize grain (13.7%). The new foods adopted since arrival were pizza, breakfast cereals and fast foods, but also included new fruits and vegetables. Takeaway food such as Pizza Hut or McDonalds featured prominently in the SSA post‐migration diet. Reasons for eating out were favourite food (48.3%), routine family outing (38.3%), special occasion (33.3%) and no time to cook (25%). A significant change in meal pattern was the inclusion of breakfast, although 21% reported skipping breakfast.

Conclusion:  Many of the observed dietary changes were not consistent with good health and may predispose this population to rapid weight gain and chronic disease. Rapid modernisation and the Anglo‐Australian culture interact in a complex way with traditional eating and socialisation practices of SSA migrants. Understanding these forces can allow effective health promotion and community development strategies to be developed for the future health of SSA migrants and their communities.
Accessibility for parents of weight management information on the Internet
Authors: OWAIMRIN Amal , STEINBECK Katharine
Published: May 2006

Objective:  The aim of the present study was to describe the accessibility, quality and readability of web base content on the Internet for childhood obesity management from a parental viewpoint. As more than 25% of Australian children are overweight or obese, it is likely that parents access the Internet for advice on obesity management for their child.

Design:  Links to websites were generated using three search engines and three phrases. The first 10 website links were selected from each of nine searches. Ten aspects of obesity management were identified for the analysis of childhood obesity and related websites. The Fry readability graph was used to assess content readability.

Data analysis:  The data were analysed using spss Version 10, Minitab and Microsoft Excel 2000. anova was used to compare clinical criteria between website type.

Results:  A total of 90 links were generated with 60 relevant for analysis. In total, 30 were specific to childhood obesity and 47 websites were either obesity‐specific or weight‐related. Childhood obesity websites were community‐based or commercial. Most websites relevant to childhood obesity management came at no cost, in comparison with general weight‐related sites. Childhood obesity websites scored generally high on accuracy of content. Overall, website readability was at an undergraduate level.

Conclusions:  There appears to be a paucity of accessible information on the Internet related to childhood weight management, which parents could access. Childhood obesity management websites should ideally include clinically approved management guidelines and follow e‐health codes of ethical practice.
Promoting breast health: older women's perceptions of an innovative intervention to enhance screening
Authors: Wood Robin Y. , Della‐Monica Nola R.
Published: May 2006

Aims and objectives.  This study is a continuation of prior funded research in which we tested the use of age and ethnically sensitive video breast health kits to increase knowledge about breast cancer and enhance the screening practices of breast self‐examination and mammography among older Caucasian and African‐American women.

Background.  Breast cancer is the most frequent cancer in women worldwide and accounts for 23% of all cancers. Mammography is currently the best procedure available for mass screening of breast cancer. However, underutilization of mammography is a problem among older women in the United States. Elders are at the greatest risk for developing and dying from breast cancer but they are the least likely group to be screened routinely with mammograms or to practice breast self‐examination, particularly if they are African‐American.

Design.  Participatory qualitative evaluation focus groups were used to assess the overall impact of the video kit intervention programme and to elucidate the quantitative findings of the original study.

Methods.  Four focus groups were conducted in two diverse settings with a purposive sample of 23 participants (N = 23). The overall sample was predominantly African‐American (87%) with mean age of 71 ± 7.9 years and mean education completed of 12 ± 3.4 years.

Results.  Five major themes emerged from group discussions: usability and appeal of the intervention, fear and empowerment, personal relevance and intergenerational sharing, impact on screening behaviours, and story telling.

Conclusions.  Analyses suggest that customized media materials constructed especially for older African‐American women empowered participants in this sample to action regarding their own breast health.

Relevance to clinical practice.  These findings may translate to global populations where risk is increasing but screening programmes are not widely available. Given that older women are historically difficult to access and impact, further design and evaluation of innovative and sensitive educational programmes such as the one described here are recommended.
Moving forward together: evaluation of an action group involving staff and relatives within a nursing home for older people with dementia
Authors: Barry Aveyard , Davies Sue
Published: May 2006

Background.  This paper describes the implementation and evaluation of an action group within a nursing home for older people with dementia. Over a two‐year period, researchers worked with staff, residents and relatives on a series of initiatives aimed at improving experiences of living and working within the home. The action group, involving staff, residents and their relatives was the vehicle through which a number of important changes were achieved. The project was underpinned by ideas about relationship‐centred care and the Senses Framework.

Methods.  A constructivist methodology informed both the initial development and the evaluation of the project. This paper reports findings from interviews with staff and relatives and process recordings of group discussions.

Findings.  Data from the evaluation provide evidence of ways in which the project has contributed to creating the senses (security, significance, belonging, purpose, continuity and achievement) for each of the key stakeholder groups. Factors supporting and hindering the project were also identified.

Conclusions.  The development approach using the Senses Framework adopted within the project is a useful model for partnership working in settings providing continuing care for older people.

Relevance to clinical practice.  Findings from this small‐scale but intensive project suggest that staff within care homes should seek to engage with a range of stakeholders in order to improve experiences for all involved in long‐term care. Academic staff within schools of nursing should consider innovative, action‐oriented approaches to supporting developments within care homes.
Students’ ideals for nursing older people in practice
Authors: Alabaster Erica S.
Published: May 2006

Aim.  Drawing on research exploring nursing students’ experiences of working with older people, this paper aims to demonstrate how context and culture can impact on the realization of their ideals.

Background.  The principles underpinning individualized and person‐centred approaches to care resonate with those focal to gerontologic nursing. Restrictive contexts of care and pervasive workplace cultures render nurses unable to deliver care in accord with these.

Design and method.  This interpretive study was informed by phenomenological–hermeneutic theory. A purposive sample (n = 10) was recruited from a single educational institution. Data were generated in two phases using loosely structured interviews and supplementary activity. Themes explicating their experiences were identified via systematized detailed analysis and issues pertaining to nursing students’ orientation towards older people cut across these.

Findings and discussion.  Students perceived that older people were prone to depersonalization and marginalization, so sought to show respect by coming to know individuals, form human connections with them and personalize care accordingly. Giving respect, promoting personhood, asserting reciprocal identity and maintaining dignity were prominent features of this but were often frustrated by practices and cultures encountered in mainstream settings.

Conclusions.  Nursing students’ approaches to older people are contextual and reflect elements of person‐centred ideology. Their attempts upholding their ideals are liable to be subverted by workplace norms. Preparatory education should address these, assist students to learn how to attend to personhood in restrictive environments and offer targeted placements in age‐specific and non‐acute services.

Relevance to clinical practice.  Demographic trends mean that working with older people has increased significance for nurses in most settings. Person‐centredness is seen as beneficial for older people but contemporary service imperatives and enduring practices are inhibitory, preventing entrants to nursing from developing related skills.
Preserving personhood in dementia research: a literature review
Authors: Cowdell Fiona
Published: May 2006

The aim of this literature review was to investigate studies that actively engage older people with dementia in research ‘with’ rather than ‘on’ them. The focus of the paper is the methods that researchers have used to ensure that studies are ethical, meaningful and preserve the personhood of individuals. The intention is to present a selection of papers rather than undertake an exhaustive review. It is well recognized that the prevalence of dementia in older adults is increasing, this increase is reflected by a huge rise in the amount of research into this area. The biomedical model continues to dominate dementia research however there is a small, but growing, body of research that actively seeks to engage people with dementia. This increase in research that actively engages people with dementia has developed in parallel with the ‘new culture’ of dementia care in which Kitwood (Dementia Reconsidered: The Person Comes First. Open University Press, Buckingham, 1997) exhorts us to respect the personhood of people with dementia. This review identifies 22 studies that sought the views and experiences of older people with dementia. There is evidence in each paper that the researchers had given thought to ensuring that their work was ethical, meaningful and preserved the personhood of individuals. The skill with which this aim was achieved varied considerably from formulaic approaches to those that clearly demonstrate that the researchers have a mindset that is grounded in a powerful belief in, and application of, the concepts of genuine respect for older people with dementia. The examples of good practice that have been drawn from these papers have direct application to both future research and to the provision of clinical care.
Delirium: a new appraisal of an old problem
Authors: Irving Kate , Fick Donna , Foreman Marquis
Published: May 2006

Delirium is a prevalent condition associated with high morbidity and mortality. Studies investigating delirium date back centuries but the subject has received increased attention in the last two decades. This recent attention focuses on, risk factors, early recognition, consequences and management of delirium. The aim of this paper was to provide an updated review of issues concerning the assessment and identification of delirium. Assessment is central to the effective management but delirium continues to be under‐recognized by the healthcare team. This review sets the scene for the following papers on practice and the future direction for the management of delirium.
How we do it: Frequency of skin necrosis after BAHA surgery
Authors: Tjellström A. , Granström G.
Published: May 2006

Keypoints

• To establish a lasting reaction free skin penetration the skin at the penetration site must not move in relation to the coupling.

• The skin should also be free of hair follicles in order to facilitate everyday cleaning.

• A specially designed dermatome will ensure a 0.6‐mm thick hairless skin flap.

• By applying a very gentle pressure on the flap the risk of skin necrosis during the healing phase is reduced.
How we do it: Implementing change – a multi‐centre audit of an evidence‐based protocol on post‐thyroidectomy calcium maintenance
Authors: Gillett D. , Fahmy F. , Liew L. , Massey S. , Shotton J.C.
Published: May 2006

Keypoints

• Our previous retrospective audit (Clinical Otolaryngology, December 2004) identified considerable variation in post‐thyroidectomy calcium assessment. This led to a well‐structured protocol.

• The protocol was introduced into two trusts. The results were prospectively collated for 64 thyroid procedures over a period of 6 months.

• All patients that warranted it were tested on day 1, and 71% were tested on day 2 – highlighting a more structured approach, and avoiding unnecessary vene‐ puncture in all thyroid lobectomy patients.

• Such protocols have been proven to be an important tool in the effort to improve the quality and lower the cost of care.

• Resistance to change, established practise and lack of data collection resources prevented this protocol from becoming established in more regional trusts.
Head & neck cancer incidence in Wales 1992‐‐2001
Authors: Khan A.M. , Tomkinson A.
Published: May 2006

Introduction. There are 12 cancer registries. The process of cancer registration within the United Kingdom is similar. The Welsh Cancer Intelligence & Surveillance Unit (WCISU) has published a report ‘Cancer Incidence in Wales 1992‐‐2001’.

Objective. The aim of the study was to validate head and neck section of the report.

Material and method. Data of cancer patients travels from the clinical notes through clinical coding to Patient Administration System (PAS) at each Trust, then to the Patient Episode Database for Wales (PEDW), and finally to WCISU. The processed data used for the publication of this report was retrieved from WCISU and was compared to that received from the clinical notes, PAS and PEDW.

Results. 12% of the notes examined were inappropriately coded in terms of gross anatomical tumour site. If non‐melanoma skin cancers are included in the definition of Head and Neck Cancer 80% (17\,101) of the patients appear to not be included in the WCISU report. If skin cancer is excluded from the definition 57% (5750) of head and neck cancer patients appear to not be included.

Conclusion. The definition of Head & Neck Cancer appears to differ between clinicians and that used in the WCISU report. This difference will create an apparent gross underestimate in the true incidence of Head and Neck cancer in Wales when viewed from a clinical or workload perspective. It appears that this report could not be used for the present and future planning of Head & Neck services in Wales.
Tissue engineering strategies for reinnervation of the larynx
Authors: Kingham P.J. , Terenghi G. , Birchall M.A.
Published: May 2006

Objectives. Injury to the recurrent laryngeal nerve (RLN) results in synkinesis and a dysfunctional larynx. Novel nerve repair techniques might enhance the speed of RLN regeneration and encourage accurate muscle reinnervation. Our first approach has been to apply neurotrophins (NT) to the site of repair using artificial nerve conduits. Currently we are investigating whether adult stem cells can be differentiated to provide a source of Schwann cells for future cell‐based therapies.

Method. In a pig model, the phrenic nerve was anastomosed with the RLN abductor branch1 and repaired using poly‐hydroxybutyrate wrap‐around conduits either untreated or impregnated with NT‐3 (500 ng/mL). Markers of nerve regeneration (neurofilament) and muscle denervation/reinnervation (NCAM) were assessed to determine the efficiency of repair. Stem cells were isolated from adipose tissue and treated with glial growth factors for 2 weeks before phenotypic characterisation.

Results. Compared with controls, NT‐3 treated animals showed significantly elevated levels of neurofilament protein in the distal nerve segment at 2 months (n = 5, P < 0.01). Injury increased the number of denervated, NCAM positive abductor muscle fibres from 1.3 ± 0.68% to 33.9 ± 5.8% at 2 months and 3.7 ± 2.3% at 4 months. NT‐3 did not significantly reduce these numbers. Differentiated adipose derived stem cells adopted a bi‐polar morphology similar to Schwann cells and expressed S100 and GFAP glial proteins.

Conclusions. NT‐3 treatment promotes early nerve regeneration but is insufficient to enhance long‐term muscle reinnervation. Differentiated adipose derived stem cells may represent a novel source of Schwann cells for future RLN repair studies.

Reference

1 Kingham P.J., Birchall M.A., Burt R., et al. (2005) Reinnervation of laryngeal muscles: a study of changes in myosin heavy chain expression. Muscle Nerve. 32(6), 761‐‐766
NPTA: an audit of an audit and some worrying conclusions
Authors: Pothier D.D. , Nankivell P.C. , Hunasaghatta S.
Published: May 2006

Objectives. Data sent to the National Prospective Tonsillectomy Audit (NPTA) may be flawed by systematic bias. The NPTA was set up to record data concerning all tonsillectomies performed in England and Northern Ireland over a 15 month period.1 A potential weakness of the NPTA system is that a great deal of reliance is placed on accurate recording of complication data. We set out to determine how results from a case note review would compare to data sent by us to the NPTA.

Method. Case notes of tonsillectomy patients, who had NPTA documentation completed, were retrieved (Gloucestershire Royal 267 and Bath 294). The notes of patients who had consented to inclusion in the NPTA (Gloucestershire Royal 227 and Bath 246) were reviewed, independently of the NPTA form, for data that was required by NPTA.

Results. The review of the case notes showed a far higher rate of complications than the data sent to the NPTA. Rates of delayed discharge were higher by a factor of 1.67 and 7 times, the readmission rate was 1.54 and 2.43 times higher and the return to theatre rate and secondary bleed rate from the case note review was over double that of the data we sent to the NPTA.

Conclusions. The construct of the NPTA makes the data regarding the initial tonsillectomy easier to record than any complications thereafter. If the other participants in the NPTA have standards of data submission similar to ours, the conclusions drawn upon those data should be regarded with great caution.

Reference

1 RCSEng, BAOHNS. National Prospective Tonsillectomy Audit Informtion Leaflet. http://www.tonsil‐audit.org/documents/information_leaflet.pdf . 2005. Last accessed 6/9/2005
Immunohistochemical expression of p53 and MDM2 within head and neck squamous cell carcinoma
Authors: Tandon S. , Beer H. , Jones T.M. , Birchall M. , Boyd M. , Helliwell T.R.
Published: May 2006

Objectives. To determine the presence, location and degree of expression of p53 and MDM2, by use of immunohistochemistry, in squamous cell carcinoma of the head and neck (HNSCC).

Design. Laboratory based observational study.

Setting. University Hospital Aintree, Liverpool and The University of Liverpool.

Participants. Twenty‐three consecutive patients with HNSCC were studied. Ethics approval and informed patient consent were gained. Paraffin sections of carcinoma were stained for p53 and MDM2. Sections were assessed by stratified random sampling of the periphery and centre of the tumour for nuclear staining.

Main outcomes measures. (i) Number of positive cases for p53 and MDM2; (ii) percentage of cells positive for p53 and MDM2; (iii) variation of positive cells within the tumour.

Results. The range of p53 positivity was 0–100%; 10 cases were negative for p53, five cases were intermediate for p53, seven cases were highly positive for p53. The range of MDM2 positivity was 0–16%; 10 cases were negative for MDM2, four cases were intermediate for MDM2, nine cases were highly positive for MDM2. 10 cases were predominantly p53 positive, eight cases were predominantly MDM2 positive and five cases were negative for both p53 and MDM2. There was no consistent difference between the edge and the centre for either antibody, however for MDM2, there is increased expression in peri‐necrotic areas.

Conclusions. (i) HNSCC shows different patterns of p53 and MDM2 co‐expression, which has potential biological and clinical significance; (ii) peri‐necrotic expression of MDM2 may be explained by a response to hypoxia.
Biosynthetic Gene Cluster for the Polyenoyltetramic Acid α-Lipomycin
Authors: Bihlmaier C. , Welle E. , Hofmann C. , Welzel K. , Vente A. , Breitling E. , Müller M. , Glaser S. , Bechthold A.
Published: May 2006

The gram-positive bacterium
Streptomyces aureofaciens
Tü117 produces the acyclic polyene antibiotic α-lipomycin. The entire biosynthetic gene cluster (
lip
gene cluster) was cloned and characterized. DNA sequence analysis of a 74-kb region revealed the presence of 28 complete open reading frames (ORFs), 22 of them belonging to the biosynthetic gene cluster. Central to the cluster is a polyketide synthase locus that encodes an eight-module system comprised of four multifunctional proteins. In addition, one ORF shows homology to those for nonribosomal peptide synthetases, indicating that α-lipomycin belongs to the classification of hybrid peptide-polyketide natural products. Furthermore, the
lip
cluster includes genes responsible for the formation and attachment of
d
-digitoxose as well as ORFs that resemble those for putative regulatory and export functions. We generated biosynthetic mutants by insertional gene inactivation. By analysis of culture extracts of these mutants, we could prove that, indeed, the genes involved in the biosynthesis of lipomycin had been cloned, and additionally we gained insight into an unusual biosynthesis pathway.
In Vitro Activities of DX-619 and Comparison Quinolones against Gram-Positive Cocci
Authors: Wickman Paul A. , Black Jennifer A. , Moland Ellen Smith , Thomson Kenneth S.
Published: May 2006

The in vitro activity of the novel quinolone DX-619 was compared to those of currently available quinolones against U.S. clinical isolates of
Staphylococcus aureus
, coagulase-negative staphylococci,
Enterococcus
spp.,
Streptococcus pyogenes
, and
Streptococcus pneumoniae
. DX-619 was the most potent quinolone overall, indicating possible utility as an anti-gram-positive quinolone.
Analysis of the Loading and Hydroxylation Steps in Lankamycin Biosynthesis in
Streptomyces rochei
Authors: Arakawa Kenji , Kodama Kazuya , Tatsuno Satoshi , Ide Sayoko , Kinashi Haruyasu
Published: May 2006

The biosynthetic gene cluster of lankamycin (LM), a 14-member macrolide antibiotic, is encoded on the 210-kb linear plasmid pSLA2-L in
Streptomyces rochei
7434AN4. LM contains a 3-hydroxy-2-butyl group at the C-13 position, which is different from an ethyl group in erythromycin. The following two possibilities could be considered for the origin of this starter moiety of LM biosynthesis: (i) an extra module exists in the biosynthetic gene cluster and loads an additional acetate molecule, or (ii) 3-hydroxy-2-butyrate or its equivalent is loaded and incorporated as a starter. The former possibility was eliminated by the complete sequencing of pSLA2-L, which showed no extra module. On the other hand, the latter was confirmed by incorporation of deuterium in [3-
2
H]
dl
-isoleucine into the C-14 position of LM. The timing of hydroxylation reactions at the C-15 and C-8 positions of LM was studied by constructing disruptants of two P450 hydroxylase genes,
lkmF
(
orf26
) and
lkmK
(
orf37
). The
lkmF
disruptant produced 8-deoxylankamycin, while the
lkmK
disruptant produced both 15-deoxylankamycin and 8,15-dideoxylankamycin. These results clearly showed that LkmF is a C-8 hydroxylase and LkmK is a C-15 hydroxylase in LM biosynthesis and in addition suggested the order of hydroxylation steps; namely, hydroxylation may occur at first at C-15 by LkmK and then at C-8 by LkmF.
Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against
Pseudomonas aeruginosa
Authors: Bergen Phillip J. , Li Jian , Rayner Craig R. , Nation Roger L.
Published: May 2006

There is a dearth of information on the pharmacodynamics of “colistin,” despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of
Pseudomonas aeruginosa
in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., ∼0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against
P. aeruginosa
. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving “colistin,” in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.
Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in
Staphylococcus aureus
Authors: Friedman Lisa , Alder Jeff D. , Silverman Jared A.
Published: May 2006

Daptomycin is a lipopeptide antibiotic with potent activity against gram-positive bacteria. Complete-genome comparisons of laboratory-derived
Staphylococcus aureus
with decreased susceptibility to daptomycin and their susceptible parent were used to identify genes that contribute to reduced susceptibility to daptomycin. Selective pressure of growth in sublethal concentrations of daptomycin resulted in the accumulation of mutations over time correlating with incremental decreases in susceptibility. Single point mutations resulting in amino acid substitutions occurred in three distinct proteins: MprF, a lysylphosphatidylglycerol synthetase; YycG, a histidine kinase; and RpoB and RpoC, the β and β′ subunits of RNA polymerase. Sequence analysis of
mprF
,
yycF
,
yycG
,
rpoB
, and
rpoC
in clinical isolates that showed treatment-emergent increases in daptomycin MICs revealed point mutations in
mprF
and a nucleotide insertion in
yycG
, suggesting a role for these genes in decreased susceptibility to daptomycin in the hospital setting.
Activities of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin, against
Haemophilus influenzae
and
Moraxella catarrhalis
Authors: Bogdanovich Tatiana , Clark Catherine , Ednie Lois , Lin Gengrong , Smith Kathy , Shapiro Stuart , Appelbaum Peter C.
Published: May 2006

Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 μg/ml and 8.0 μg/ml for 321 clinical isolates of
Haemophilus influenzae
and between ≤0.004 μg/ml and 1.0 μg/ml for 49 clinical isolates of
Moraxella catarrhalis
. Ceftobiprole MIC
50
and MIC
90
values for
H. influenzae
were 0.06 μg/ml and 0.25 μg/ml for β-lactamase-positive strains (
n
= 262), 0.03 μg/ml and 0.25 μg/ml for β-lactamase-negative strains (
n
= 40), and 0.5 μg/ml and 2.0 μg/ml for β-lactamase-negative ampicillin-resistant strains (
n
= 19), respectively. Ceftobiprole MIC
50
and MIC
90
values for β-lactamase-positive
M. catarrhalis
strains (
n
= 40) were 0.12 μg/ml and 0.5 μg/ml, respectively, whereas the ceftobiprole MIC range for β-lactamase-negative
M. catarrhalis
strains (
n
= 9) was ≤0.004 to 0.03 μg/ml. Ceftriaxone MICs usually were generally at least twofold lower than those of ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against
H. influenzae
, with MIC
90
values of azithromycin and telithromycin of 2 μg/ml and 4 μg/ml, respectively. Except for selected quinolone-nonsusceptible
H. influenzae
strains, moxifloxacin proved highly active, with MIC
90
values of 0.12 μg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2× MIC by 24 h against all 10
H. influenzae
strains surveyed. Only modest increases in MICs were found for
H. influenzae
or
M. catarrhalis
clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of
H. influenzae
or
M. catarrhalis
clones with elevated ceftobiprole MICs is quite low.
In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against
Mycobacterium ulcerans
Authors: Ji Baohong , Lefrançois Sébastien , Robert Jerome , Chauffour Aurélie , Truffot Chantal , Jarlier Vincent
Published: May 2006

Seven antimicrobials were tested in vitro against 29 clinical isolates of
Mycobacterium ulcerans
. R207910 demonstrated the lowest MIC
50
and MIC
90
, followed by moxifloxacin (MXF), streptomycin (STR), rifampin (RIF), amikacin (AMK), linezolid (LZD), and PA-824. All but PA-824 demonstrated an MIC
90
significantly less than the clinically achievable peak serum level. Administered as monotherapy to mice, RIF, STR, AMK, MXF, R207910, and LZD demonstrated some degree of bactericidal activity, whereas PA-824 failed to prevent mortality and to reduce the mean number of CFU in the footpads. Because 4 or 8 weeks of treatment by the combinations RIF-MXF, RIF-R207910, and RIF-LZD displayed bactericidal effects similar to those of RIF-STR and RIF-AMK, these three combinations might be considered as orally administered combined regimens for treatment of Buruli ulcer. Taking into account the cost, potential toxicity, and availability, the combination RIF-MXF appears more feasible for application in the field; additional experiments with mice are warranted to define further its activity against
M. ulcerans
. In addition, a pilot clinical trial is proposed to test the efficacy of RIF-MXF for treatment of Buruli ulcer.
Antibody-Guided Alpha Radiation Effectively Damages Fungal Biofilms
Authors: Martinez L. R. , Bryan R. A. , Apostolidis C. , Morgenstern A. , Casadevall A. , Dadachova E.
Published: May 2006

The use of indwelling medical devices—pacemakers, prosthetic joints, catheters—is rapidly growing and is often complicated by infections with biofilm-forming microbes that are resistant to antimicrobial agents and host defense mechanisms. We investigated for the first time the use of microbe-specific monoclonal antibodies (MAbs) as delivery vehicles for targeting biofilms with cytocidal radiation. MAb 18B7 (immunoglobulin G1 [IgG1]), which binds to capsular polysaccharides of the human pathogenic fungus
Cryptococcus neoformans
, penetrated cryptococcal biofilms, as shown by confocal microscopy. When the alpha radiation-emitter 213-Bismuth (
213
Bi) was attached to MAb 18B7 and the radiolabeled MAb was added to
C. neoformans
biofilms, there was a 50% reduction in biofilm metabolic activity. In contrast, when the IgM MAb 13F1 labeled with
213
Bi was used there was no penetration of the fungal biofilm and no damage. Unlabeled 18B7,
213
Bi-labeled nonspecific MAbs, and gamma and beta types of radiation did not have an effect on biofilms. The lack of efficacy of gamma and beta radiation probably reflects the radioprotective properties of polysaccharide biofilm matrix. Our results indicate that
C. neoformans
biofilms are susceptible to treatment with antibody-targeted alpha radiation, suggesting a novel option for the prevention or treatment of microbial biofilms on indwelling medical devices.
Fluoroquinolone-Resistant Urinary Isolates of
Escherichia coli
from Outpatients Are Frequently Multidrug Resistant: Results from the NorthAmerican Urinary Tract Infection Collaborative Alliance-QuinoloneResistance Study
Authors: Karlowsky James A. , Hoban Daryl J. , DeCorby Melanie R. , Laing Nancy M. , Zhanel George G.
Published: May 2006

Ciprofloxacin-resistant
Escherichia coli
isolates (
n
= 1,858) from outpatient midstream urine specimens at 40 North American clinical
laboratories in 2004 to 2005 were frequently resistant to ampicillin
(79.8% of isolates) and trimethoprim-sulfamethoxazole (66.5%);
concurrent resistance to cefdinir (9.0%) or nitrofurantoin (4.0%) was
less common. Only 10.8% of isolates were resistant to ciprofloxacin
alone. Fluoroquinolone-resistant isolates of
E. coli
from
urine were frequently multidrug
resistant.
Molecular Validation of LpxC as an Antibacterial Drug Target in
Pseudomonas aeruginosa
Authors: Mdluli Khisimuzi E. , Witte Pamela R. , Kline Toni , Barb Adam W. , Erwin Alice L. , Mansfield Bryce E. , McClerren Amanda L. , Pirrung Michael C. , Tumey L. Nathan , Warrener Paul , Raetz Christian R. H. , Stover C. Kendall
Published: May 2006

LpxC [UDP-3-
O-
(
R
-3-hydroxymyristoyl)-GlcNAc deacetylase] is a metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharide. A previous study (H. R. Onishi, B. A. Pelak, L. S. Gerckens, L. L. Silver, F. M. Kahan, M. H. Chen, A. A. Patchett, S. M. Galloway, S. A. Hyland, M. S. Anderson, and C. R. H. Raetz, Science 274:980-982, 1996) identified a series of synthetic LpxC-inhibitory molecules that were bactericidal for
Escherichia coli
. These molecules did not inhibit the growth of
Pseudomonas aeruginosa
and were therefore not developed further as antibacterial drugs. The inactivity of the LpxC inhibitors for
P. aeruginosa
raised the possibility that LpxC activity might not be essential for all gram-negative bacteria. By placing the
lpxC
gene of
P. aeruginosa
under tight control of an arabinose-inducible promoter, we demonstrated the essentiality of LpxC activity for
P. aeruginosa
. It was found that compound L-161,240, the most potent inhibitor from the previous study, was active against a
P. aeruginosa
construct in which the endogenous
lpxC
gene was inactivated and in which LpxC activity was supplied by the
lpxC
gene from
E. coli
. Conversely, an
E. coli
construct in which growth was dependent on the
P. aeruginosa lpxC
gene was resistant to the compound. The differential activities of L-161,240 against the two bacterial species are thus the result primarily of greater potency toward the
E. coli
enzyme rather than of differences in the intrinsic resistance of the bacteria toward antibacterial compounds due to permeability or efflux. These data validate
P. aeruginosa
LpxC as a target for novel antibiotic drugs and should help direct the design of inhibitors against clinically important gram-negative bacteria.
Antipneumococcal Activity of DW-224a, a New Quinolone, Compared to Those of Eight Other Agents
Authors: Kosowska-Shick Klaudia , Credito Kim , Pankuch Glenn A. , Lin Gengrong , Bozdogan Bülent , McGhee Pamela , Dewasse Bonifacio , Choi Dong-Rack , Ryu Jei Man , Appelbaum Peter C.
Published: May 2006

DW-224a is a new broad-spectrum quinolone with excellent antipneumococcal activity. Agar dilution MIC was used to test the activity of DW-224a compared to those of penicillin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin against 353 quinolone-susceptible pneumococci. The MICs of 29 quinolone-resistant pneumococci with defined quinolone resistance mechanisms against seven quinolones and an efflux mechanism were also tested. DW-224a was the most potent quinolone against quinolone-susceptible pneumococci (MIC
50
, 0.016 μg/ml; MIC
90
, 0.03 μg/ml), followed by gemifloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. β-Lactam MICs rose with those of penicillin G, and azithromycin resistance was seen mainly in strains with raised penicillin G MICs. Against the 29 quinolone-resistant strains, DW-224a had the lowest MICs (0.06 to 1 μg/ml) compared to those of gemifloxacin, clinafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. DW-224a at 2× MIC was bactericidal after 24 h against eight of nine strains tested. Other quinolones gave similar kill kinetics relative to higher MICs. Serial passages of nine strains in the presence of sub-MIC concentrations of DW-224a, moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin were performed. DW-224a yielded resistant clones similar to moxifloxacin and gemifloxacin but also yielded lower MICs. Azithromycin selected resistant clones in three of the five parents tested. Amoxicillin-clavulanate and cefuroxime did not yield resistant clones after 50 days.
Pharmacokinetics and Safety of Oral Posaconazole in Neutropenic Stem Cell Transplant Recipients
Authors: Gubbins Paul O. , Krishna Gopal , Sansone-Parsons Angela , Penzak Scott R. , Dong Li , Martinho Monika , Anaissie Elias J.
Published: May 2006

The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC
0-24
), was 1.96 mg · h/liter in group I and was 51% higher in group II and in group III. Increases in AUC
0-24
and maximum plasma concentration (
C
max
) in groups II and III were dose related. The AUC
0-24
and
C
max
values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC
0-24
and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and
C
max
) at steady state (
P
= 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.