bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconciliation of diverse telepathology system designs. Historic issues and implications for emerging markets and new applications
Authors: Weinstein Ronald S. , Graham Anna R. , Lian Fangru , Braunhut Beth L. , Barker Gail R. , Krupinski Elizabeth A. , Bhattacharyya Achyut K.
Published: March 2012

Telepathology, the distant service component of digital pathology, is a growth industry. The word “telepathology” was introduced into the English Language in 1986. Initially, two different, competing imaging modalities were used for telepathology. These were dynamic (real time) robotic telepathology and static image (store‐and‐forward) telepathology. In 1989, a hybrid dynamic robotic/static image telepathology system was developed in Norway. This hybrid imaging system bundled these two primary pathology imaging modalities into a single multi‐modality pathology imaging system. Similar hybrid systems were subsequently developed and marketed in other countries as well. It is noteworthy that hybrid dynamic robotic/static image telepathology systems provided the infrastructure for the first truly sustainable telepathology services. Since then, impressive progress has been made in developing another telepathology technology, so‐called “virtual microscopy” telepathology (also called “whole slide image” telepathology or “WSI” telepathology). Over the past decade, WSI has appeared to be emerging as the preferred digital telepathology digital imaging modality. However, recently, there has been a re‐emergence of interest in dynamic‐robotic telepathology driven, in part, by concerns over the lack of a means for up‐and‐down focusing (i.e., Z‐axis focusing) using early WSI processors. In 2010, the initial two U.S. patents for robotic telepathology (issued in 1993 and 1994) expired enabling many digital pathology equipment companies to incorporate dynamic‐robotic telepathology modules into their WSI products for the first time. The dynamic‐robotic telepathology module provided a solution to the up‐and‐down focusing issue. WSI and dynamic robotic telepathology are now, rapidly, being bundled into a new class of telepathology/digital pathology imaging system, the “WSI‐enhanced dynamic robotic telepathology system”. To date, six major WSI processor equipment companies have embraced the approach and developed WSI‐enhanced dynamic‐robotic digital telepathology systems, marketed under a variety of labels. Successful commercialization of such systems could help overcome the current resistance of some pathologists to incorporate digital pathology, and telepathology, into their routine and esoteric laboratory services. Also, WSI‐enhanced dynamic robotic telepathology could be useful for providing general pathology and subspecialty pathology services to many of the world's underserved populations in the decades ahead. This could become an important enabler for the delivery of patient‐centered healthcare in the future.
A travel report of the implementation of virtual whole slide images in routine surgical pathology
Authors: Nap Marius , Teunissen ROB , Pieters Math
Published: March 2012

Virtual microscopy is the terminology used to indicate the use of digitized images of whole slides for inspection of cells and tissue sections on computer screens as an add‐on or replacement for conventional microscopy using bright field or other types of illumination in combination with a wide variety of microscope brands. Although technically there is no longer a limit in the size and colour composition of the images, the logistics of embedding virtual microscopy in daily routine of a diagnostic process are still a relatively open area where new pitfalls and opportunities can be found. In this article, we described various aspects in the process. None of them had been planned in advance, but mostly originated from observations done during the different steps towards implementation of virtual microscopy in daily routine, for example, the choice between the different scanner types and their (dis)advantages, issues on storing and retrieval and at last, the effect of digitalization on the diagnostic process. This approach resulted in a manuscript that in a way has more the appearance of a story than of a scientific study with strict protocols, with a clear cut question in advance, a research plan and expected outcome. Depending on the purpose of the virtual slides in a given situation, different solutions must be found locally.
Evaluation of Rosco Neo‐Sensitabs for phenotypic detection and subgrouping of ESBL‐, AmpC‐ and carbapenemase‐producing Enterobacteriaceae
Authors: Hansen Frank , Hammerum Anette M. , Skov Robert L. , Giske Christian G. , Sundsfjord Arnfinn , Samuelsen Ørjan
Published: March 2012

The increasing prevalence of ESBL‐, AmpC‐ and carbapenemase‐producing Enterobacteriaceae necessitates reliable phenotypic tests for detection and categorization. The main objective of this study was to evaluate ROSCO Neo‐Sensitabs with different β‐lactam‐β‐lactam inhibitor combinations for phenotypic detection and categorization of β‐lactamases in Enterobacteriaceae. Using standard CLSI/EUCAST methodology, differences in zones of inhibitions between a β‐lactam alone compared with the combination with a β‐lactamase inhibitor as well as subjective synergy observations were determined for 172 well characterized Enterobacteriaceae strains with defined resistance mechanisms. The results showed that for all ESBL‐positive strains (n = 66), combinations of clavulanic acid synergy with cefotaxime, ceftazidime or cefepime, were observed. All acquired AmpC β‐lactamases (n = 17) were detected using cloxacillin combined with cefotaxime and/or ceftazidime (both combinations were required). Carbapenemase producers (n = 59) with the exception of one KPC‐producer were correctly grouped using the combination of meropenem ± aminophenylboronic acid (APBA) or dipicolinic acid (DPA). Ethylene diamine tetraacetic acid (EDTA) also inhibited all metallo‐β‐lactamases, but as with DPA, one false positive result was observed. Based upon these data, we propose a tablet layout for 14 cm agar plates, which could be used as a whole or in a targeted approach for detection and categorizing of relevant acquired β‐lactamases in Enterobacteriaceae.
Integrating the common risk factor approach into a social determinants framework
Authors: Watt Richard G. , Sheiham Aubrey
Published: March 2012

The common risk factor approach (CRFA) has been highly influential in integrating oral health into general health improvement strategies. However, dental policy makers and oral health promoters have interpreted theCRFAtoo narrowly. They have focussed too heavily on the common behavioural risks, rather than on the broader shared social determinants of chronic diseases. A behavioural preventive approach alone will have minimal impact in tackling oral health inequalities and indeed may widen inequalities across the population. Based on recentWHOpolicy recommendations, this study presents the case for updating theCRFAin accordance with the social determinants agenda. The theoretical basis for a social determinants framework for oral health inequalities is presented, and implications for oral health improvement strategies are highlighted. Future action to address oral health inequalities in middle‐ and high‐income countries requires a radical policy reorientation towards tackling the structural and environmental determinants of chronic diseases. In more equal and fairer societies, all sections of the social hierarchy experience better health and social well‐being.
Invasive aspergillosis in a Putty‐nosed monkey (Cercopithecus nictitans) with adrenocortical Cushing’s syndrome
Authors: Jurczynski K. , Gruber‐Dujardin E. , Widmer D. , Kaup F.‐J. , Mätz‐Rensing K.
Published: March 2012

Background  An 18‐year‐old captive female putty‐nosed‐monkey (Cercopithecus nictitans) with a history of long‐term infertility and hyperglucocorticism was euthanized because of perforating thoracic trauma induced by group members and subsequent development of neurological signs.

Methods  Complete necropsy and histopathological examination of formalin‐fixed tissue samples was carried out.

Results  The monkey showed invasive pulmonary and cerebral infection with Aspergillus fumigatus together with adrenocortical neoplasia and signs of Cushing’s syndrome, such as alopecia with atrophic skin changes, evidence for diabetes mellitus and marked immunosuppression.

Conclusions  Spontaneous endocrinopathies are rarely described in non‐human primates. Here we report the first case of spontaneous adrenocortical hyperglucocorticism predisposing to systemic aspergillosis in a putty‐nosed monkey.
Current advances and perspectives in the treatment of advanced melanoma
Authors: Livingstone Elisabeth , Zimmer Lisa , Vaubel Julia , Schadendorf Dirk
Published: March 2012

Melanoma has long been considered as an extremely therapy‐resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti‐CTLA‐4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF‐inhibitor vemurafenib, which has shown a significant impact on progression‐free survival and overall survival in patients with the BRAFV600E mutation.

In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.
Oral health‐related quality of life of older people from three South American cities
Authors: Fuentes‐García Alejandra , Lera Lydia , Sánchez Hugo , Albala Cecilia
Published: March 2012

Objective:  To describe subjective oral health status and its association with overall health conditions and socioeconomic factors in the elderly (60 years and older) living in the capital cities with the oldest average populations in South America.

Background:  Oral diseases are a public health problem, frequently neglected in older adults. In recent years, the subjective assessment of psychological and social consequences of the problems related to oral health has been valued. One of the instruments used to estimate the Oral Health‐Quality of Life is the Geriatric Oral Health Assessment (GOHAI).

Material and methods:  Representative samples from SABE study (1999–2000) of Santiago (n = 1301), Buenos Aires (n = 1043), and Montevideo (n = 1450) aged 60 and over community‐dwelling people. We assessed OH‐QoL (GOHAI), self‐reported missing teeth, denture use, and self‐rated‐health, among other indicators. Logistic regression models(GOHAI < 58) for each city, adjusted by sex and age, were applied.

Results:  GOHAI average scores were higher in Montevideo (54.8 ± 6.1) than in Buenos Aires (53.1 ± 7.4) and Santiago (49.9 ± 8.6). A pronounced gradient of the oral condition and GOHAI scores were observed within the three‐cities. Denture use ‐less prevalent in Santiago and more common among women‐ is a protective factor against a poor OH‐QoL.

Conclusion:  Socioeconomic inequalities in oral health status and OH‐QoL are observed in the three cities. The increasing life expectancy emphasizes the need to integrate prevention and treatment efforts, as a way to improve OH‐QoL over the course of a lifetime.
Prevalence of removable partial dentures users treated at the Aracatuba Dental School – UNESP
Authors: Pellizzer Eduardo P. , Almeida Daniel Augusto de Faria , Falcón‐Antenucci Rosse M. , Sánchez Daniela Mayumi I.K. , Zuim Paulo Renato J. , Verri Fellippo R.
Published: March 2012

doi: 10.1111/j.1741‐2358.2012.00653.x
 
Prevalence of removable partial dentures users treated at the Aracatuba Dental School – UNESP

Objectives:  The aim of this study was to evaluate the frequency of removable partial dentures (RPD) at the Aracatuba Dental School.

Methods:  The study was conducted by analysing 412 clinical history of patients attended at the RPD clinics in the period from 2000 to 2007.

Results:  412 charts were analysed: 148 (35.9%) men and 264 (64.1%) women. The mean age was 53.8 years (men) and 52.4 years (women). A total of 556 dentures were made; of these, 233 (41.90%) were maxillary and 323 (58.09%) were mandibular dentures. The most frequent Kennedy classification found was Class III (maxilla) and Class I (mandible). In the maxilla, 55% (126) of the major connectors were of the anterior–posterior palatal bar, while in the mandible, 64% (202) were the lingual bar. As regards the claps, 401 were circumferential and 318 were bar claps.

Conclusion:  The mean age of the patients was 52.9 years with higher prevalence of female patients; the most frequent Kennedy’s classification was Class I in mandible and Class III in maxilla; the most common major connector was anterior–posterior palatal bar for maxilla and lingual bar for mandible; the circumferential clasps were the most common retainer used in both jaws.
The effect of immersion cleansers on gloss, colour and sorption of acetal denture base material
Authors: Polyzois Gregory , Niarchou Artemis , Ntala Polyxeni , Pantopoulos Antonis , Frangou Mary
Published: March 2012

doi: 10.1111/j.1741‐2358.2012.00657.x

The effect of immersion cleansers on gloss, colour and sorption of acetal denture base material

Objective:  To study the effect of peroxide and hypochlorite cleansers on gloss, colour and sorption of acetal denture resins.

Materials and methods:  Pink acetal and thermoplastic acrylic resins were evaluated. Thirty‐five specimens 39 × 39 × 1.8 mm of each resin were prepared. Each group of specimens (n = 7) was then immersed into cleansers for 100 days. Group I immersed in tap water, Group II in Corega Extradent for 5 min, Group III in Corega Extradent for 8 h, Group IV in NitrAdine™ Seniors for 15 min and Group V in NaOCl 5.25%. Gloss, colour and weight measurements were taken initially and after 100 days. Data subjected to two‐way anova and Tukey’s test at α = 0.05.

Results:  Acrylic resin showed reductions of glossiness from −5 to −15 and acetal from −0.2 to −6. Colour changes (ΔΕ*) ranged from 2.64 to 7.64 for acrylic and 2.77 to 26.54 for acetal resin. Sorption for acrylic ranged from 11.64 to 17.06 μg/mm3 and 9.18 to 24.79 μg/mm3 for acetal resin. The results of (ΔΕ*) and sorption showed an interaction between denture resins and cleansers.

Conclusions:  The gloss of acetal resin was less affected by water, peroxides and NaOCl 5.25% compared with acrylic resin. Acetal resin showed clinically acceptable (ΔΕ*) whereas acrylic resin unacceptable ones for water and peroxide solutions. The immersion of acetal resin in NaOCl 5.25% showed clinically unacceptable (ΔΕ*) and higher sorption and should be avoided or should be managed with care.
Licofelone Inhibits Interleukin‐18‐Induced Pro‐Inflammatory Cytokine Release and Cellular Proliferation in Human Mesangial Cells
Authors: Wu Yuan‐Jun , Xue Mei , Chen Hui
Published: March 2012

Licofelone, a novel dual anti‐inflammatory drug that inhibits 5‐lipoxygenase (5‐LOX) and cyclooxygenase (COX), has recently been defined to have therapeutic effects in osteoarthritis. Both 5‐LOX and COX play functional roles in the pathogenesis of glomerulonephritis in children as well. Interleukin‐18 is a pro‐inflammatory cytokine. It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells (HMC) exposed to interleukin‐18. In this study, HMC were cultured and exposed to interleukin‐18 with or without pre‐treatment of licofelone. COX‐2 and 5‐LOX enzyme activities in mesangial cells were determined with chromometry or high‐performance liquid chromatography. Prostaglandin E2, cysteinyl leukotriene, monocyte chemotactic protein‐1 and interferon‐γ concentrations in culture medium were measured using an enzyme‐linked immunosorbent assay. Western blotting was employed to detect phosphorylated mitogen‐activated protein kinases ERK1/2, p38 and JNK1/2 in HMC. It was found that licofelone attenuated interleukin‐18‐induced COX‐2 enzyme activity in HMC and prostaglandin E2 release in a dose‐dependent manner. Similarly, licofelone inhibited interleukin‐18‐induced 5‐LOX enzyme activity and leukotriene release. Licofelone reduced interleukin‐18‐induced phosphorylation of p38 mitogen–activated protein kinase and suppressed monocyte chemotactic protein‐1 and interferon‐γ synthesis. Moreover, licofelone inhibited IL‐18‐induced proliferation of mesangial cells. We conclude that licofelone inhibits interleukin‐18‐induced pro‐inflammatory cytokine release and cellular proliferation in HMC, which may represent a really interesting therapeutic approach for glomerulonephritis in children.
THE CENTRAL PLACE OF RACE IN CRIME AND JUSTICE—THE AMERICAN SOCIETY OF CRIMINOLOGY'S 2011 SUTHERLAND ADDRESS*
Authors: PETERSON RUTH D.
Published: March 2012

In the United States and elsewhere, racial and ethnic disparities in crime and criminal justice are relatively ubiquitous. Yet the meaning of such disparities is not well understood. To address this concern, periodically there have been calls for research that takes into account the broader structural context of the racially and ethnically inequitable crime and justice patterns. However, a comprehensive approach to understanding such inequality is seldom applied in research. In this article, I review findings from a program of research on crime across race–ethnic neighborhoods that I have undertaken with Lauren J. Krivo and other colleagues to provide, and assess, such a framework. The starting point of our approach is that ethnoracial inequality in neighborhood crime is an outgrowth of a racialized social structure maintained largely through racial residential segregation. As anticipated, the findings illustrate the value added from research that embeds its assessment of crime and justice within an understanding of structured societal inequality. From these results, I call for placing race and ethnicity at the center of the study of crime and justice.
Juvenile ossifying fibroma of mandible – a case report
Authors: Sharma S. , Majumder K. , Gupta D.S. , Tandon P N.
Published: March 2012

Juvenile ossifying fibroma is a benign lesion with aggressive local growth. It is similar to an ossifying fibroma, although it is more aggressive and of earlier onset. The tumour mainly occurs in juveniles, majority of the patients being 15 years or younger. Radiologically as well as at surgery, the lesion is well demarcated from its surroundings. In this article, we report a case of juvenile ossifying fibroma of mandibular anterior region extending from canine to canine region with expansion of both buccal and lingual cortical plates with a history of 6 month duration in an 8‐year‐old girl. The treatment was complete enucleation of the tumour mass and curettage of the bony cavity with primary closure. The patient is on regular follow‐up of 2 years with no recurrence.
Evaluation of Fbxw7 expression and its correlation with the expression of c‐Myc, cyclin E and p53 in human hepatocellular carcinoma
Authors: Tu Kangsheng , Zheng Xin , Zan Xianfeng , Han Shaoshan , Yao Yingmin , Liu Qingguang
Published: March 2012

Aim:  F‐box and WD repeat domain‐containing 7 (Fbxw7) is a cell cycle regulatory gene that targets for ubiquitination and proteasomal degradation various cell cycle regulators such as c‐Myc and cyclin E. Defects in the Fbxw7 gene that lead to cell cycle re‐entry and expedite the G1‐S transition is thought to be one of the causes of cancer development. However, its expression and clinical importance for hepatocellular carcinoma (HCC) patients remains undetermined. This prompted us to investigate its expression level in HCC patients to establish its clinical significance.

Methods:  Sixty surgically resected paired HCC and normal tumor‐adjacent tissues were freshly collected. Fbxw7 expression at both mRNA and protein level was examined by reverse transcription polymerase chain reaction and immunohistochemistry. The protein expression of c‐Myc, cyclin E and p53 was evaluated by immunohistochemistry to identify correlations with Fbxw7.

Results:  The mRNA and protein expression of Fbxw7 was significantly downregulated in the HCC tumor tissues compared to the normal tumor‐adjacent tissues (P < 0.01, respectively). Fbxw7 protein was expressed at significantly lower levels in patients with high histological grade and advanced tumor–node–metastasis stage. In HCC tissues, Fbxw7 protein expression was negatively correlated with c‐Myc, cyclin E and p53 (r = −0.459, P < 0.05; r = −0.573, P < 0.001; r = −0.579, P < 0.05, respectively).

Conclusion:  In HCC, reduced Fbxw7 expression closely correlated with clinicopathological characteristics and may have prognostic potential through the enhanced function of cell cycle regulatory proteins.
Bias in estimating animal travel distance: the effect of sampling frequency
Authors: Marcus Rowcliffe J. , Carbone Chris , Kays Roland , Kranstauber Bart , Jansen Patrick A.
Published: March 2012

1. The distance travelled by animals is an important ecological variable that links behaviour, energetics and demography. It is usually measured by summing straight‐line distances between intermittently sampled locations along continuous animal movement paths. The extent to which this approach underestimates travel distance remains a rarely addressed and unsolved problem, largely because true movement paths are rarely, if ever, available for comparison. Here, we use simulated movement paths parameterized with empirical movement data to study how estimates of distance travelled are affected by sampling frequency.

2. We used a novel method to obtain fine‐scale characteristics of animal movement from camera trap videos for a set of tropical forest mammals and used these characteristics to generate detailed movement paths. We then sampled these paths at different frequencies, simulating telemetry studies, and quantified the accuracy of sampled travel distance estimation.

3. For our focal species, typical telemetry studies would underestimate distances travelled by 67–93%, and extremely high sampling frequencies (several fixes per minute) would be required to get tolerably accurate estimates. The form of the relationship between tortuosity, sample frequency, and distance travelled was such that absolute distance cannot accurately be estimated by the infrequent samples used in typical tracking studies.

4. We conclude that the underestimation of distance travelled is a serious but underappreciated problem. Currently, there is no reliable, widely applicable method to obtain approximately unbiased estimates of distance travelled by animals. Further research on this problem is needed.
Idiopathic eosinophilic meningoencephalitis in a Dutch Warmblood gelding
Authors: Loibl J. , Thaller D. , van den Hoven R. , Schwarz B.
Published: March 2012

An increased content of eosinophils in cerebrospinal fluid (CSF) and eosinophilic infiltration of brain tissue are observed in eosinophilic meningoencephalitis (EME). After exclusion of various infectious diseases and further known causes of EME in other species, the diagnosis idiopathic EME was made at necropsy in the case reported here. To the authors' knowledge, this is the first report of idiopathic EME in a horse similar to the disorder occurring in dogs.
Resistance of equine tibiae and radii to side impact loads
Authors: Piskoty G. , Jäggin S. , Michel S. A. , Weisse B. , Terrasi G. P. , Fürst A.
Published: March 2012

Reasons for performing study: There are no detailed studies describing the resistance of equine tibiae and radii to side impact loads, such as a horse kick and a better understanding of the general long bone impact behavioural model is required.

Objectives: To quantify the typical impact energy required to fracture or fissure an equine long bone, as well as to determine the range and time course of the impact force under conditions similar to that of a horse kick.

Methods: Seventy‐two equine tibiae and radii were investigated using a drop impact tester. The prepared bones were preloaded with an axial force of 2.5 kN and were then hit in the middle of the medial side. The impact velocity of the metal impactor, weighting 2 kg, was varied within the range of 6–11 m/s. The impact process was captured with a high‐speed camera from the craniomedial side of the bone. The videos were used both for slow‐motion observation of the process and for quantifying physical parameters, such as peak force via offline video tracking and subsequent numerical derivation of the ‘position vs. time’ function for the impactor.

Results: The macroscopic appearance of the resultant bone injuries was found to be similar to those produced by authentic horse kicks, indicating a successful simulation of the real load case. The impact behaviours of tibiae and radii do not differ considerably in terms of the investigated general characteristics. Peak force occurred between 0.15–0.30 ms after the start of the impact. The maximum contact force correlated with the 1.45‐power of the impact velocity if no fracture occurred (Fmax≅ 0.926 ·vi1.45). Peak force scatter was considerably larger within the fractured sub‐group compared with fissured bones. The peak force for fracture tended to lie below the aforementioned function, within the range of Fmax= 11–23 kN (‘fracture load’). The impact energy required to fracture a bone varied from 40–90 J.

Conclusions: The video‐based measuring method allowed quantifying of the most relevant physical parameters, such as contact force and energy balance.

Potential relevance: The results obtained should help with the development of bone implants and guards, supporting theoretical studies, and in the evaluation of bone injuries.
A Lie-theoretic interpretation of multivariate hypergeometric polynomials
Authors: Iliev Plamen
Published: March 2012

In 1971, Griffiths used a generating function to define polynomials in d variables orthogonal with respect to the multinomial distribution. The polynomials possess a duality between the discrete variables and the degree indices. In 2004, Mizukawa and Tanaka related these polynomials to character algebras and the Gelfand hypergeometric series. Using this approach, they clarified the duality and obtained a new proof of the orthogonality. In the present paper, we interpret these polynomials within the context of the Lie algebra $\mathfrak {sl}_{d+1}(\mathbb {C})$. Our approach yields yet another proof of the orthogonality. It also shows that the polynomials satisfy d independent recurrence relations each involving d2+d+1 terms. This, combined with the duality, establishes their bispectrality. We illustrate our results with several explicit examples.
Non-normal abelian covers
Authors: Alexeev Valery , Pardini Rita
Published: March 2012

An abelian cover is a finite morphism X→Y of varieties which is the quotient map for a generically faithful action of a finite abelian group G. Abelian covers with Y smooth and X normal were studied in [R. Pardini, Abelian covers of algebraic varieties, J. Reine Angew. Math. 417 (1991), 191–213; MR 1103912(92g:14012)]. Here we study the non-normal case, assuming that X and Y are S2 varieties that have at worst normal crossings outside a subset of codimension greater than or equal to two. Special attention is paid to the case of ℤr2-covers of surfaces, which is used in [V. Alexeev and R. Pardini, Explicit compactifications of moduli spaces of Campedelli and Burniat surfaces, Preprint (2009), math.AG/arXiv:0901.4431] to construct explicitly compactifications of some components of the moduli space of surfaces of general type.
Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors
Authors: Tomita Susumu , Castillo Pablo E.
Published: March 2012

Abstract  Kainate receptors (KARs) are a subfamily of ionotropic glutamate receptors (iGluRs) that mediate excitatory synaptic transmission, regulate neurotransmitter release, and show a remarkably selective distribution in the brain. Compared to other iGluRs, the precise contribution of KARs to brain function is less understood. Unlike recombinant KARs, native KARs exhibit characteristically slow channel kinetics. The underlying explanation for this dissimilar kinetics has remained elusive until recently. New research has identified Neto1 and Neto2 as KAR auxiliary subunits that determine unique properties of synaptic KARs, including their slow kinetics and high affinity for agonist. Whether these auxiliary subunits regulate KAR trafficking and targeting at the synapse is less clear. By regulating channel gating, Neto1 and Neto2 can increase the diversity of KAR functional properties. These auxiliary subunits may represent a starting point for a better understanding of the role played by neuronal KARs under normal and pathological conditions, but also, they may provide an alternative target for the development of new drugs regulating KARs and brain function.
The resonant component of human physiological hand tremor is altered by slow voluntary movements
Authors: Lakie Martin , Vernooij Carlijn A. , Osborne Timothy M. , Reynolds Raymond F.
Published: March 2012

Key points 

Postural physiological hand tremor has a prominent component at ∼8 Hz unlike the associated EMG. Consequently, the gain between EMG and tremor is sharply peaked at ∼8 Hz.

Deduction and a simple model using pre‐recorded EMG or random noise as an input show that the ∼8 Hz peak is a consequence of resonance.

During voluntary movement the gain peak enlarges and shifts to a lower frequency but the EMG spectrum shows no corresponding changes. This reflects muscle thixotropy. Adjustment of the muscle properties of the model reproduces the effect.

These findings suggest that the rhythm of hand tremor in posture and movement is related to muscle and limb mechanics rather than a neural oscillator.

The discovery that the gain relating EMG to acceleration is very different when static and moving has implications for the control of movement in health and disease.
Riluzole blocks human muscle acetylcholine receptors
Authors: Deflorio Cristina , Palma Eleonora , Conti Luca , Roseti Cristina , Manteca Alessia , Giacomelli Elena , Catalano Myriam , Limatola Cristina , Inghilleri Maurizio , Grassi Francesca
Published: March 2012

Key points 

Riluzole is the only drug available against amyotrophic lateral sclerosis (ALS), a fatal disease characterized by death of motor neurones.

Recently it has been shown to block muscle ACh receptors (AChRs), raising concerns about possible side‐effects on neuromuscular transmission in patients.

In this work we studied the effect of riluzole on the function of muscle AChRs in vitro and on neuromuscular transmission in ALS patients.

Data indicate that riluzole is apparently safe regarding neuromuscular transmission in patients.

However, riluzole may affect the function of AChRs expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated.
Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients
Authors: Moltó José , Valle Marta , Miranda Cristina , Cedeño Samandhy , Negredo Eugenia , Clotet Bonaventura
Published: March 2012

The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavir-ritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary.
Activity of Oxacillin versus That of Vancomycin against Oxacillin-Susceptible
mecA
-Positive Staphylococcus aureus Clinical Isolates Evaluated by Population Analyses, Time-Kill Assays, and a Murine Thigh Infection Model
Authors: Labrou Maria , Michail George , Ntokou Eleni , Pittaras Theodore E. , Pournaras Spyros , Tsakris Athanassios
Published: March 2012

We compared the activity of dicloxacillin with that of vancomycin against 15 oxacillin-susceptible, methicillin-resistant
Staphylococcus aureus
(OS-MRSA) clinical isolates. By population analyses, we found that 6 OS-MRSA isolates were able to grow in the presence of up to 8 μg/ml dicloxacillin and 9 isolates were able to grow in 12 to >32 μg/ml dicloxacillin; all isolates grew in up to 2 μg/ml vancomycin. Both drugs exhibited similar bactericidal activities. In experimental infections, the therapeutic efficacy of dicloxacillin was significant (
P
< 0.05 versus untreated controls) in 10 OS-MRSA isolates and vancomycin was effective (
P
< 0.05) against 12 isolates; dicloxacillin had an efficacy that was comparable to that of vancomycin (
P
> 0.05) in 8 isolates. The favorable response to dicloxacillin treatment might suggest that antistaphylococcal penicillins could be used against OS-MRSA infections.
Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines
Authors: Díaz-Delfín Julieta , Domingo Pere , Mateo Maria Gracia , Gutierrez Maria del Mar , Domingo Joan Carles , Giralt Marta , Villarroya Francesc
Published: March 2012

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation
in vitro
. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 μM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 μM) or even at lower concentrations of efavirenz (2 μM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.
Sublimable C5A Delivery Provides Sustained and Prolonged Anti-HIV Microbicidal Activities
Authors: Maskiewicz Richard , Bobardt Michael , Chatterji Udayan , Gunaseelan Simi , Dezzutti Charlene S. , Penin Francois , Gallay Philippe A.
Published: March 2012

We have identified a short amphipathic helical peptide, called C5A, which exhibits potent microbicidal activities
in vitro
and which offers protection from vaginal HIV transmission
in vivo
in a humanized mouse model. However, there are many obstacles to overcome before C5A can be considered a true microbicidal candidate. First, it must be stabilized against enzymatic degradation in a continuously warm and moist environment. Second, it must be delivered in a controlled manner to achieve long-term and coitally independent efficacy. We demonstrate in this
in vitro
study that the combination of two matrices with different subliming properties ((hexamethylcyclotrisiloxane [HMCS] and cyclododecane [CDD]) containing 10% labile C5A yielded the best results in terms of controlled release and preserved anti-HIV activity of the peptide when pre-exposed to cell-free medium or cell culture at body temperature for up to 2 months.
Pharmacokinetics of Ferroquine, a Novel 4-Aminoquinoline, in Asymptomatic Carriers of Plasmodium falciparum Infections
Authors: Supan Christian , Mombo-Ngoma Ghyslain , Dal-Bianco Matthias P. , Ospina Salazar Carmen L. , Issifou Saadou , Mazuir Florent , Filali-Ansary Aziz , Biot Christophe , Ter-Minassian Daniel , Ramharter Michael , Kremsner Peter G. , Lell Bertrand
Published: March 2012

Ferroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomatic
Plasmodium falciparum
infection were administered a single oral dose (
n
= 40) or a repeated oral dose (
n
= 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (
n
= 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([
C
max
] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study,
C
max
and overall cumulated exposure to ferroquine (AUC
cum
) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (
t
max
) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.
A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis
Authors: Xu Tao , Tripathi Siddharth K. , Feng Qin , Lorenz Michael C. , Wright Marsha A. , Jacob Melissa R. , Mask Melanie M. , Baerson Scott R. , Li Xing-Cong , Clark Alice M. , Agarwal Ameeta K.
Published: March 2012

6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogensCandida albicans,Aspergillus fumigatus, andTrichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeastSaccharomyces cerevisiaeto investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants ofS. cerevisiaelacking transcription factors that regulate fatty acid β-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted inC. albicans. The transcriptional response and fatty acid profile ofC. albicanswere comparable to those obtained inS. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed inC. albicans. In a fluconazole-resistant clinical isolate ofC. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments inC. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficialCandidainfections.
Rapid, Field-Deployable Method for Genotyping and Discovery of Single-Nucleotide Polymorphisms Associated with Drug Resistance in Plasmodium falciparum
Authors: Daniels Rachel , Ndiaye Daouda , Wall Mikeal , McKinney Jason , Séne Papa Diogoye , Sabeti Pardis C. , Volkman Sarah K. , Mboup Souleymane , Wirth Dyann F.
Published: March 2012

Despite efforts to reduce malaria morbidity and mortality, drug-resistant parasites continue to evade control strategies. Recently, emphasis has shifted away from control and toward regional elimination and global eradication of malaria. Such a campaign requires tools to monitor genetic changes in the parasite that could compromise the effectiveness of antimalarial drugs and undermine eradication programs. These tools must be fast, sensitive, unambiguous, and cost-effective to offer real-time reports of parasite drug susceptibility status across the globe. We have developed and validated a set of genotyping assays using high-resolution melting (HRM) analysis to detect molecular biomarkers associated with drug resistance across six genes in
Plasmodium falciparum
. We improved on existing technical approaches by developing refinements and extensions of HRM, including the use of blocked probes (LunaProbes) and the mutant allele amplification bias (MAAB) technique. To validate the sensitivity and accuracy of our assays, we compared our findings to sequencing results in both culture-adapted lines and clinical isolates from Senegal. We demonstrate that our assays (i) identify both known and novel polymorphisms, (ii) detect multiple genotypes indicative of mixed infections, and (iii) distinguish between variants when multiple copies of a locus are present. These rapid and inexpensive assays can track drug resistance and detect emerging mutations in targeted genetic loci in
P. falciparum
. They provide tools for monitoring molecular changes associated with changes in drug response across populations and for determining whether parasites present after drug treatment are the result of recrudescence or reinfection in clinical settings.
Quinolone-Induced Upregulation of Osteopontin Gene Promoter Activity in Human Lung Epithelial Cell Line A549
Authors: Shiratori Beata , Zhang Jing , Usami Osamu , Chagan-Yasutan Haorile , Suzuki Yasuhiko , Nakajima Chie , Uede Toshimitsu , Hattori Toshio
Published: March 2012

Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin (62%), gatifloxacin (82%), sparfloxacin, (79%), and sitafloxacin (60%). Enhancement of OPN secretion was shown to be due to the effect of quinolones on the OPN gene promoter activity. We also examined the role of quinolones on apoptosis and found that sparfloxacin decreased the late apoptosis of A549 cells, but garenoxacin did not show the antiapoptotic effect. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation.
Characterization of UC781-Tenofovir Combination Gel Products for HIV-1 Infection Prevention in an
Ex Vivo
Ectocervical Model
Authors: Cost Marilyn , Dezzutti Charlene S. , Clark Meredith R. , Friend David R. , Akil Ayman , Rohan Lisa Cencia
Published: March 2012

HIV continues to be a problem worldwide. Topical vaginal microbicides represent one option being evaluated to stop the spread of HIV. With drug candidates that have a specific action against HIV now being studied, it is important that, when appropriate and based on the mechanism of action, the drug permeates the tissue so that it can be delivered to specific targets which reside there. Novel formulations of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) and the nonnucleoside reverse transcriptase inhibitor UC781 have been developed and evaluated here. Gels with three distinct rheological properties were prepared. The three gels released both UC781 and TFV under
in vitro
conditions at concentrations equal to or above the reported 50% effective concentrations (EC
50
s). The drug concentrations in ectocervical tissues were well in excess of the reported EC
50
s. The gels maintain ectocervical viability and prevent infection of ectocervical explants after a HIV-1 challenge. This study successfully demonstrates the feasibility of using this novel combination of antiretroviral agents in an aqueous gel as an HIV infection preventative.
Carbapenem Therapy for Bacteremia Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli or Klebsiella pneumoniae: Implications of Ertapenem Susceptibility
Authors: Lee Nan-Yao , Lee Ching-Chi , Huang Wei-Han , Tsui Ko-Chung , Hsueh Po-Ren , Ko Wen-Chien
Published: March 2012

A retrospective study was conducted at two medical centers in Taiwan to evaluate the clinical characteristics, outcomes, and risk factors for mortality among patients treated with a carbapenem for bacteremia caused by extended-spectrum-beta-lactamase (ESBL)-producing organisms. A total of 251 patients with bacteremia caused by ESBL-producing
Escherichia coli
and
Klebsiella pneumoniae
isolates treated by a carbapenem were identified. Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs ≤ 0.25 μg/ml) were 83.8% and 76.4%, respectively; those to meropenem were 100% and 99.3%, respectively; and those to imipenem were 100% and 97.9%, respectively. There were no significant differences in the critical illness rate (
P
= 0.1) or sepsis-related mortality rate (
P
= 0.2) for patients with bacteremia caused by ESBL-producing
K. pneumoniae
(140 isolates, 55.8%) and
E. coli
(111 isolates, 44.2%). Multivariate analysis of variables related to sepsis-related mortality revealed that the presence of severe sepsis (odds ratio [OR], 15.9; 95% confidence interval [CI], 5.84 to 43.34;
P
< 0.001), hospital-onset bacteremia (OR, 4.65; 95% CI, 1.42 to 15.24;
P
= 0.01), and ertapenem-nonsusceptible isolates (OR, 5.12; 95% CI, 2.04 to 12.88;
P
= 0.001) were independent risk factors. The patients receiving inappropriate therapy had a higher sepsis-related mortality than those with appropriate therapy (
P
= 0.002), irrespective of ertapenem, imipenem, or meropenem therapy. Infections due to the ertapenem-susceptible isolates (MICs ≤ 0.25 μg/ml) were associated with a more favorable outcome than those due to ertapenem-nonsusceptible isolates (MICs > 0.25 μg/ml), if treated by a carbapenem. However, the mortality for patients with bacteremic episodes due to isolates with MICs of ≤0.5 μg/ml was similar to the mortality for those whose isolates had MICs of >0.5 μg/ml (
P
= 0.8). Such a finding supports the rationale of the current CLSI 2011 criteria for carbapenems for
Enterobacteriaceae
.