bluuebunny/crossref_metadata_2025 huggingface dataset:
Antifungal activity of galanin‐ message‐ associated peptide and neuropeptide Y against different non‐albicansCandida strains
Authors: Rauch I. , Holzmeister S. , Hell M. , Sperl W. , Kofler B.
Published: June 2008

Introduction:  Additional to C. albicans, in the last years several non‐albicansCandida strains evolved to be a serious clinical problem. A certain challenge is the frequent resistance of these strains to common antifungal agents. Antimicrobial peptides (AMPs) participate in the innate immune response by providing a rapid first line defence against infection, thereby showing different mechanisms of action than antibiotic agents already used in the clinic. The neuropeptides galanin‐ message associated peptide (GMAP) and neuropeptide Y (NPY) are expressed by neuronal and non‐neuronal tissues in various organs including the skin, which constitutes the first barrier against external stress. Both peptides have been shown to affect Candida albicans growth. Therefore, we tested whether GMAP and NPY exhibit a growth‐inhibiting effect also against clinical isolates of non‐albicansCandida strains.

Methods:  A cell viability assay was used to examine microbial growth of C. parapsilosis, C. krusei, C. glabrata, C. tropicalis, C. lusitaniae and C. utilis.

Results:  We could demonstrate that GMAP and NPY possess growth‐inhibiting activity against Candida strains tested. Interestingly there was a high variability, in some cases even between different isolates of the same strain. GMAP was effective against C. krusei and C. utilis. Antifungal activity against C. tropicalis, C. lusitaniae, C. glabrata and C. parapsilosis depended on the isolate. NPY inhibited growth of C. krusei, C. tropicalis and C. utilis and to some extend C. lusitaniae and C. parapsilosis.

Conclusion:  We demonstrate here that GMAP and NPY are also effective against certain non‐albicansCandida strains. With growing numbers of resistant strains, these antimicrobial neuropeptides could be lead to new prophylactic and therapeutic strategies of Candida infections.

Supported by grants of the Jubiläumsfonds (Nr. 11996) and the Paracelsus Private Medical University (Nr.05/01/003).
Progression of malignant melanoma is associated with reduced 25‐hydroxyvitamin D serum levels
Authors: Nürnberg B. , Schadendorf D. , Gärtner B. , Pföhler C. , Herrmann W. , Tilgen W. , Reichrath J.
Published: June 2008

Solar UV‐exposure, particularly intensive short‐time and recreational sun exposure, is considered to be the major etiologic factor for melanoma. But on the other hand 90% of all requisite vitamin D has to be formed in the skin through the action of the sun – a serious problem due to the fact that new scientific findings convincingly demonstrate vitamin D deficiency to be associated with a variety of severe diseases including various types of cancer (e.g. colon, prostate and breast cancer). According to recent reports sun exposure is associated with a relatively favorable prognosis and increased survival rate in various malignancies, including malignant melanoma. It has been speculated that these findings were related to UV exposure‐induced relatively high serum levels of vitamin D which may lead to a more favorable course of melanoma. To prove this hypothesis the present study aimed to correlate the serum level of 25‐hydroxyvitamin D (which represents the readily measurable ‘storage’ precursor form of vitamin D) with tumor thickness at time of diagnosis and course of disease in patients with melanoma. The study population consisted of 212 patients with histologically proven cutaneous melanomas of different stages: stage I (n = 50); stage II (n = 20); stage III (n = 20); stage IV (n = 122). Basal 25‐hydroxyvitamin D levels were analyzed (DiaSorin LIAISON 25‐OH Vitamin D‐Assay) in those patients and compared with a control group (n = 80). Additionally, each participant was requested to fill out a questionnaire about the history of sun exposure. Interestingly, basal 25‐hydroxyvitamin D levels were lower in melanoma patients as compared to the control group, although this difference was statistically not significant. Moreover, progression of malignant melanoma was associated with statistically significantly reduced 25‐hydroxyvitamin D serum levels. In conclusion, our findings add to the growing body of evidence that 25‐hydroxyvitamin D serum levels may be of importance for pathogenesis and progression of malignant melanoma.
Guest lecture: ‘Love at first smell: olfactory neurons with MHC‐like peptide binding properties’
Authors: Leinders‐Zufall Trese
Published: June 2008

Social interactions, such as finding and identifying a mate, often rely on the ability to sense molecular cues carrying information about genetic relationship and individuality. Genes residing in the major histocompatibility complex (MHC) influence body odor and reproductive decisions in many vertebrate species. In mice, the olfactory sensory neurons respond to small peptides that also serve as ligands of MHC molecules. These MHC peptides constitute a large family of social recognition signals detected by sensory neurons in at least two olfactory subsystems, the mammalian main and the accessory olfactory systems. Interestingly, MHC peptides can be detected at extremely low concentrations, in the picomolar range, suggesting that specific mechanisms have evolved in the mammalian nose to assess the structural diversity of these molecules. Our results suggest a novel mechanism explaining the enigmatic influence of MHC genotypic diversity on behavior. This discovery proposes a mechanism by which animals identify other individuals of their species based on the unique structures of their immune‐system proteins.
The Ca2+ binding capacity of epidermal furin is disrupted by H2O2‐mediated oxidation in vitiligo
Authors: Spencer J. D. , Gibbons N. C. J. , Böhm M. , Schallreuter K. U.
Published: June 2008

It was previously established that epidermal keratinocytes and melanosomes express the Ca2+‐dependent precursor convertase furin. All prohormone convertases including furin are regulated by Ca2+. Meanwhile, it is noteworthy that proopiomelanocortin (POMC) cleavage is processed by furin, in addition to the classical PC1 and PC2 convertases, leading to the production of ACTH, β‐LPH and β‐endorphin. Since numerous epidermal peptides and enzymes are affected by H2O2‐mediatedoxidation, including the POMC derived peptides α‐MSH and β‐endorphin, as shown in the epidermis of patients with vitiligo, it was of interest whether furin could also be a possible target for this oxidation mechanism. Confirming the presence of furin in epidermal keratinocytes and melanocytes using immunoflurescence, RT‐PCR, and Western blotting, we further demonstrate significantly decreased in situ immunoreactivity of furin in the epidermis of patients with progressive vitiligo suggesting H2O2‐mediated oxidation. This was substantiated by [45Ca2+] binding studies with human recombinant furin identifying the loss of one Ca2+‐binding site from the enzyme after oxidation with H2O2. Computer simulation supported alteration of one of the two Ca2+‐binding sites on furin. Overall, our results demonstrate that the Ca2+ dependent proteolytic activity of this convertase is a target for H2O2‐mediated oxidation which in turn could contribute to the reduced epidermal expression of the POMC derived peptides α‐MSH and β‐endorphin as documented earlier in patients with vitiligo.
Corticotropin releasing hormone (CRH), melanocortins (MC) and thyrotropin releasing hormone (TRH) stimulate pigmentation and melanocyte function in the human hair follicle
Authors: Gáspár E. , Hardenbicker C. , Plate C. , Bodó E. , Hoting E. , Giesen M. , Paus R.
Published: June 2008

Melanocortins (MC) such as adrenocorticotropic hormon (ACTH) and α‐melanocyte‐stimulating hormone (αMSH) are neuropeptides derived from the prohormone proopiomelanocortin (POMC). It is now well established that the human skin is not only a target but also a local source for MCs. Almost all cutaneous cell types express MCs and MC‐receptor (MCRs) in vitro. The POMC peptides, their receptors and CRH the main inducer of POMC gene/protein expression in the pituitary and in skin ‐were also detected in human scalp hair follicles (HFs). MCs regulate pigmentation: stimulate melanogenesis, dendricity and proliferation in epidermal melanocytes, and similar effect was reported recently on cultured melanocytes derived from the outer root sheath of human HFs. TRH is the most proximal member of the hypothalamic‐pituitary‐thyroid (HPT) axis. In amphibian skin, TRH also regulates POMC release, which leads to skin darkening via αMSH‐MC1R interactions. Recently we found TRH and TRH‐R expression in human HFs. Therefore, we examined the – as yet ill‐explored – effect of exogenous CRH, ACTH, αMSH and TRH on melanin production, melanocytes number and dendricity in normal, microdissected, organ‐cultured human anagen scalp HFs. Melanin production was measured by quantitaive Masson‐Fontana histochemistry, and melanocyte dendricity were assessed by immunohistochemistry against the melanosome marker gp100 (Nki‐beteb). The melanin content increased significantly after αMSH (10–100 nM) and TRH(1–10 ng/ml) addition to the medium. Total Nki‐beteb immunoreactivity was significantly elevated in the HF melanocytes treated with αMSH, thus confirming the Masson‐Fontana results. TRH, CRH (10 nM–100 pM) and MC (10–100 nM) also stimulated dendrite formation of HF pigmentary unit melanocytes. CRH, MCs and TRH as well were able to compensate the significant decline of the melanin content caused by catagen induction with TGFβ2. This provides unequivocal evidence that CRH, ACTH and a‐MSH stimulate normal human hair follicle pigmentation in situ. We also show for first time that TRH, a key regulator of pigmentation in amphibian skin, might play similar role in human HF.
Variables that predict admission to hospital from an emergency department observation unit
Authors: Chan Trevor , Arendts Glenn , Stevens Mary
Published: June 2008

Objective:  To determine factors predictive for patients requiring ongoing hospital admission from the emergency department observation unit (EDOU).

Methods:  Prospective observational study on all patients admitted to the EDOU over 3 months. The primary outcome measure was patients requiring subsequent admission to hospital from the EDOU.

Results:  Of 860 EDOU admissions occurring from 8337 ED presentations, 145 (16.9%) were subsequently admitted as inpatients. Of all analysed variables, four (inability to independently mobilize in the ED, requiring ongoing active treatment while in the EDOU, requiring referral to another subspecialty prior to transfer to the EDOU and requiring multidisciplinary allied health assessment while in the EDOU) were significantly associated with admission to hospital.

Conclusions:  Variables exist that predict a ‘failed’ short stay admission. These might be used to identify patients less suitable for admission to the EDOU and better suited to admission directly under a hospital team.
Teaching paediatric resuscitation skills in a developing country: Introduction of the Advanced Paediatric Life Support course into Vietnam
Authors: Young Simon , Hutchinson Adrian , Nguyen Van Tu , Le Thanh Hai , Nguyen Dich Van , Vo Thi Kim Hue
Published: June 2008

In 2001, a nationwide study revealed deficiencies in the emergency care of seriously ill and injured children in Vietnam. In response, a project was initiated to conduct the Advanced Paediatric Life Support course in Vietnam and ascertain whether this course would provide a practical and sustainable method of improving the knowledge and skills of medical and nursing staff in this area. After approval to use the course was secured and funding obtained, the project commenced in 2003. Key Vietnamese personnel travelled to Australia to complete the course, undertake instructor training and gain organizational experience. Teaching materials were translated, reviewed and modified to account for local diseases and clinical practices while maintaining the fundamental principles of the parent course. Commencing in March 2004, 10 courses were conducted by Australian and Vietnamese instructors, training 239 doctors and nurses from a wide variety of clinical backgrounds. Additionally, three instructor courses were conducted, training 52 new instructors. As the skill and confidence of the Vietnamese instructors grew, the number and responsibilities of the international faculty reduced. The infrastructure now exists for the course to operate in a sustainable fashion within Vietnam. We believe that this project demonstrates that the course can be successfully modified to provide teaching in paediatric emergency care in a developing country.
Increasing cause of cough among adults
Authors: Boulouffe Caroline , Vanpee Dominique
Published: June 2008

Cough is a frequent reason for ED consultation. When one considers the epidemiological data, whooping cough must be considered in the differential of subacute cough. Clinical symptomatology is slightly different in the adult and unvaccinated child. An infection by Bordetella pertussis should be suspected when the history shows a persistent cough for more than 1 week in conjunction with other clinical elements. Several methods are available to establish a diagnosis: culture, PCR and bacterial serology. An early diagnosis will allow effective treatment, limit the transmission to unvaccinated infants, reduce complications and prevent extensive and expensive check‐ups for chronic cough.
Changes of Cerebral Current Source by Audiovisual Erotic Stimuli in Premature Ejaculation Patients
Authors: Hyun Jae-Seog , Kam Sung-Chul , Kwon Oh-Young
Published: June 2008

Introduction

Premature ejaculation (PE) is one of the most common forms of male sexual dysfunction. The mechanisms of PE remain poorly understood, despite its high prevalence.

Aim

To investigate the pathophysiology and casuses of PE in the central nervous system, we tried to observe the changes in brain current source distribution by audiovisual induction of sexual arousal.

Methods

Electroencephalograpies were recorded in patients with PE (45.0 ± 10.3 years old, N=18) and in controls (45.6 ± 9.8 years old, N=18) during four 10-minute segments of resting, watching a music video excerpt, resting, and watching an erotic video excerpt. Five artifact-free 5-second segments were used to obtain cross-spectral low-resolution brain electromagnetic tomography (LORETA) images.

Main Outcome Measures

Statistical nonparametric maps (SnPM) were obtained to detect the current density changes of six frequency bands between the erotic video session and the music video session in each group. Comparisons were also made between the two groups in the erotic video session.

Results

In the SnPM of each spectrum in patients with PE, the current source density of the alpha band was significantly reduced in the right precentral gyrus, the right insula, and both superior parietal lobules (P <0.01). Comparing the two groups in the erotic video session, the current densities of the beta-2 and -3 bands in the PE group were significantly decreased in the right parahippocampal gyrus and left middle temporal gyrus (P <0.01).

Conclusions

Neuronal activity in the right precental gyrus, the right insula, both the superior parietal lobule, the right parahippocampal gyrus, and the left middle temporal gyrus may be decreased in PE patients upon sexual arousal. Further studies are needed to evaluate the meaning of decreased neuronal activities in PE patients.
Prevalence, Severity, and Risk Factors for Erectile Dysfunction in a Representative Sample of 3,548 Portuguese Men Aged 40 to 69 Years Attending Primary Healthcare Centers: Results of the Portuguese Erectile Dysfunction Study
Authors: Teles Alberto Galvão , Carreira Mário , Alarcão Violeta , Sociol. D. , Aragüés José Maria , Lopes Luís , Mascarenhas Mário , Costa Joaquim Garcia e
Published: June 2008

Introduction

Many studies of the prevalence of erectile dysfunction have been conducted in several countries. This is the first Portuguese study that provides current and comparative data on the prevalence of erectile dysfunction.

Aim

The main objective was to estimate the prevalence of erectile dysfunction in men aged 40 to 69 years and correlate erectile dysfunction to certain risk factors.

Main Outcome Measures

Evaluation of erectile dysfunction was achieved using the International Index of Erectile Function (IIEF), a 15-item questionnaire that has been developed and validated as a brief and reliable self-administered scale for accessing erectile function.

Methods

The Portuguese Erectile Dysfunction Study was based on a questionnaire that included socio-demographic variables, information on lifestyle and risk factors, and the IIEF. In total, 3,548 questionnaires were administered to men aged 40 to 69 years in 50 primary healthcare centers between July 2004 and January 2005 in a combination of both self-administration and interviews. Erectile dysfunction was defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse.

Results

The response rate was 81.3%. The total prevalence of erectile dysfunction was 48.1% (age-adjusted). Prevalence increases with age: 29%, 50%, and 74% in men aged 40 to 49 years, 50 to 59 years, and 60 to 69 years, respectively. Severity of erectile dysfunction also increases with age: 1%, 2%, and 10% of complete erectile dysfunction in men aged 40 to 49 years, 50 to 59 years, and 60 to 69 years, respectively.

Conclusions

The prevalence of erectile dysfunction is strongly related to age. There is also a correlation with the health status of participants.
Negative Impact of Metabolic Syndrome on the Responsiveness to Sildenafil in Japanese Men
Authors: Suetomi Takahiro , Kawai Koji , Hinotsu Shiro , Joraku Akira , Oikawa Takehiro , Sekido Noritoshi , Miyanaga Naoto , Shimazui Toru , Akaza Hideyuki
Published: June 2008

Introduction

Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS).

Aim

We analyzed the impact of MS on the responsiveness to sildenafil.

Methods

A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil.

Main Outcome Measures

To clarify the negative impact of MS on the responsiveness to sildenafil.

Results

The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17–9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population.

Conclusion

We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased.
Alternate-Day Tadalafil in the Management of Honeymoon Impotence
Authors: Ghanem Hussein , El-Dakhly Mohamed , Shamloul Rany
Published: June 2008

Introduction

Sildenafil has been used successfully in the treatment of honeymoon impotence. However, no study investigated the potential effect of tadalafil in the treatment of honeymoon impotence.

Aim

The aim of this study is to evaluate the effectiveness of alternate-day tadalafil therapy in the management of unconsummated marriages.

Methods

This is a descriptive study comprised of a series of 45 patients. The time frame for the study was 2 years. Forty-five consecutive patients underwent a complete medical and sexual history as well as a focused physical examination. Education about the male and female genital anatomy and the sexual response cycle was carried out. Alternate-day tadalafil 10-mg therapy was administered for 2 weeks with the duration extended as needed.

Main Outcome Measures

Primary efficacy endpoints were successful vaginal intromission and change in the abridged version of the International Index of Erectile Function (IIEF-5).

Results

Of 45 patients included in our study, 41 (91%) were able to achieve vaginal intromission and perform sexually. Thirty-four patients (76%) needed tadalafil for less than 1 month, five (11%) for up to 3 months, and two (4%) for more than 3 months. Four patients (9%) were unsuccessful. IIEF-5 improved significantly with alternate-day tadalafil treatment in this subgroup of patients (P <0.001). Treatment failures were managed by intracavernous injection therapy, combined with psychosexual therapy, depending on the cause.

Conclusions

Tadalafil therapy was safe and effective in the short-term management of this selected group of honeymoon impotence patients. Controlled studies are needed to further confirm these findings.
X-ray flares, neutrino-cooled discs and the dynamics of late accretion in gamma-ray burst engines
Authors: Lazzati Davide , Perna Rosalba , Begelman Mitchell C.
Published: June 2008

We compute the average luminosity of X-ray flares as a function of time, for a sample of 10 long-duration gamma-ray burst (GRB) afterglows. The mean luminosity, averaged over a time-scale longer than the duration of the individual flares, declines as a power law in time with index approximately -1.5. We elaborate on the properties of the central engine that can produce such a decline. Assuming that the engine is an accreting compact object, and for a standard conversion factor between accretion rate and jet luminosity, the switch between a neutrino-cooled thin disc and a non-cooled thick disc takes place at the transition from the prompt to the flaring phase. We discuss the implications of this coincidence under different scenarios for the powering of the GRB outflow. We also show that the interaction of the outflow with the envelope of the progenitor star cannot produce flares out of a continuous relativistic flow, and conclude that it is the dynamics of the disc or the jet launching mechanism that generates an intrinsically unsteady outflow on time-scales much longer than the dynamical time-scale of the system. This is consistent with the fact that X-ray flares are observed in short-duration GRBs as well as in long-duration ones.
Slug Test Analysis to Evaluate Permeability of Compressible Materials
Authors: Choi Hangseok , Nguyen The‐Bao , Lee Chulho
Published: June 2008

The line‐fitting methods such as the Hvorslev method and the Bouwer and Rice method provide a rapid and simple means to analyze slug test data for estimating in situ hydraulic conductivity (k) of geologic materials. However, when analyzing a slug test in a relatively compressible geologic formation, these conventional methods may have difficulties fitting a straight line to the semilogarithmic plot of the test data. Data from relatively compressible geologic formations frequently show a concave‐upward curvature because of the effect of the compressibility or specific storage (Ss). To take into account the compressibility of geologic formations, a modified line‐fitting method is introduced, which expands on Chirlin’s (1989) approach to the case of a partially penetrating well with the basic‐time‐lag fitting method. A case study for a compressible till is made to verify the proposed method by comparing the results from the proposed methods with those obtained using a type‐curve method (Kansas Geological Survey method [Hyder et al. 1994]).
Basin‐Scale Transmissivity and Storativity Estimation Using Hydraulic Tomography
Authors: Kuhlman Kristopher L , Hinnell Andrew C. , Mishra Phoolendra K. , Yeh Tian‐Chyi Jim
Published: June 2008

While tomographic inversion has been successfully applied to laboratory‐ and field‐scale tests, here we address the new issue of scale that arises when extending the method to a basin. Specifically, we apply the hydraulic tomography (HT) concept to jointly interpret four multiwell aquifer tests in a synthetic basin to illustrate the superiority of this approach to a more traditional Theis analysis of the same tests. Transmissivity and storativity are estimated for each element of a regional numerical model using the geostatistically based sequential successive linear estimator (SSLE) inverse solution method. We find that HT inversion is an effective strategy for incorporating data from potentially disparate aquifer tests into a basin‐wide aquifer property estimate. The robustness of the SSLE algorithm is investigated by considering the effects of noisy observations, changing the variance of the true aquifer parameters, and supplying incorrect initial and boundary conditions to the inverse model. Ground water flow velocities and total confined storage are used as metrics to compare true and estimated parameter fields; they quantify the effectiveness of HT and SSLE compared to a Theis solution methodology. We discuss alternative software that can be used for implementing tomography inversion.
Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat
Authors: Jansson R. , Malm M. , Roth C. , Ashton M.
Published: June 2008

This study aimed to investigate if the absorption of the human African trypanosomiasis agent eflornithine was stereospecific and dose dependent after oral administration. Male Sprague-Dawley rats were administered single doses of racemic eflornithine hydrochloride as an oral solution (750, 1,500, 2,000, or 3,000 mg/kg of body weight) or intravenously (375 or 1,000 mg/kg of body weight). Sparse blood samples were obtained for determination of eflornithine enantiomers by liquid chromatography with evaporative light-scattering detection (lower limit of quantification [LLOQ], 83 μM for 300 μl plasma). The full plasma concentration-time profile of racemic eflornithine following frequent sampling was determined for another group of rats, using a high-performance liquid chromatography-UV method (LLOQ, 5 μM for 50 μl plasma). Pharmacokinetic data were analyzed in NONMEM for the combined racemic and enantiomeric concentrations. Upon intravenous administration, the plasma concentration-time profile of eflornithine was biphasic, with marginal differences in enantiomer kinetics (mean clearances of 14.5 and 12.6 ml/min/kg forl- andd-eflornithine, respectively). The complex absorption kinetics were modeled with a number of transit compartments to account for delayed absorption, transferring the drug into an absorption compartment from which the rate of influx was saturable. The mean bioavailabilities forl- andd-eflornithine were 41% and 62%, respectively, in the dose range of 750 to 2,000 mg/kg of body weight, with suggested increases to 47% and 83%, respectively, after a dose of 3,000 mg/kg of body weight. Eflornithine exhibited enantioselective absorption, with the more potentl-isomer being less favored, a finding which may help to explain why clinical attempts to develop an oral treatment have hitherto failed. The mechanistic explanation for the stereoselective absorption remains unclear.
Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors
Authors: Miller Alita A. , Bundy Gordon L. , Mott John E. , Skepner Jill E. , Boyle Timothy P. , Harris Douglas W. , Hromockyj Alexander E. , Marotti Keith R. , Zurenko Gary E. , Munzner Jennifer B. , Sweeney Michael T. , Bammert Gary F. , Hamel Judith C. , Ford Charles W. , Zhong Wei-Zhu , Graber David R. , Martin Gary E. , Han Fusen , Dolak Lester A. , Seest Eric P. , Ruble J. Craig , Kamilar Gregg M. , Palmer John R. , Banitt Lee S. , Hurd Alexander R. , Barbachyn Michael R.
Published: June 2008

QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (−)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the β subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.
Relationship between Various Definitions of Prior Antibiotic Exposure and Piperacillin-Tazobactam Resistance among Patients with Respiratory Tract Infections Caused by
Pseudomonas aeruginosa
Authors: Patel Nimish , McNutt Louise-Anne , Lodise Thomas P.
Published: June 2008

Contemporary literature lacks a definition of prior antibiotic exposure which captures all patients at risk of developing piperacillin-tazobactam-resistant
Pseudomonas aeruginosa
(PTR-PA). The results indicated that individual antibiotics that are associated with PTR-PA differ depending on the definition of prior antibiotic exposure utilized. When the specific antibiotic used was replaced by the number of prior exposures, the number of exposures was the only variable associated with an increased risk of antibiotic resistance at each time threshold.
Emergence of Macrolide Resistance Gene
mph
(B) in
Streptococcus uberis
and Cooperative Effects with
rdmC
-Like Gene
Authors: Achard Adeline , Guérin-Faublée Véronique , Pichereau Vianney , Villers Corinne , Leclercq Roland
Published: June 2008

Streptococcus uberis
UCN60 was resistant to spiramycin (MIC = 8 μg/ml) but susceptible to erythromycin (MIC = 0.06 μg/ml), azithromycin (MIC = 0.12 μg/ml), josamycin (MIC = 0.25 μg/ml), and tylosin (MIC = 0.5 μg/ml). A 2.5-kb HindIII fragment was cloned from
S. uberis
UCN60 DNA on plasmid pUC18 and introduced into
Escherichia coli
AG100A, where it conferred resistance to spiramycin by inactivation. The sequence analysis of the fragment showed the presence of an
rdmC
-like gene that putatively encoded a protein belonging to the alpha/beta hydrolase family and of the first 196 nucleotides of the
mph
(B) gene putatively encoding a phosphotransferase known to inactivate 14-, 15-, and 16-membered macrolides in
E. coli
. The entire
mph
(B) gene was then identified in
S. uberis
UCN60. The two genes were expressed alone or in combination in
E. coli
,
Staphylococcus aureus
, and
Enterococcus faecalis
. Analysis of MICs revealed that
rdmC
-like alone did not confer resistance to erythromycin, tylosin, and josamycin in those three hosts. It conferred resistance to spiramycin in
E. coli
and
E. faecalis
but not in
S. aureus. mph
(B) conferred resistance in
E. coli
to erythromycin, tylosin, josamycin, and spiramycin but only low levels of resistance in
E. faecalis
and
S. aureus
to spiramycin (MIC = 8 μg/ml). The combination of
mph
(B) and
rdmC
-like genes resulted in a resistance to spiramycin and tylosin in the three hosts that significantly exceeded the mere addition of the resistance levels conferred by each resistance mechanism alone.
Pharmacodynamics of Minocycline against
Staphylococcus aureus
in an In Vitro Pharmacokinetic Model
Authors: Bowker Karen E. , Noel Alan R. , MacGowan Alasdair P.
Published: June 2008

Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant
Staphylococcus aureus
(MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log
10
-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (
P
< 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with
r
2
of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and −1-log-unit, −2-log-unit, and −3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.
Plasmid-Mediated
qnrB2
and Carbapenemase Gene
bla
KPC-2
Carried on the Same Plasmid in Carbapenem-Resistant Ciprofloxacin-Susceptible
Enterobacter cloacae
Isolates
Authors: Chmelnitsky Inna , Navon-Venezia Shiri , Strahilevitz Jacob , Carmeli Yehuda
Published: June 2008

Fourteen out of 16 carbapenem-resistant quinolone-susceptible
Enterobacter cloacae
isolates were found to carry
qnrB2
and
bla
KPC-2
genes encoded on the same plasmid. One isolate also carried the
aac(6
′)-
Ib-cr
gene. Coexistence of quinolone resistance determinants and
bla
KPC-2
on the same plasmid in quinolone-susceptible
E. cloacae
isolates may have important clinical implications.
Oral Vaccination of Guinea Pigs with aMycobacterium bovisBacillus Calmette-Guérin Vaccine in a Lipid Matrix Protects against Aerosol Infection with VirulentM. bovis
Authors: Clark Simon , Cross Martin L. , Nadian Allan , Vipond Julia , Court Pinar , Williams Ann , Hewinson R. Glyn , Aldwell Frank E. , Chambers Mark A.
Published: June 2008

Increased incidence of bovine tuberculosis (TB) in the United Kingdom caused by infection withMycobacterium bovisis a cause of considerable economic loss to farmers and the government. The Eurasian badger (Meles meles) represents a wildlife source of recurrentM. bovisinfections of cattle in the United Kingdom, and its vaccination against TB withM. bovisbacillus Calmette-Guérin (BCG) is an attractive disease control option. Delivery of BCG in oral bait holds the best prospect for vaccinating badgers over a wide geographical area. Using a guinea pig pulmonary challenge model, we evaluated the protective efficacy of candidate badger oral vaccines, based on broth-grown or ball-milled BCG, delivered either as aqueous suspensions or formulated in two lipids with differing fatty acid profiles (one being animal derived and the other being vegetable derived). Protection was determined in terms of increasing body weight after aerosol challenge with virulentM. bovis, reduced dissemination ofM. bovisto the spleen, and, in the case of one oral formulation, restricted growth ofM. bovisin the lungs. Only oral BCG formulated in lipid gave significant protection. These data point to the potential of the BCG-lipid formulation for further development as a tool for controlling tuberculosis in badgers.
Personality disorders and nonfatal unintentional injuries among US adults
Authors: Chen G , Sinclair S , Smith G A , Kelleher K , Pajer K A , Gardner W , Xiang H
Published: June 2008

Objective:

To investigate the association between personality disorders and nonfatal unintentional injuries in a representative sample of US adults.

Methods:

Data on self-reported nonfatal unintentional injuries during the 12 months before the interview were obtained from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were analyzed; 43 093 adults ⩾18 years participated in the NESARC wave I survey in 2001–02. Personality disorders were determined using the NIAAA Alcohol Use Disorders and Associated Disabilities Interview Schedule-DSM-IV.

Results:

Individuals with at least one personality disorder had a significantly higher 12-month incidence of injuries than people without any personality disorder (p<0.001). After accounting for sociodemographic characteristics or other mental disorders, OR was 1.54 (95% CI 1.39 to 1.71) for individuals with one personality disorder and 1.80 (95% CI 1.58 to 2.05) for individuals with two or more personality disorders compared with people with no personality disorder.

Conclusion:

Personality disorders were associated with a significantly increased risk of unintentional injuries. This information has important implications for the treatment of patients with these disorders.
Traffic and the risk of vehicle-related pedestrian injury: a decision analytic support tool
Authors: Chalabi Z , Roberts I , Edwards P , Dowie J
Published: June 2008

Background:

Pedestrian injuries are a leading cause of death and disability. Transport policy decisions have a major impact on the risk of pedestrian injury, but the effects cannot usually be quantified in controlled studies. However, mathematical modeling can help to establish the injury consequences of transport policy decisions.

Methods:

A stochastic mathematical model was developed to estimate the effect of alternative transport scenarios on pedestrian injury risk. The model is based on a mechanistic description of pedestrian injury causation and comprises four sub-models: vehicle dynamics, pedestrian dynamics, collision incidence, and injury severity.

Results:

The model was used to estimate the yearly pedestrian injury rate for a baseline scenario, corresponding to current traffic conditions in London, UK, and three alternative scenarios, comprising reductions in vehicle speed, traffic volume, and vehicle mass. The model simulated a baseline injury rate of 88 per 100 000. Compared with baseline, a 15% reduction in mean speed resulted in a 21% reduction in injury rate and a 75% reduction in fatality rate. A 15% reduction in traffic volume resulted in a 14% reduction in injury rate and a 25% reduction in fatality rate. Reducing vehicle mass by 15% did not reduce the number of injuries, but a 25% reduction resulted in less severe injuries.

Conclusions:

The model simulated well the rates and severity of pedestrian injury corresponding to the baseline scenario and made predictions for different transport policy scenarios. However, it is offered primarily as a generic decision support tool for the assessment of alternative policies by transport authorities.
Restraining orders among victims of intimate partner homicide
Authors: Vittes K A , Sorenson S B
Published: June 2008

Background:

Most intimate partner homicides (IPHs) follow a long history of violence and occur while the victim is ending the relationship. Restraining orders are a common legal recourse by which to seek protection from an abusive partner. This study expands on prior research by examining the restraining order history of IPH victims by characteristics of the victim, assailant, and homicide.

Methods:

State-wide databases containing information about restraining orders and homicides were linked, and bivariate and multivariate statistics were then calculated to identify differences between IPH victims who had and had not been issued a restraining order.

Results:

About 11% of 231 women killed by male intimates had been issued a restraining order. About one-fifth of the female IPH victims who had a restraining order were killed within 2 days of the order being issued; about one-third were killed within a month. Nearly half of those with a restraining order had been protected by multiple orders. Victims killed in a shared residence (versus elsewhere) had lower odds of having a restraining order, whereas victims from rural (versus urban) counties, married (versus dating) victims, and Latino (versus non-Latino) victim–offender dyads had higher odds of having a restraining order. The type of weapon used was not associated with whether the victim had been under the protection of a restraining order.

Conclusions:

Most female IPH victims did not have a restraining order when they were killed. Further research is needed to determine whether restraining orders protect against IPH and, if they do, on how to increase their utilization.
Reducing black/white disparity: changes in injury mortality in the 15–24 year age group, United States, 1999–2005
Authors: Hu G , Baker S P
Published: June 2008

In 1999, the injury death rate for black males aged 15–24 in the USA was 80% greater than for white males: 148.5 vs 82.5/100 000, a difference of 66/100 000. Injury-specific changes between 1999 and 2005 in death rates for the 15–24 age group and in racial disparity were analysed using data from CDC’s WISQARS. The gap between black and white all-injury death rates in males was reduced by 24%, to a difference of 50/100 000, largely because of greater decreases in the rates for motor vehicle crashes and firearm suicide in young black men than young white men, and large increases in suicide by suffocation and unintentional poisoning in the latter. Among females, despite a reduction in the black/white gap in firearm homicide rates, the gap between the races in total injury rates changed from a small black excess to a higher rate in young white women, which was due primarily to greater increases in these white women than black women in unintentional poisoning and suicide by suffocation, and greater decreases in black women than white women in firearm suicide.
COCHLIOBOLUS SATIVUS: VI. ISOLATION OF NUTRITIONALLY EXACTING MUTANTS BY FILTRATION ENRICHMENT
Authors: Tinline R. D.
Published: June 2008

Nutritionally exacting mutants of Cochliobolus sativus, a fungus with multinucleate, multicellular spores, were readily isolated by a filtration enrichment method. The method is similar to one described by Fries and is based upon the differential growth of auxotrophs and prototrophs in minimal medium. Most of the prototrophic propagules were removed by filtration. Propagules in the filtrate were concentrated by centrifugation, plated on complete medium, and subsequently tested for nutritional requirements.In comparative studies on four methods of isolation, namely, total isolation, mass transfer; total isolation, hyphal-tip transfer; filtration enrichment, mass transfer; and filtration enrichment, hyphal-tip transfer, the yield of auxotrophic mutants was 0, 0.04, 1.16, and 1.83%, respectively.
CULTURAL STUDIES OF BOLETACEAE: CARPOPHORES OF PHLEBOPUS LIGNICOLA IN CULTURE
Authors: Pantidou Maria E.
Published: June 2008

Phlebopus lignicola (Kallenbach) Moser is the second species of Boletaceae to fruit in culture. The developmental stages and the histology of the fruit bodies are described and compared with those of Phlebopus sulphureus (Fr.) Singer.
A SIMPLIFIED PROCEDURE FOR DEMONSTRATING THE PARASEXUAL CYCLE IN ASPERGILLUS
Authors: Barron G. L. , MacNeill B. H.
Published: June 2008

A simplified procedure for demonstrating the parasexual cycle is presented. The sequence of laboratory experiments, using a conidial strain rather than an ascosporic strain of Aspergillus nidulans, requires a minimum of time and materials, and can be completed successfully within a 14-week period.
A METHOD FOR MEASURING SPECTRAL ENERGY DISTRIBUTION OF LIGHT SOURCES
Authors: McAllan J. W. , Wood F. A.
Published: June 2008

The method describes an inexpensive modification of the Beckman DU spectrophotometer which permits rapid recording of the spectral energy distribution reflected from a magnesium carbonate surface. Comparison with a standard tungsten source corrects the effects of selective reflectivity and phototube response to different wavelengths. The method should be useful to biologists interested in the effects of light on organisms.
VITAMIN REQUIREMENTS OF A LOW-TEMPERATURE BASIDIOMYCETE
Authors: Ward E. W. B.
Published: June 2008

The vitamin requirements of an unidentified basidiomycete, the cause of severe snow mold of grasses and legumes in Western Canada, have been determined in shake culture. In a medium composed of D-glucose, L-asparagine, and mineral salts, a mixture of several vitamins supported optimum growth, but an absolute requirement was demonstrated only for thiamine. Pyridoxine stimulated growth in the presence of thiamine. The optimum concentration of thiamine was 50 μg per liter and below this level growth was proportional to concentration. Pyridoxine was effective in the range 50–100 μg per liter in the presence of 50 μg per liter of thiamine. The requirement for thiamine could be satisfied by a mixture of equivalent amounts of thiazole and pyrimidine but not by either alone.
FUNGI FROM THE RHIZOSPHERE OF BANANA IN HONDURAS
Authors: Goos Roger D. , Timonin M. I.
Published: June 2008

A survey was made of fungi found in the rhizosphere, the rhizoplane, and macerated root tissue of the Gros Michel banana in a 60-year-old planting in Honduras. Fifty-one species of fungi, representing 37 genera, were isolated, among them three taxa, Pseudoarachniotus reticulatus, Preussia terricola, and Absidia cylindrospora var. rhizomorpha, described elsewhere as new. Verticillium theobromae, a known pathogen on aerial parts of banana, was isolated from both rhizosphere soil and the rhizoplane. Aspergillus versicolor, Nodulisporium sp., Periconia sp., and Scopulariopsis brevicaulis were isolated from root tissue, but were not found in either the rhizosphere or rhizoplane. Cylindrocarpon sp., Fusarium episphaeria, and Rhinocladiella sp. were found in both the rhizoplane and macerated root tissue, but were not found in rhizosphere soil. Memnoniella echinata, Myrothecium sp., Pyrenocheate sp., and Torula sp. were isolated only from the rhizoplane.
CHAETOMIUM ARCUATUM SPEC. NOV. AND C. LUCKNOWENSE SPEC. NOV.: TWO NEW SPECIES FROM INDIAN SOILS
Authors: Rai J. N. , Tewari J. P.
Published: June 2008

Two new species of Chaetomium Kunze and Schmidt, C. arcuatum spec. nov. and C. lucknowense spec. nov., isolated from Lucknow soil (pH 6.0–7.0), have been described.
SOME FUNGAL PARASITES OF ONAGRACEAE
Authors: Savile D. B. O.
Published: June 2008

Plasmopara latifolii sp. nov. and Mycosphaerella chamaenerii sp. nov. are described on Epilobium latifolium. Endophyllum alaskanum sp. nov. is described on Epilobium anagallidifolium. The host and morphological distinctions of Pucciniastrum epilobii and P. pustulatum are discussed. Host and geographic range extensions, particularly in Canada, are given for Synchytrium spp., Peronospora arthuri, Plasmopara epilobii, Erysiphe polygoni, Sphaerotheca macularis, Doassansia epilobii, Pucciniastrum spp., Puccinia veratri, P. circaeae, P. gigantea, P. scandica, P. epilobii ssp. palustris, Septoria oenotherae, and Ramularia montana.