bluuebunny/crossref_metadata_2025 huggingface dataset:
Whither the Responsibility to Protect? Humanitarian Intervention and the 2005 World Summit
Authors: Bellamy Alex J.
Published: July 2006

At the 2005 World Summit, the world‘s leaders committed themselves to the “responsibility to protect”, recognizing both that all states have a responsibility to protect their citizens from genocide, war crimes, ethnic cleansing and crimes against humanity and that the UN should help states to discharge this responsibility using either peaceful means or enforcement action. This declaration ostensibly marks an important milestone in the relationship between sovereignty and human rights but its critics argue that it will make little difference in practice to the world’s most threatened people. The purpose of this article is to ask how consensus was reached on the responsibility to protect, given continuing hostility to humanitarian intervention expressed by many (if not most) of the world‘s states and whether the consensus will contribute to avoiding future Kosovos (cases where the Security Council is deadlocked in the face of a humanitarian crises) and future Rwandas (cases where states lack the political will to intervene). It suggests that four key factors contributed to the consensus: pressure from proponents of the International Commission on Intervention and State Sovereignty, its adoption by Kofi Annan and the UN’s High Level Panel, an emerging consensus in the African Union, and the American position. Whilst these four factors contributed to consensus, each altered the meaning of the responsibility to protect in important ways, creating a doctrine that many states can sign up to but that does little to prevent future Kosovos and Rwandas and may actually inhibit attempts to build a consensus around intervention in future cases.
The Gendered Dimensions of Conflict's Aftermath: A Victim-Centered Approach to Compensation
Authors: Zeigler Sara L. , Gunderson Gregory Gilbert
Published: July 2006

Although international security studies tend to focus on the nature of armed conflict and how nations fare in the face of such conflicts, our attention has been drawn to the challenge of managing the peace. Specifically, given the enormity of the damage caused by state-sponsored violence, both in terms of property and in terms of human damage, how can the people of a nation that has served as a battleground be assisted in their recovery from the devastation caused by conflict? Ongoing trauma from armed conflict has peculiarly gendered dimensions and requires solutions that are attentive to those dimensions. Here, we focus on remedies that shift from perpetrator-centered tribunals to victim-centered compensation commissions. Using the United Nations Compensation Commission established to provide restitution to Kuwaiti citizens following the Iraqi invasion as an example, we argue that the restitution model is a more humane and ethical option for managing the aftermath of conflict than war crimes tribunals, which employ a retributive philosophy. Using the limited evidence available on compensation and rebuilding, we make concrete recommendations for an approach to post-conflict adjudication that makes the well-being of victims its top priority.
Rebalancing Growth in China: A Three‐Handed Approach
Authors: Blanchard Olivier , Giavazzi Francesco
Published: July 2006

The present paper is an attempt to define the contours of the right macroeconomic strategy for China. In a nutshell, we believe that the package includes a decrease in saving, with a focus on private saving, an increase in the supply of services, in particular health services, and an appreciation of the RMB. This is why we refer to this strategy as a “three‐handed approach”: action on the fiscal and budgetary front, accompanied by currency revaluation. We start by asking how the Chinese economy got to where it is, what the strategy has been since the beginning of the reforms, and what the main characteristics of the economy are today. We then ask what is the desirable path for the future, and which are the main policy trade‐offs implied by such a path. Finally, we put the various pieces together to describe what we believe is a consistent policy package.

(Edited by Xiaoming Feng)
Real Exchange Rate in China: A Long‐run Perspective
Authors: Gao Haihong
Published: July 2006

This paper investigates the RMB exchange rate from a long‐run viewpoint. Whether China's rapid economic growth brought about real exchange rate appreciation between 1975 and 2002 is empirically examined, based on a supply‐side model, the Balassa—Semuelson Hypothesis (BSH). The same test is conducted on Japan, Hong Kong, Korea, Malaysia, Singapore, Thailand, the Philippines, Indonesia and India. Our result indicates that the BSH only exists where the industrial structure has been upgraded and the economy has been successfully transformed from an agricultural economy to a manufacturing economy. Interestingly, China, among those where the BSH does not present, appears to be upgrading its industrial and trade structure. We then try to answer the question of why past rapid growth has no significant relationship with the RMB real exchange rate and what factors are underlying the trend of the RMB real exchange rate. We expect an appreciating trend of RMB real exchange rate in the foreseeable future, presuming that China's industrial upgrading process continues and the factors pertaining to the BSH's prediction, such as rise of wage rates in both tradables and nontradables, become more significant.

(Edited by Xiaoming Feng)
Global Energy and Environmental Impacts of an Expanding China
Authors: McKibbin Warwick J.
Published: July 2006

China accounts for 10 percent of global energy use and will continue to rely on coal for generating approximately 75 percent of its energy over coming decades. The environmental problems associated with coal burning are a concern for China as well as regionally and globally. The present paper summarizes China's energy structure and likely future energy requirements, while exploring the impact of energy use on air quality, black carbon emission, sulphur dioxide (SO2) emissions, and carbon dioxide emissions. Although China has begun to take action on local environmental problems from energy, there is still much to be done. In particular, the problem of black carbon and carbon dioxide emissions needs to be addressed. The present paper proposes addressing carbon dioxide emissions through a longer‐term strategy that acknowledges the need for China to continue to grow without a short‐term carbon constraint but with clear pricing of the short‐term and long‐term cost of carbon dioxide.

(Edited by Xiaoming Feng)
How we do it: The viability of free mucosal grafts on exposed bone in lacrimal surgery – a prospective study
Authors: Mahendran S. , Stevens‐King A. , Yung M.W.
Published: July 2006

Keypoints

• To ascertain viability of free mucosal of grafts on bare bone and degree of contracture in vivo.

• Prospective study to ascertain graft survival where a small piece of mucosa, with a single centrally placed prolene suture for future identification, removed during endoscopic dacrocystorhinostomy (DCR) was replaced to cover exposed bone at the end of the procedure. The presence of the graft and the degree of contracture was assessed endoscopically in outpatients at the second and fourth weeks.

• All patients who fulfilled the inclusion criteria who underwent DCR in the study period April–October 2002.

• All the grafts survived intact at 4 weeks after the operation. Grafts underwent up to 20% contracture over this period.

• Free mucosal grafts survive well when applied to denuded bone in DCR operation.
How we do it: Analysing GP referral priorities: the unforeseen effect of ‘Choose and Book’
Authors: Pothier D.D. , Repanos C. , Awad Z.
Published: July 2006

Keypoints

• The introduction of Choose and Book may have a significant effect on the proportion of urgent referrals seen by ENT surgeons.

• Much of the responsibility for prioritisation will be transferred to the GP.

• Patients who are considered urgent by the ENT surgeon will be added to those considered urgent by the GP.

• Our results show that there was little agreement between GPs and ENT surgeon on what constitutes an urgent referral.

• The combined effect of joint prioritisation and the removal of the ‘soon’ category resulted in a 270% increase in ‘urgent’ referrals in our sample.

• This potentially unforeseen consequence of the Choose and Book system should be taken into consideration by ENT departments to allow for an expansion of the ‘urgent’ category.
The significance of MRI findings for non‐rhinological disease*
Authors: McNeill E. , O'Hara J. , Carrie S.
Published: July 2006

Objectives:  Mucosal changes in the paranasal sinuses are detected in 30–50% of scans for non‐rhinological disease. This study assesses the relationship between symptoms of rhinosinusitis and radiological evidence of sinus pathology in patients undergoing magnetic resonance imaging (MRI) scans for unrelated pathology.

Design:  Prospective observational study, evaluating symptoms of rhinosinusitis in patients undergoing MRI scanning of the internal acoustic meati. A visual analogue scale (VAS) of rhinological symptoms was completed immediately before scanning, specifying symptoms present at the time of completing the questionnaire. Symptom scores were recorded by one of the investigators, blinded to the MRI images. Two investigators independently rated sinus mucosal thickening for each scan, both of whom were blinded to the symptom scores. Lund and Mackay scoring systems were used for both symptom and radiological scores, which were then compared.

Setting:  Otolaryngology and Radiology Departments in a large teaching hospital.

Participants:  Fifty consecutive patients were recruited over a 2‐month period.

Main outcome measures:  Visual analogue scale symptom scores were compared with radiological scores for sinus mucosal thickening.

Results:  No statistically significant relationship was demonstrated between rhinological symptoms and radiological features suggestive of rhinosinusitis in patients undergoing MRI scanning for non‐rhinological disease.

Conclusions:  The relationship between rhinological symptoms and MRI findings of sinus pathology is not straightforward. Management decisions should be made on the basis of nasal history and endoscopy, rather than radiological findings. This is the first study assessing this relationship by documenting symptoms on the day of scanning, using a validated scoring system.
Assessment of subjective scales for selection of patients for nasal septal surgery
Authors: Boyce J.M. , Eccles R.
Published: July 2006

Objective:  To investigate the use of subjective measures to assist the surgeon in patient selection for septal surgery.

Study design:  Prospective, observational. Approved by local ethics committee.

Setting:  ENT outpatient department, University Hospital of Wales.

Participants:  Forty‐six participants on the waiting list for septal surgery for nasal obstruction.

Main outcome measure:  Measurement of nasal partitioning of airflow by rhinospirometer (GM Instruments, Scotland), subjective scales, and investigator's assessment of septal deviation.

Results:  The subjective scores, and investigator's assessment of septal deviation, were compared with the rhinospirometer objective measurements for correlation, sensitivity and specificity. The rhinospirometry results showed that 20% of the patients on the waiting list had objective measures of partitioning of nasal airflow within a normal range for healthy subjects. The ordinal scale proved to be more useful than the visual analogue scale for patient selection. The subjective scores of airflow partitioning from the double ordinal scale correlated well with the rhinospirometry measurements (r = 0.8). The ordinal scale also had a sensitivity of 81% and a specificity of 60%. The investigator's subjective assessment of septal deviation had a high sensitivity at around 100% but had a lower specificity (30%).

Conclusions:  The use of a subjective ordinal scale to measure partitioning of airflow greatly increased the specificity of patient selection and it is proposed that this scale may be useful to the surgeon when assessing patients for septal surgery.
Reduced-Order Finite Element Models of Viscoelastically Damped Beams Through Internal Variables Projection
Authors: Trindade Marcelo A.
Published: July 2006

For a growing number of applications, the well-known passive viscoelastic constrained layer damping treatments need to be augmented by some active control technique. However, active controllers generally require time-domain modeling and are very sensitive to system changes while viscoelastic materials properties are highly frequency dependent. Hence, effective methods for time-domain modeling of viscoelastic damping are needed. This can be achieved through internal variables methods, such as the anelastic displacements fields and the Golla-Hughes-McTavish. Unfortunately, they increase considerably the order of the model as they add dissipative degrees of freedom to the system. Therefore, the dimension of the resulting augmented model must be reduced. Several researchers have presented successful methods to reduce the state space coupled system, resulting from a finite element structural model combined with an internal variables viscoelastic model. The present work presents an alternative two-step reduction method for such problems. The first reduction is applied to the second-order model, through a projection of the dissipative modes onto the structural modes. It is then followed by a second reduction applied to the resulting coupled state space model. The reduced-order models are compared in terms of performance and computational efficiency for a cantilever beam with a passive constrained layer damping treatment. Results show a reduction of up to 67% of added dissipative degrees of freedom at the first reduction step leading to much faster computations at the second reduction step.
Homogenization of Quasi-Periodic Structures
Authors: Andrianov Igor V. , Awrejcewicz Jan , Diskovsky Alexander A.
Published: July 2006

A novel asymptotical approach to integrate differential equations governing quasi-regular structures, particularly suitable on the stage of construction design, is proposed.
Granular Damping in Forced Vibration: Qualitative and Quantitative Analyses
Authors: Fang X. , Tang J.
Published: July 2006

Granular damping is a passive vibration suppression technique which attenuates the response of a vibrating structure by the use of a granule-filled enclosure attached to or embedded in the structure. While promising in many applications especially under harsh conditions, the granular damping mechanism is very complicated and highly nonlinear. In this paper, we perform correlated analytical modeling and numerical studies to evaluate qualitatively and quantitatively the energy dissipation in granular damping. First, an improved analytical model based on the multiphase flow theory is developed for the description of granular motion inside the damper, which accounts for the complete effects of collisions/impacts and dynamic frictions among the granules and between the granules and the enclosure. This model can efficiently characterize the damping effect with high fidelity over a very wide range of parameters, and thus can be used to develop guidelines for parametric studies. With this as a basis, detailed numerical studies using the discrete element method are also carried out to analyze the underlying mechanisms and then provide mechanistic insight for granular damping. In this paper, we focus our attention on the granular damping effect on forced vibrations, which has potential application to a variety of systems.
Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant
Mycobacterium tuberculosis
Authors: Hazbón Manzour Hernando , Brimacombe Michael , Bobadilla del Valle Miriam , Cavatore Magali , Guerrero Marta Inírida , Varma-Basil Mandira , Billman-Jacobe Helen , Lavender Caroline , Fyfe Janet , García-García Lourdes , León Clara Inés , Bose Mridula , Chaves Fernando , Murray Megan , Eisenach Kathleen D. , Sifuentes-Osornio José , Cave M. Donald , Ponce de León Alfredo , Alland David
Published: July 2006

The molecular basis for isoniazid resistance in
Mycobacterium tuberculosis
is complex. Putative isoniazid resistance mutations have been identified in
katG
,
ahpC
,
inhA
,
kasA
, and
ndh
. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical
M. tuberculosis
isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in
katG
,
ahpC
, and
inhA
were strongly associated with isoniazid resistance, while
kasA
mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in
katG
315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the
inhA
promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in
katG
,
ahpC
, and
inhA
were associated with rifampin resistance, but only
katG
315 mutations were associated with ethambutol resistance. There was also a significant inverse association between
katG
315 mutations and mutations in
ahpC
or
inhA
and between mutations in
kasA
and mutations in
ahpC
. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.
In Vitro Interactions between Piperaquine, Dihydroartemisinin, and Other Conventional and Novel Antimalarial Drugs
Authors: Davis Timothy M. E. , Hamzah Juliana , Ilett Kenneth F. , Karunajeewa Harin A. , Reeder John C. , Batty Kevin T. , Hackett Sara , Barrett P. Hugh R.
Published: July 2006

In an in vitro assessment of antimalarial combinations, dihydroartemisinin (DHA) showed no interaction or was mildly antagonistic when combined with piperaquine, pyronaridine, or naphthoquine. Interactions between 4-aminoquinolines and related drugs were also indifferent/antagonistic. The clinical significance of mildly antagonistic DHA combinations is uncertain but may become important if parasite drug sensitivity declines.
Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge
Authors: Steffen H. , Rieg S. , Wiedemann I. , Kalbacher H. , Deeg M. , Sahl H.-G. , Peschel A. , Götz F. , Garbe C. , Schittek B.
Published: July 2006

Dermcidin (DCD) is a recently described antimicrobial peptide, which is constitutively expressed in eccrine sweat glands and transported via sweat to the epidermal surface. By postsecretory proteolytic processing in sweat the dermcidin protein gives rise to several truncated DCD peptides which differ in length and net charge. In order to understand the mechanism of antimicrobial activity, we analyzed the spectrum of activity of several naturally processed dermcidin-derived peptides, the secondary structure in different solvents, and the ability of these peptides to interact with or permeabilize the bacterial membrane. Interestingly, although all naturally processed DCD peptides can adopt an α-helical conformation in solvents, they have a diverse and partially overlapping spectrum of activity against gram-positive and gram-negative bacteria. This indicates that the net charge and the secondary structure of the peptides are not important for the toxic activity. Furthermore, using carboxyfluorescein-loaded liposomes, membrane permeability studies and electron microscopy we investigated whether DCD peptides are able to permeabilize bacterial membranes. The data convincingly show that irrespective of charge the different DCD peptides are not able to permeabilize bacterial membranes. However, bacterial mutants lacking specific cell envelope modifications exhibited different susceptibilities to killing by DCD peptides than wild-type bacterial strains. Finally, immunoelectron microscopy studies indicated that DCD peptides are able to bind to the bacterial surface; however, signs of membrane perturbation were not observed. These studies indicate that DCD peptides do not exert their activity by permeabilizing bacterial membranes.
First Detection of the Plasmid-Mediated Class A Carbapenemase KPC-2 in Clinical Isolates of
Klebsiella pneumoniae
from South America
Authors: Virginia Villegas Maria , Lolans Karen , Correa Adriana , Jose Suarez Carlos , Lopez Jaime A. , Vallejo Marta , Quinn John P.
Published: July 2006

The plasmid-mediated class A carbapenemase KPC-2 was isolated from unrelated
Klebsiella pneumoniae
isolates in Medellin, Colombia. These KPC enzymes are the first from South America and the second isolation outside of the United States. The expanding geographic spread of KPC carbapenemases underscores the importance of clinical recognition of these enzymes.
Genetic Basis for Natural and Acquired Resistance to the Diarylquinoline R207910 in Mycobacteria
Authors: Petrella Stephanie , Cambau Emmanuelle , Chauffour Aurelie , Andries Koen , Jarlier Vincent , Sougakoff Wladimir
Published: July 2006

The
atpE
gene encoding the subunit
c
of the ATP synthase of
Mycobacterium tuberculosis
, the target of the new diarylquinoline drug R207910, has been sequenced from in vitro mutants resistant to the drug. The previously reported mutation A63P and a new mutation, I66M, were found. The genetic diversity of
atpE
in 13 mycobacterial species was also investigated, revealing that the region involved in resistance to R207910 is conserved, except in
Mycobacterium xenopi
in which the highly conserved residue Ala63 is replaced by Met, a modification that may be associated with the natural resistance of
M. xenopi
to R207910.
Inhibition ofPlasmodium falciparumGrowth In Vitro and Adhesion to Chondroitin-4-Sulfate by the Heparan Sulfate Mimetic PI-88 and Other Sulfated Oligosaccharides
Authors: Adams Yvonne , Freeman Craig , Schwartz-Albiez Reinhard , Ferro Vito , Parish Christopher R. , Andrews Katherine T.
Published: July 2006

A panel of sulfated oligosaccharides was tested for antimalarial activity and inhibition of adhesion to the placental malaria receptor chondroitin-4-sulfate (CSA). The heparan sulfate mimetic PI-88, currently undergoing phase II anticancer trials, displayed the greatest in vitro antimalarial activity againstPlasmodium falciparum(50% inhibitory concentration of 7.4 μM) and demonstrated modest adhesion inhibition to cell surface CSA.
Class II Transposon-Borne Structure Harboring Metallo-β-Lactamase Gene
bla
VIM-2
in
Pseudomonas putida
Authors: Poirel Laurent , Cabanne Ludovic , Collet Louis , Nordmann Patrice
Published: July 2006

A plasmid-encoded class II transposon element was identified in a carbapenem-resistant
Pseudomonas putida
isolate. Tn
1332
, closely related to Tn
1331
, harbored the metallo-β-lactamase gene
bla
VIM-2
in addition to four other antibiotic resistance genes,
aacA4
,
aadA1
,
bla
OXA-9
, and
bla
TEM-1
, and two novel insertion sequences, IS
Ppu17
and IS
Ppu18
.
Synthetic Histidine-Rich Peptides Inhibit
Candida
Species and Other Fungi In Vitro: Role of Endocytosis and Treatment Implications
Authors: Zhu Jingsong , Luther Paul W. , Leng Qixin , Mixson A. James
Published: July 2006

A family of histidine-rich peptides, histatins, is secreted by the parotid gland in mammals and exhibits marked inhibitory activity against a number of
Candida
species. We were particularly interested in the mechanism by which histidine-rich peptides inhibit fungal growth, because our laboratory has synthesized a variety of such peptides for drug and nucleic acid delivery. In contrast to naturally occurring peptides that are linear, peptides made on synthesizers can be varied with respect to their degrees of branching. Using this technology, we explored whether histidine-lysine (HK) polymers of different complexities and degrees of branching affect the growth of several species of
Candida
. Polymers with higher degrees of branching were progressively more effective against
Candida albicans
, with the four-branched polymer, H2K4b, most effective. Furthermore, H2K4b accumulated efficiently in
C. albicans
, which may indicate its ability to transport other antifungal agents intracellularly. Although H2K4b had greater antifungal activity than histatin 5, their mechanisms were similar. Toxicity in
C. albicans
induced by histatin 5 or branched HK peptides was markedly reduced by 4,4′-diisothiocyanato-stilbene-2,2′-disulfonate, an inhibitor of anion channels. We also determined that bafilomycin A1, an inhibitor of endosomal acidification, significantly decreased the antifungal activity of H2K4b. This suggests that the pH-buffering and subsequent endosomal-disrupting properties of histidine-rich peptides have a role in their antifungal activity. Moreover, the ability of the histidine component of these peptides to disrupt endosomes, which allows their escape from the lysosomal pathway, may explain why these peptides are both effective antifungal agents and nucleic acid delivery carriers.
Development of an Orogastrointestinal Mucosal Model of Candidiasis with Dissemination to Visceral Organs
Authors: Clemons Karl V. , Gonzalez Gloria M. , Singh Gaurav , Imai Jackie , Espiritu Marife , Parmar Rachana , Stevens David A.
Published: July 2006

Studies were done to develop a murine model that mimics the pattern of mucosal candidiasis followed by disseminated disease seen in patients given cytotoxic chemotherapy. Developmental studies showed that suppression of mice with 5-fluorouracil beginning 3 days prior to infection and given every 7 days thereafter necessitated antibacterial treatment but resulted in a reproducible model.
Candida albicans
given in the drinking water resulted in oral infection by day 3 that significantly increased from days 10 to 15 and mucosal infection with 4 to 7 log
10
Candida
CFU in the esophagus, stomach, small intestine, and cecum. Dissemination to livers occurred and was 100% on days 5 to 15; fewer animals had kidney infection. The median kidney or liver CFU were 2 or 3 log
10
CFU, respectively, on day 15; despite this, mortality was low through 21 days of infection. As a demonstration of the utility of the model to test antifungal activity, daily treatment with 10 or 50 mg/kg itraconazole significantly reduced dissemination to the liver and kidneys and reduced tongue CFU compared to controls. Overall, these studies indicate that a nonlethal model of oral and gastrointestinal mucosal candidiasis with dissemination can be established in mice. Drug efficacy in treating localized infection and in preventing or treating disseminated infection can be studied.
Comparative Pharmacodynamics of Gentamicin against
Staphylococcus aureus
and
Pseudomonas aeruginosa
Authors: Tam Vincent H. , Kabbara Samer , Vo Giao , Schilling Amy N. , Coyle Elizabeth A.
Published: July 2006

Aminoglycosides are often used to treat severe infections with gram-positive organisms. Previous studies have shown concentration-dependent killing by aminoglycosides of gram-negative bacteria, but limited data are available for gram-positive bacteria. We compared the in vitro pharmacodynamics of gentamicin against
Staphylococcus aureus
and
Pseudomonas aeruginosa
. Five
S. aureus
strains were examined (ATCC 29213 and four clinical isolates). Time-kill studies (TKS) in duplicate (baseline inocula of 10
7
CFU/ml) were conducted to evaluate bacterial killing in relation to increasing gentamicin concentrations (0 to 16 times the MIC). Serial samples were obtained over 24 h to quantify bacterial burden. Similar TKS with
P. aeruginosa
ATCC 27853 were conducted, and the time courses of the all bacterial strains were mathematically modeled for quantitative comparison. A dose fractionation study (using identical daily doses of gentamicin) in an in vitro hollow-fiber infection model (HFIM) over 5 days was subsequently used for data validation for the two ATCC strains. Model fits to the data were satisfactory;
r
2
values for the
S. aureus
and
P. aeruginosa
ATCC strains were 0.915 and 0.956, respectively. Gentamicin was found to have a partially concentration-dependent killing effect against
S. aureus
; concentrations beyond four to 8 times the MIC did not result in significantly faster bacterial killing. In contrast, a concentration-dependent profile was demonstrated in suppressing
P. aeruginosa
regrowth after initial decline in bacterial burden. In HFIM, thrice-daily gentamicin dosing appeared to be superior to once-daily dosing for
S. aureus
, but they were similar for
P. aeruginosa
. Different killing profiles of gentamicin were demonstrated against
S. aureus
and
P. aeruginosa
. These results may guide optimal dosing strategies of gentamicin in
S. aureus
infections and warrant further investigations.
Cisplatin Inhibition of Anthrax Lethal Toxin
Authors: Moayeri Mahtab , Wiggins Jason F. , Lindeman Robin E. , Leppla Stephen H.
Published: July 2006

Bacillus anthracis
lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages derived from certain inbred strains. LT is comprised of a receptor binding component, protective antigen (PA), which delivers the enzymatic component, lethal factor (LF), into cells. We found that mouse macrophages were protected from toxin by the antitumor drug
cis
-diammineplatinum (II) dichloride (cisplatin). Cisplatin was shown to inhibit LT-mediated cleavage of cellular mitogen-activated protein kinases (MEKs) without inhibiting LF's in vitro proteolytic activity. Cisplatin-treated PA lost 100% of its ability to function in toxicity assays when paired with untreated LF, despite maintaining the ability to bind to cells. Cisplatin-treated PA was unable to form heptameric oligomers required for LF binding and translocation. The drug was shown to modify PA in a reversible noncovalent manner. Not surprisingly, cisplatin also blocked the actions of anthrax edema toxin and of LF-
Pseudomonas aeruginosa
exotoxin A fusion peptide (FP59), both of which require PA for translocation. Treatment of BALB/cJ mice or Fischer F344 rats with cisplatin at biologically relevant concentrations completely protected the animals from a coadministered lethal dose of LT. However, treatment with cisplatin 2 hours before or after animals received a lethal bolus of toxin did not protect them.
New Azasterols against
Trypanosoma brucei
: Role of 24-Sterol Methyltransferase in Inhibitor Action
Authors: Gros Ludovic , Castillo-Acosta Victor Manuel , Jiménez Carmen Jiménez , Sealey-Cardona Marco , Vargas Sofia , Manuel Estévez Antonio , Yardley Vanessa , Rattray Lauren , Croft Simon L. , Ruiz-Perez Luis M. , Urbina Julio A. , Gilbert Ian H. , Pacanowska Dolores González
Published: July 2006

A series of azasterol derivatives, designed as potential inhibitors of the Δ
24
-sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. Values in the nanomolar range were obtained for 50% effective dose against the
Trypanosoma brucei
subsp.
rhodesiense
bloodstream form cultured in vitro. In order to investigate the mode of action,
Trypanosoma brucei
subsp.
brucei
24-SMT was cloned and overexpressed and compounds were assayed for inhibitory activity. None of the inhibitors tested appeared to be active against the enzyme. Sterol composition analysis showed that only cholestane type sterols are present in membranes of bloodstream forms while ergosterol is a major component of procyclic sterol extracts. Interestingly, Northern blot analysis showed the presence of 24-SMT mRNA in both the procyclic and the bloodstream forms of the parasite, although levels of mRNA were threefold lower in the latter. Likewise, Western blot analysis and activity determinations evidenced the existence of active enzyme in both forms of the parasite. We conclude that the designed compounds act at sites other than 24-SMT in
Trypanosoma brucei
.
Comparative Analysis of Sequences Flanking
tet
(W) Resistance Genes in Multiple Species of Gut Bacteria
Authors: Kazimierczak Katarzyna A. , Flint Harry J. , Scott Karen P.
Published: July 2006

tet
(W) is one of the most abundant tetracycline resistance genes found in bacteria from the mammalian gut and was first identified in the rumen anaerobe
Butyrivibrio fibrisolvens
1.230, where it is highly mobile and its transfer is associated with the transposable chromosomal element Tn
B1230
. In order to compare the genetic basis for
tet
(W) carriage in different bacteria, we studied sequences flanking
tet
(W) in representatives of seven bacterial genera originating in diverse gut environments. The sequences 657 bp upstream and 43 bp downstream of
tet
(W) were 96 to 100% similar in all strains examined. A common open reading frame (ORF) was identified downstream of
tet
(W) in five different bacteria, while another conserved ORF that flanked
tet
(W) in
B. fibrisolvens
1.230 was also present upstream of
tet
(W) in a human colonic
Roseburia
isolate and in another rumen
B. fibrisolvens
isolate. In one species,
Bifidobacterium longum
(strain F8), a novel transposase was located within the conserved 657-bp region upstream of
tet
(W) and was flanked by imperfect direct repeats. Additional direct repeats 6 bp long were identified on each end of a chromosomal ORF interrupted by the insertion of the putative transposase and the
tet
(W) gene. This
tet
(W) gene was transferable at low frequencies between
Bifidobacterium
strains. A putative minielement carrying a copy of
tet
(W) was identified in
B. fibrisolvens
transconjugants that had acquired the
tet
(W) gene on Tn
B1230
. Several different mechanisms, including mechanisms involving plasmids and conjugative transposons, appear to be involved in the horizontal transfer of
tet
(W) genes, but small core regions that may function as minielements are conserved.
Hydrophobic α-Helices 1 and 2 of Herpes Simplex Virus gH Interact with Lipids, and Their Mimetic Peptides Enhance Virus Infection and Fusion
Authors: Gianni Tatiana , Fato Romana , Bergamini Christian , Lenaz Giorgio , Campadelli-Fiume Gabriella
Published: July 2006

Entry of herpes simplex virus into cells occurs by fusion and requires four glycoproteins. gD serves as the receptor binding glycoprotein. Of the remaining glycoproteins, gH carries structural and functional elements typical of class 1 fusion glycoproteins, in particular α-helix 1 (α-H1), with properties of a candidate fusion peptide, and two heptad repeats. Here, we characterized α-H2 and compared it to α-H1. α-H2 (amino acids 513 to 531) is of lower hydrophobicity than α-H1. Its deletion or mutation decreased virus infection and cell fusion. Its replacement with heterologous fusion peptides did not rescue infection and cell fusion beyond the levels exhibited by the α-H2-deleted gH. This contrasts with α-H1, which cannot be deleted and can be functionally replaced with heterologous fusion peptides (T. Gianni et al., J. Virol.
79:
2931-2940, 2005). Synthetic peptides mimicking α-H1 and α-H2 induced fusion of nude lipid vesicles. Importantly, they increased infection of herpes simplex virus, pseudorabies virus, bovine herpesvirus 1, and vesicular stomatitis virus. The α-H1 mimetic peptide was more effective than the α-H2 peptide. Consistent with the findings that gH carries membrane-interacting segments, a soluble form of gH, but not of gD or gB, partitioned with lipid vesicles. Current findings highlight that α-H2 is an important albeit nonessential region for virus entry and fusion. α-H1 and α-H2 share the ability to target the membrane lipids; they contribute to virus entry and fusion, possibly by destabilizing the membranes. However, α-H2 differs from α-H1 in that it is of lower hydrophobicity and cannot be replaced with heterologous fusion peptides.
SECOND ORDER NEURONS AND LEARNING IN COHEN-GROSSBERG NETWORKS
Authors: GOPALSAMY K.
Published: July 2006

The well known Cohen-Grossberg network is modified to include second order neural interconnections and also to have a learning component. Sufficient conditions are obtained for the existence of a globally exponentially stable equilibrium. The model provides a two-fold generalization of the Cohen-Grossberg network in the sense if one removes the learning component, then one gets a network with second order synaptic interactions; if both the learning component and the second order interactions are removed, then the model reduces to the standard Cohen-Grossberg network.
ROTATING BLACK HOLES IN METRIC-AFFINE GRAVITY
Authors: BAEKLER PETER , HEHL FRIEDRICH W.
Published: July 2006

Within the framework of metric-affine gravity (MAG, metric and an independent linear connection constitute space–time), we find, for a specific gravitational Lagrangian and by using prolongation techniques, a stationary axially symmetric exact solution of the vacuum field equations. This black hole solution embodies a Kerr–de Sitter metric and the post-Riemannian structures of torsion and nonmetricity. The solution is characterized by mass, angular momentum, and shear charge, the latter of which is a measure for violating Lorentz invariance.
Effect of hyperinsulinemia on amino acid utilization and oxidation independent of glucose metabolism in the ovine fetus
Authors: Brown Laura D. , Hay William W.
Published: July 2006

We studied the effect of acute hyperinsulinemia on amino acid (AA) utilization and oxidation rates independent of insulin-enhanced glucose metabolism in fetal sheep. Metabolic studies were conducted in each fetus ( n = 11) under three experimental periods. After control period (C) study, a fetal hyperinsulinemic-euglycemic-euaminoacidemic (HI-euG-euAA) clamp was established, followed by a hyperinsulinemic-hypoglycemic-euaminoacidemic (HI-hypoG-euAA) clamp to decrease glucose metabolic rates toward C values. Infusions of3H20, l-[1-13C]leucine, and [14C(U)]glucose were administered to measure blood flow, leucine oxidation, and fetal glucose uptake, utilization, and oxidation in each period. Fetal glucose utilization rate increased 1.7-fold with hyperinsulinemia (C 5.8 ± 0.8 mg·kg−1·min−1, HI-euG-euAA 10 ± 1.3 mg·kg−1·min−1, P < 0.0001), returning to rates not different from C with hypoglycemia (HI-hypoG-euAA 7.1 ± 0.9 mg·kg−1·min−1vs. C value, P = 0.15). Fetal glucose oxidation rate increased 1.7-fold with hyperinsulinemia (C 3.1 ± 0.2 mg·kg−1·min−1, HI-euG-euAA 5.4 ± 0.4 mg·kg−1·min−1, P < 0.0001) and decreased to near control rates with hypoglycemia (4.0 ± 0.3 HI-hypoG-euAA vs. C value, P = 0.006). AA utilization rates increased with hyperinsulinemia for all essential and most nonessential AAs ( P < 0.001) and did not change when insulin-induced increases in glucose utilization returned to control rates. Leucine oxidation rate increased 1.7-fold with hyperinsulinemia (C 1.0 ± 0.3 μmol·min−1·kg−1, HI-euG-euAA 1.7 ± 0.3 μmol·min−1·kg−1, P < 0.002) and did not change when glucose oxidation rate was decreased with hypoglycemia. These results demonstrate that, in fetal sheep, insulin promotes AA utilization and oxidation independent of its simultaneous effects on glucose metabolism. In acute hyperinsulinemic conditions, AA oxidation does not change when insulin-induced glucose utilization is prevented.
Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention
Authors: Ge Yuqiang , Bagnall Alan , Stricklett Peter K. , Strait Kevin , Webb David J. , Kotelevtsev Yuri , Kohan Donald E.
Published: July 2006

Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal- and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal- and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide.
Fluid flow in the juxtaglomerular interstitium visualized in vivo
Authors: Rosivall László , Mirzahosseini Shahrokh , Toma Ildikó , Sipos Arnold , Peti-Peterdi János
Published: July 2006

Earlier electron microscopy studies demonstrated morphological signs of fluid flow in the juxtaglomerular apparatus (JGA), including fenestrations of the afferent arteriole (AA) endothelium facing renin granular cells. We aimed to directly visualize fluid flow in the JGA, the putative function of the fenestrated endothelium, using intravital multiphoton microscopy of Munich-Wistar rats and C57BL6 mice. Renin content of the AA correlated strongly with the length of the fenestrated, filtering AA segment. Fluorescence of the extracellular fluid marker lucifer yellow (LY) injected into the cannulated femoral vein in bolus was followed in the renal cortex by real-time imaging. LY was detected in the interstitium around the JG AA before the plasma LY filtered into Bowman's capsule and early proximal tubule. The fluorescence intensity of LY in the JGA interstitium was 17.9 ± 3.5% of that in the AA plasma ( n = 6). The JGA fluid flow was oscillatory, consisting of two components: a fast (one every 5–10 s) and a slow (one every 45–50 s) oscillation, most likely due to the rapid transmission of both the myogenic and tubuloglomerular feedback (TGF)-mediated hemodynamic changes. LY was also detected in the distal tubular lumen about 2–5 s later than in the AA, indicating the flow of JGA interstitial fluid through the macula densa. In the isolated microperfused JGA, blocking the early proximal tubule with a micropipette caused significant increases in MD cell volume by 62 ± 4% ( n = 4) and induced dilation of the intercellular lateral spaces. In summary, significant and dynamic fluid flow exists in the JGA which may help filter the released renin into the renal interstitium (endocrine function). It may also modulate TGF and renin signals in the JGA (hemodynamic function).
A combined1H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR-α null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome
Authors: Atherton Helen J. , Bailey Nigel J. , Zhang Wen , Taylor John , Major Hilary , Shockcor John , Clarke Kieran , Griffin Julian L.
Published: July 2006

The mobilization of triacylglycerides from storage in adipocytes to the liver is a vital response to the fasting state in mammalian metabolism. This is accompanied by a rapid translational activation of genes encoding mitochondrial, microsomal, and peroxisomal β-oxidation in the liver, in part under the regulation of peroxisome proliferator-activated receptor-α (PPAR-α). A failure to express PPAR-α results in profound metabolic perturbations in muscle tissue as well as the liver. These changes represent a number of deficits that accompany diabetes, dyslipidemia, and the metabolic syndrome. In this study, the metabolic role of PPAR-α has been investigated in heart, skeletal muscle, liver, and adipose tissue of PPAR-α null mice at 1 mo of age using metabolomics. To maximize the coverage of the metabolome in these tissues,1H-NMR spectroscopy, magic angle spinning1H-NMR spectroscopy, gas chromatography-mass spectrometry, and liquid chromatography-mass spectrometry were used to examine metabolites in aqueous tissue extracts and intact tissue. The data were analyzed by the multivariate approaches of principal components analysis and partial least squares. Across all tissues, there was a profound decrease in glucose and a number of amino acids, including glutamine and alanine, and an increase in lactate, demonstrating that a failure to express PPAR-α results in perturbations in glycolysis, the citric acid cycle, and gluconeogenesis. Furthermore, despite PPAR-α being weakly expressed in adipose tissue, a profound metabolic perturbation was detected in this tissue.
Trans-10, cis-12 conjugated linoleic acid causes inflammation and delipidation of white adipose tissue in mice: a microarray and histological analysis
Authors: LaRosa P. Christopher , Miner Jess , Xia Yuannan , Zhou You , Kachman Steve , Fromm Michael E.
Published: July 2006

A combined histological and microarray analysis of the white adipose tissue (WAT) of mice fed trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) was performed to better define functional responses. Mice fed t10c12 CLA for 14 days lost 85% of WAT mass, 95% of adipocyte lipid droplet volume, and 15 or 47% of the number of adipocytes and total cells, respectively. Microarray profiling of replicated pools ( n = 2 per day × diet) of control and treated mice ( n = 140) at seven time points after 1–17 days of t10c12 CLA feeding found between 2,682 and 4,216 transcript levels changed by twofold or more. Transcript levels for genes involved in glucose and fatty acid import or biosynthesis were significantly reduced. Highly expressed transcripts for lipases were significantly reduced but still abundant. Increased levels of mRNAs for two key thermogenesis proteins, uncoupling protein 1 and carnitine palmitoyltransferase 1, may have increased energy expenditures. Significant reductions of mRNAs for major adipocyte regulatory factors, including peroxisome proliferator activated receptor-γ, sterol regulatory binding protein 1, CAAT/enhancer binding protein-α, and lipin 1 were correlated with the reduced transcript levels for key metabolic pathways in the WAT. A prolific inflammation response was indicated by the 2- to 100-fold induction of many cytokine transcripts, including those for IL-6, IL-1β, TNF ligands, and CXC family members, and an increased density of macrophages. The mRNA changes suggest that a combination of cell loss, increased energy expenditure, and residual transport of lipids out of the adipocytes may account for the cumulative mass loss observed.