bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-Effectiveness of Different Screening Strategies (Single or Dual) for the Diagnosis of Tuberculosis Infection in Healthcare Workers
Authors: del Campo M. Teresa , Fouad Hadia , Solís-Bravo M. Marcela , Sánchez-Uriz M. Angeles , Mahíllo-Fernández Ignacio , Esteban Jaime
Published: October 2012

Objective.

To evaluate the cost-effectiveness of a dual strategy of tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT-G) for screening of latent tuberculosis infection (LTBI) in healthcare workers (HCWs) and, as a secondary objective, to study relationships between TST results, QFT-G results, and sociodemographic factors.

Design.

Cross-sectional prospective study.

Setting.

University hospital in Madrid.

Participants.

A total of 103 HCWs.

Methods.

QFT-G was requested for all positive TST results; QFT-G results were compared with TST results, and their relationships with sociodemographic factors were analyzed. A cost-effectiveness analysis was conducted for the dual strategy (TST/QFT-G) and for TST or QFT alone, taking into account the indication of and compliance with isoniazid, the risk of hepatotoxicity, and postexposure tuberculosis.

Results.

Of all HCWs studied, 42.3% showed a positive result by QFT-G, and 49.5% had received bacille Calmette-Guérin (BCG) vaccination; no significant association was detected between BCG and QFT-G results. Increased TST was linked to higher positive QFT-G values (TST of 5–9.9 mm, 27.6%; TST of 15 mm or more, 56.5%; P = .03). The probability of positive QFT-G results was 1.04 times higher for each year of age (odds ratio, 1.04 [95% confidence interval, 1.01–1.09]; P = .0257). The incremental cost per active TB case prevented was lower for TST/QFT-G than for the other strategies studied (€14,211 per 1,000 HCWs). The number of people treated for LTBI per case of active TB prevented (number needed to treat) for TST/QFT-G was lower than for TST alone (17.2 vs 95.3 and 88.7 with the 5- and 10-mm cutoff value, respectively) or QFT-G alone (69.6).

Conclusions.

Dual strategy with TST/QFT-G is more cost-effective than TST or QFT-G alone for the diagnosis of LTBI in HCWs.
Epidemiology of Vancomycin-Resistant Enterococci with Reduced Susceptibility to Daptomycin
Authors: Judge Theresa , Pogue Jason M. , Marchaim Dror , Ho Kevin , Kamatam Srinivasa , Parveen Shakila , Tiwari Namita , Nanjireddy Priyanka , Bheemreddy Suchitha , Biedron Caitlin , Reddy Sagar Mallikethi Lepakshi , Khammam Vijaykumar , Chalana Indu K. , Tumma Rajachendra Shekher , Collins Vicki , Yousuf Adnan , Lephart Paul R. , Martin Emily T. , Rybak Michael J. , Kaye Keith S. , Hayakawa Kayoko
Published: October 2012

A retrospective case–case control study was conducted, including 60 cases with daptomycin-nonsusceptible vancomycin-resistant enterococci (DNS-VRE) matched to cases with daptomycin-susceptible VRE and to uninfected controls (1:1:3 ratio). Immunosuppression, presence of comorbid conditions, and prior exposure to antimicrobials were independent predictors of DNS-VRE, although prior daptomycin exposure occurred rarely. In summary, a case–case control study identified independent risk factors for the isolation of DNS-VRE: immunosuppression, multiple comorbid conditions, and prior exposures to cephalosporines and metronidazole.
A note on Wu-Zheng’s splitting conjecture
Authors: Yu Chengjie
Published: October 2012

Cao’s splitting theorem says that for any complete Kähler-Ricci flow

(
M
,
g
(
t
)
)

(M,g(t))

with

t
∈
[
0
,
T
)

t\in [0,T)

,

M
M

simply connected and nonnegative bounded holomorphic bisectional curvature,

(
M
,
g
(
t
)
)

(M,g(t))

is holomorphically isometric to

C

k

×
(
N
,
h
(
t
)
)

\mathbb {C}^k\times (N,h(t))

, where

(
N
,
h
(
t
)
)

(N,h(t))

is a Kähler-Ricci flow with positive Ricci curvature for

t
>
0

t>0

. In this article, we show that

k
=
n
−
r

k=n-r

, where

r
r

is the Ricci rank of the initial metric. As a corollary, we also confirm a splitting conjecture of Wu and Zheng when curvature is assumed to be bounded.
Radil controls neutrophil adhesion and motility through β2-integrin activation
Authors: Liu Lunhua , Aerbajinai Wulin , Ahmed Syed M. , Rodgers Griffin P. , Angers Stephane , Parent Carole A.
Published: October 2012

Integrin activation is required to facilitate multiple adhesion-dependent functions of neutrophils, such as chemotaxis, which is critical for inflammatory responses to injury and pathogens. However, little is known about the mechanisms that mediate integrin activation in neutrophils. We show that Radil, a novel Rap1 effector, regulates β1- and β2-integrin activation and controls neutrophil chemotaxis. On activation and chemotactic migration of neutrophils, Radil quickly translocates from the cytoplasm to the plasma membrane in a Rap1a-GTP–dependent manner. Cells overexpressing Radil show a substantial increase in cell adhesion, as well as in integrin/focal adhesion kinase (FAK) activation, and exhibit an elongated morphology, with severe tail retraction defects. This phenotype is effectively rescued by treatment with either β2-integrin inhibitory antibodies or FAK inhibitors. Conversely, knockdown of Radil causes severe inhibition of cell adhesion, β2-integrin activation, and chemotaxis. Furthermore, we found that inhibition of Rap activity by RapGAP coexpression inhibits Radil-mediated integrin and FAK activation, decreases cell adhesion, and abrogates the long-tail phenotype of Radil cells. Overall, these studies establish that Radil regulates neutrophil adhesion and motility by linking Rap1 to β2-integrin activation.
Histone H1 compacts DNA under force and during chromatin assembly
Authors: Xiao Botao , Freedman Benjamin S. , Miller Kelly E. , Heald Rebecca , Marko John F.
Published: October 2012

Histone H1 binds to linker DNA between nucleosomes, but the dynamics and biological ramifications of this interaction remain poorly understood. We performed single-molecule experiments using magnetic tweezers to determine the effects of H1 on naked DNA in buffer or during chromatin assembly in Xenopus egg extracts. In buffer, nanomolar concentrations of H1 induce bending and looping of naked DNA at stretching forces below 0.6 pN, effects that can be reversed with 2.7-pN force or in 200 mM monovalent salt concentrations. Consecutive tens-of-nanometer bending events suggest that H1 binds to naked DNA in buffer at high stoichiometries. In egg extracts, single DNA molecules assemble into nucleosomes and undergo rapid compaction. Histone H1 at endogenous physiological concentrations increases the DNA compaction rate during chromatin assembly under 2-pN force and decreases it during disassembly under 5-pN force. In egg cytoplasm, histone H1 protects sperm nuclei undergoing genome-wide decondensation and chromatin assembly from becoming abnormally stretched or fragmented due to astral microtubule pulling forces. These results reveal functional ramifications of H1 binding to DNA at the single-molecule level and suggest an important physiological role for H1 in compacting DNA under force and during chromatin assembly.
Two distinct SSB protein families in nucleo-cytoplasmic large DNA viruses
Authors: Kazlauskas Darius , Venclovas Česlovas
Published: October 2012

Motivation: Eukaryote-infecting nucleo-cytoplasmic large DNA viruses (NCLDVs) feature some of the largest genomes in the viral world. These viruses typically do not strongly depend on the host DNA replication systems. In line with this observation, a number of essential DNA replication proteins, such as DNA polymerases, primases, helicases and ligases, have been identified in the NCLDVs. One other ubiquitous component of DNA replisomes is the single-stranded DNA-binding (SSB) protein. Intriguingly, no NCLDV homologs of canonical OB-fold-containing SSB proteins had previously been detected. Only in poxviruses, one of seven NCLDV families, I3 was identified as the SSB protein. However, whether I3 is related to any known protein structure has not yet been established.

Results: Here, we addressed the case of ‘missing’ canonical SSB proteins in the NCLDVs and also probed evolutionary origins of the I3 family. Using advanced computational methods, in four NCLDV families, we detected homologs of the bacteriophage T7 SSB protein (gp2.5). We found the properties of these homologs to be consistent with the SSB function. Moreover, we implicated specific residues in single-stranded DNA binding. At the same time, we found no evolutionary link between the T7 gp2.5-like NCLDV SSB homologs and the poxviral SSB protein (I3). Instead, we identified a distant relationship between I3 and small protein B (SmpB), a bacterial RNA-binding protein. Thus, apparently, the NCLDVs have the two major distinct sets of SSB proteins having bacteriophage and bacterial origins, respectively.

Contact:  venclovas@ibt.lt

Supplementary information:  Supplementary data are available at Bioinformatics online.
FFPopSim: an efficient forward simulation package for the evolution of large populations
Authors: Zanini Fabio , Neher Richard A.
Published: October 2012

Motivation: The analysis of the evolutionary dynamics of a population with many polymorphic loci is challenging, as a large number of possible genotypes needs to be tracked. In the absence of analytical solutions, forward computer simulations are an important tool in multi-locus population genetics. The run time of standard algorithms to simulate sexual populations increases as 8L with the number of loci L, or with the square of the population size N.

Results: We have developed algorithms to simulate large populations with arbitrary genetic maps, including multiple crossovers, with a run time that scales as 3L. If the number of crossovers is restricted to at most one, the run time is reduced to L2L. The algorithm is based on an analogue of the Fast Fourier Transform (FFT) and allows for arbitrary fitness functions (i.e. any epistasis). In addition, we include a streamlined individual-based framework. The library is implemented as a collection of C++ classes and a Python interface.

Availability:  http://code.google.com/p/ffpopsim/.

Contact:  richard.neher@tuebingen.mpg.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Chimeric elk/mouse prion proteins in transgenic mice
Authors: Tamgüney Gültekin , Giles Kurt , Oehler Abby , Johnson Natrina L. , DeArmond Stephen J. , Prusiner Stanley B.
Published: October 2012

Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.
The X proteins of bornaviruses interfere with type I interferon signalling
Authors: Wensman Jonas Johansson , Munir Muhammad , Thaduri Srinivas , Hörnaeus Katarina , Rizwan Muhammad , Blomström Anne-Lie , Briese Thomas , Lipkin W. Ian , Berg Mikael
Published: October 2012

Borna disease virus (BDV) is a neurotropic, negative-stranded RNA virus causing persistent infection and progressive neurological disorders in a wide range of warm-blooded animals. The role of the small non-structural X protein in viral pathogenesis is not completely understood. Here we investigated whether the X protein of BDV and avian bornavirus (ABV) interferes with the type I interferon (IFN) system, similar to other non-structural proteins of negative-stranded RNA viruses. In luciferase reporter assays, we found that the X protein of various bornaviruses interfered with the type I IFN system at all checkpoints investigated, in contrast to previously reported findings, resulting in reduced type I IFN secretion.
Identification of a novel equine infectious anemia virus field strain isolated from feral horses in southern Japan
Authors: Dong Jian-Bao , Zhu Wei , Cook Frank R. , Goto Yoshitaka , Horii Yoichiro , Haga Takeshi
Published: October 2012

Although equine infectious anemia (EIA) was described more than 150 years ago, complete genomic sequences have only been obtained from two field strains of EIA virus (EIAV), EIAVWyoming and EIAVLiaoning. In 2011, EIA was detected within the distinctive feral Misaki horse population that inhabits the Toi-Cape area of southern Japan. Complete proviral sequences comprising a novel field strain were amplified directly from peripheral blood of one of these EIAV-infected horses and characterized by nucleotide sequencing. The complete provirus of Miyazaki2011-A strain is 8208 bp in length with an overall genomic organization typical of EIAV. However, this field isolate possesses just 77.2 and 78.7 % nucleotide sequence identity with the EIAVWyoming and EIAVLiaoning strains, respectively, while similarity plot analysis suggested all three strains arose independently. Furthermore, phylogenetic studies using sequences obtained from all EIAV-infected Misaki horses against known viral strains strongly suggests these Japanese isolates comprise a separate monophyletic group.
Bovine papillomavirus type 2 infects the urinary bladder of water buffalo (Bubalus bubalis) and plays a crucial role in bubaline urothelial carcinogenesis
Authors: Roperto Sante , Russo Valeria , Ozkul Ayhan , Sepici-Dincel Aylin , Maiolino Paola , Borzacchiello Giuseppe , Marcus Ioan , Esposito Iolanda , Riccardi Marita Georgia , Roperto Franco
Published: October 2012

Bovine papillomavirus type 2 (BPV-2) has been shown to infect and play a role in urinary bladder carcinogenesis of buffaloes grazed on pastures with ferns from the Marmara and Black Sea Regions of Turkey. BPV-2 DNA has been found in both neoplastic and non-neoplastic lesions of the urinary bladder. Furthermore, this virus may be a normal inhabitant of the urinary bladder since BPV-2 DNA has also been detected in clinically normal buffaloes. The viral activation by fern immunosuppressant or carcinogen may trigger the urothelial cell transformation. The E5 oncoprotein was solely detected in urothelial tumours and appeared to be co-localized with the overexpressed and phosphorylated platelet derived growth factor (PDGF) β receptor in a double-colour immunofluorescence assay. Our results indicate that the E5–PDGF β receptor interaction also occurs in spontaneous tumours of the bubaline urinary bladder, revealing an additional role of BPV-2 in bladder carcinogenesis of buffaloes.
Influence of Host Chloroplast Proteins on Tobacco mosaic virus Accumulation and Intercellular Movement
Authors: Bhat Sumana , Folimonova Svetlana Y. , Cole Anthony B. , Ballard Kimberly D. , Lei Zhentian , Watson Bonnie S. , Sumner Lloyd W. , Nelson Richard S.
Published: October 2012

Tobacco mosaic virus (TMV) forms dense cytoplasmic bodies containing replication-associated proteins (virus replication complexes [VRCs]) upon infection. To identify host proteins that interact with individual viral components of VRCs or VRCs in toto, we isolated viral replicase- and VRC-enriched fractions from TMV-infected Nicotiana tabacum plants. Two host proteins in enriched fractions, ATP-synthase γ-subunit (AtpC) and Rubisco activase (RCA) were identified by matrix-assisted laser-desorption ionization time-of-flight mass spectrometry or liquid chromatography-tandem mass spectrometry. Through pull-down analysis, RCA bound predominantly to the region between the methyltransferase and helicase domains of the TMV replicase. Tobamovirus, but not Cucumber mosaic virus or Potato virus X, infection of N. tabacum plants resulted in 50% reductions in Rca and AtpC messenger RNA levels. To investigate the role of these host proteins in TMV accumulation and plant defense, we used a Tobacco rattle virus vector to silence these genes in Nicotiana benthamiana plants prior to challenge with TMV expressing green fluorescent protein. TMV-induced fluorescent lesions on Rca- or AtpC-silenced leaves were, respectively, similar or twice the size of those on leaves expressing these genes. Silencing Rca and AtpC did not influence the spread of Tomato bushy stunt virus and Potato virus X. In AtpC- and Rca-silenced leaves TMV accumulation and pathogenicity were greatly enhanced, suggesting a role of both host-encoded proteins in a defense response against TMV. In addition, silencing these host genes altered the phenotype of the TMV infection foci and VRCs, yielding foci with concentric fluorescent rings and dramatically more but smaller VRCs. The concentric rings occurred through renewed virus accumulation internal to the infection front.
Consumer Communication and Organisational Strategies for Animal Welfare by the Food and Retail Industries in Italy
Authors: Mancini Maria Cecilia , Arfini Filippo
Published: October 2012

Consumer Communication and Organisational Strategies for Animal Welfare by the Food and Retail Industries in Italy

The treatment of animals used in production processes involves ethical principles as well as food safety and has become increasingly a focus of debate. Based on survey evidence, this article examines consumer communication and organisational strategies regarding animal welfare (AW) by food processors and retailers in Italy. It identifies three levels of commitment to animal welfare: full sensitivity with regard to ethical issues and products; animal welfare seen solely as an aspect of product quality; and indifference where animal welfare is considered purely a legal obligation. This classification could be a starting point for institutional intervention. ‘Active’ behaviour shows that AW can be used as a means of organisational renewal of supply chain mechanisms and thus could be supported by public institutions. At the same time, an effective implementation of EU AW policy requires public intervention to ensure that consumers receive the information they need to shop with awareness of AW issues. It is only through greater awareness of AW friendly techniques and their implications that willingness to pay among Italian consumers will increase. This in turn will provide the incentives for producers, processors and retailers to show more interest in AW‐friendly techniques.
A Family with Recurrent Sudden Death and No Clinical Clue
Authors: Arad Michael , Glikson Michael , El‐Ani Dalia , Monserrat‐Inglesias Lorenzo
Published: October 2012

Background: Sudden cardiac death of a child is a devastating event for the family and an enormous challenge for the attending physician.

Methods and Results: We report a family with repeat events of sudden cardiac death and recurrent ventricular fibrillation in a teenage girl, where autopsy data and clinical investigations were inconclusive. The diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was established only following finding a gene mutation in the cardiac ryanodine receptor.

Conclusions: Interpretation of autopsy data, provocation testing and genetic testing in victims of sudden death and family members are discussed to correctly identify the cause and properly manage asymptomatic carriers in such families.
Identification of Novel Anaplastic Lymphoma Kinase (ALK) Inhibitors Using a Common Feature Pharmacophore Model Derived from Known Ligands Crystallized with ALK
Authors: Xie Huan‐Zhang , Lan Hai , Pan You‐Li , Zou Jun , Wang Ze‐Rong , Li Lin‐Li , Huang Qi , Zhang Hui , Yang Sheng‐Yong
Published: October 2012

In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co‐crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping‐check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant‐driven cancer cell line, Karpas299. And six of them showed a good anti‐viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508‐5181 (from Specs), which gave a half maximal inhibitory concentration (IC50) of 5.3 μm.
The impact of ‘being assessed’ by a disabled children's team: a personal reflective account
Authors: Wilkins David
Published: October 2012

The body of ‘service user’ literature confirms the value of parental perceptions of child and family social work and the insight parents and others can offer. This paper lends my voice to the literature regarding parental perceptions, inspired by the work of Pamela Davies, who provided a personal account of the impact of a child protection investigation. This paper draws upon my experiences of being a father of two ‘disabled children’ and undergoing an assessment of need. This paper seeks to draw attention to issues of choice, power imbalances and the role of expertise. My personal experience of undergoing an assessment was that it was an emotionally fraught process, for the duration of the assessment, our family stress increased and we had a sense of having to ‘battle’ for the support we needed. As such, my personal experience fits well with the wider body of literature, which highlights the increased stress of caring for children with additional needs, the challenges of ‘fitting’ disabled children into the frameworks used to assess all children and the difficulty for parents and professionals in distinguishing between ‘normal’ parenting responsibilities and the additional responsibilities of caring for a disabled child.
Kinship care in Spain: messages from research
Authors: Montserrat Carme
Published: October 2012

Kinship foster care has experienced significant growth within the Spanish child protection system and now carries considerable weight. Over 40% of children in the public care system are formally fostered by relatives, equalling, and in some areas exceeding, the percentage of those in residential homes. This increase is not the result of a pre‐designed global programme or clearly pre‐established objectives in the system itself. Its current weight within the system has made it the focus of attention of researchers, politicians and protection system practitioners alike. The results of research carried out in Spain have revealed more positives than negatives in this type of fostering, giving rise to an in‐depth reflection on care systems, questioning the determinism of theories anchored in the intergenerational repetition of abuse and making room for perspectives more associated with resilience and children's rights. Positive results are related to fewer breakdowns, more stability, permanency beyond the age of 18, children agreeing with their placement, academic results similar to those with non‐relatives and better results after leaving care. The negatives relate to the lack of economic, educational and psychosocial support, which generally goes with this type of fostering. The experience of support programmes for these placements contributes to the debate.
The Neuroprotective Effect of Losartan through Inhibiting AT1/ASK1/MKK4/JNK3 Pathway Following Cerebral I/R in Rat Hippocampal CA1 Region
Authors: Zhang Tian‐Ling , Fu Jian‐Liang , Geng Zhi , Yang Jia‐Jun , Sun Xiao‐Jiang
Published: October 2012

Aims

It has been well documented that angiotensin II type 1 (AT1) receptor blockers (ARBs) are known to attenuate neural damage and the c‐Jun N‐terminal protein kinase 3 (JNK3) pathway and caspase‐3 signal are involved in neuronal cell death following cerebral ischemia/reperfusion (I/R). In this study, we first showed that losartan could protect neurons against cerebral I/R‐induced injury.

Methods

Cerebral ischemia model was induced by four‐vessel occlusion. Antisense oligodeoxynucleotides (ODNs) against AT1 receptor and losartan were used to detect whether the AT1 receptor implicated in cerebral I/R. Immunoprecipitation (IP) and immunoblotting (IB) were used to detect the interactions between β‐arrestin‐2 and AT1/apoptosis signal‐regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R.

Results

First, losartan decreased cerebral I/R‐induced neuronal death. Second, losartan depressed the β‐arrestin‐2‐assembled AT1/ASK1/MKK4 signaling module. Third, losartan depressed the activation of c‐jun, JNK3, Bcl‐2, caspase‐3 and the release of cytochrome c from mitochondria to cytoplasm.

Conclusion

Taken together, losartan could attenuate neural damage following the cerebral I/R via inhibiting the β‐arrestin‐2‐assembled AT1/ASK1/MKK4 signaling module and depressing the activation of c‐jun, JNK3, and caspase‐3 and the release of cytochrome c.
Combination Therapy for Manic Phases: A Critical Review of a Common Practice
Authors: Geoffroy Pierre Alexis , Etain Bruno , Henry Chantal , Bellivier Frank
Published: October 2012

All relevant guidelines recommend monotherapy as the initial treatment for manic phases of bipolar disorder (BD), with combination therapy reserved for severe cases or as a subsequent choice. However, in routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy. As a consequence, most patients are given combination therapies. An extensive search concerning combination treatment for manic episodes was conducted for relevant international randomized controlled studies, treatment guidelines and comprehensive reviews published since 1980. The scientific literature is sufficiently rich to validate the superiority of combination therapy over monotherapy in the manic phase in terms of efficacy and prevention of relapse; its safety profile is acceptable. Side effects are more frequent with combination therapy as a whole than with monotherapy, and discontinuation rates due to adverse events are higher. Continued administration of antipsychotics after a manic phase is controversial: drug classification, the course of the disease and the predominant polarity should all be considered before treatment is continued. Combinations including olanzapine and asenapine and to a lesser extent risperidone are associated with weight gain, those including quetiapine, haloperidol and asenapine with sedation, and those including aripiprazole with akathisia. This review of literature leads us to suggest that combination therapy including an atypical antipsychotic with lithium or valproate may be considered as a first‐line approach. An appropriate algorithm for making decisions about combination treatment needs to be developed and included in future guidelines.
De novo myeloid sarcoma in a 4‐month‐old infant: a case report and review of the literature
Authors: Bain Earl Eugene , Rothman Ilene , Lin Lin
Published: October 2012

Myeloid sarcoma is a rare tumor of immature myeloid cells in an extramedullary site. Myeloid sarcoma may present in a variety of locations; skin is one of the common sites. It may precede or occur concurrently with acute myeloid leukemia, chronic myeloid leukemia, other forms of myeloproliferative disorders/myelodysplastic syndrome or de novo. We report a case of a 4‐month‐old female who presented with cutaneous lesions without evidence of leukemia, determined to be de novo myeloid sarcoma. She had erythematous nodules in multiple skin sites. Biopsy revealed a diffuse atypical mononuclear cell infiltrate involving the entire dermis and extending to the subcutis. The infiltrate was diffusely positive for lysozyme, CD43, CD15, CD33, CD68 and CD117 and was negative for CD3, CD20, CD34, CD56, CD79a, CD99, myeloperoxidase, desmin, chromogranin and synaptophysin, supporting a diagnosis of myeloid sarcoma. No leukemic involvement was found on evaluation of peripheral blood or bone marrow aspiration. Chromosomal abnormalities were found at chromosomes 7, 10 and 11. The skin lesions resolved following multiple chemotherapy courses, then recurred requiring additional treatment. De novo myeloid sarcoma involving skin without evidence of leukemia can occur in an infant and may present a diagnostic challenge.
Vascular and platelet responses to aspirin in patients with coronary artery disease
Authors: Blann Andrew D. , Kuzniatsova Nadya , Lip Gregory Y. H.
Published: October 2012

Background

Variability in the response to aspirin (sometimes known as aspirin resistance) in modulating platelet activity is a potentially important clinical issue in coronary artery disease (CAD), but may be also be important in other areas of pathophysiology.

Materials and methods

Testing the hypothesis of a relationship between aspirin resistance and vascular function, inflammation and coagulation, we recruited 175 stable CAD outpatients taking 75 mg aspirin daily. Indices were compared to 58 controls not taking aspirin. Platelet activity was assessed by light transmission aggregometry (LTA) to 0·5 mg/mL arachidonic acid (AA), plasma markers soluble P selectin and thromboxane (ELISA), and resting and AA stimulated membrane P selectin and PAC‐1 expression (flow cytometry). Vascular function was assessed by arterial stiffness (Sphygmocor system), von Willebrand factor and soluble E selectin (ELISA), inflammation by high sensitivity CRP and interleukin‐6, and coagulation by tissue factor and fibrin d‐dimers levels (all immunoassay).

Results

The 5‐min LTA response AA was superior to flow cytometry in discriminating the response of platelets to aspirin. Using the cut‐off of 20% LTA response to AA, 32·6% of patients were aspirin resistant. The latter had higher soluble P selectin (P = 0·03), CRP (P = 0·029) and fibrin d‐dimers (P = 0·01) compared to those who were aspirin sensitive. There was no relationship between aspirin response status and any vascular index.

Conclusion

We conclude that LTA is a more sensitive marker of aspirin resistance than is flow cytometry for P‐selectin and PCA‐1, and that aspirin response has no influence on vascular function.
Rapid and complete reconstitution of autologous haemopoiesis after cord blood infusion in treatment‐naive patients with severe aplastic anemia receiving high‐dose cyclophosphamide/ATG therapy
Authors: Li Yanxiang , Sheng Zhixin , Niu Shaona , Ge Lifu , Ren Cuiai , Zou Yandun
Published: October 2012

Although high‐dose cyclophosphamide seems to achieve durable complete remission, there are still concerns about its too much early toxicity. So, we designed a clinical study to investigate the effects of high‐dose cyclophosphamide/ATG combined with cord blood infusion as first‐line therapy for patients with severe aplastic anemia. Patients and Method: Between January 2003 and September 2007, we treated 16 treatment‐naive patients with severe aplastic anemia with cord blood infusion after high‐dose cyclophosphamide (50 mg/kg/d × 2) and rabbit antithymocyte globulin (3 mg/kg/d × 5) therapy. Results: Although only one patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid autologous hematopoietic recovery. The median recovery time for neutrophils and platelets was only 23 and 37 d after infusion of cord blood. Of the 15 responding patients, all patients achieved treatment‐free remission: nine patients met the criteria for a complete remission; six patients achieved a partial remission. Conclusion: Infusion of cord blood after high‐dose cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a high response rate in patients with treatment‐naive patients with severe aplastic anemia. These promising results merit further investigation and confirmation on a larger number of patients.
Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration
Authors: Steinbrink F. , Evers S. , Buerke B. , Young P. , Arendt G. , Koutsilieri E. , Reichelt D. , Lohmann H. , Husstedt I.‐W. ,   the German Competence Network HIV/AIDS
Published: October 2012

Background and purpose

Biomarkers as indicators for the progression of human immunodeficiency virus (HIV)‐associated neurocognitive disorders (HAND) remain still elusive. We performed a cross‐sectional study to analyze the correlation between cognitive impairment, abnormalities in magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) markers of neurodegeneration in HIV‐infected patients.

Methods

We enrolled 94 patients (82 men and 12 women; mean age 45 ± 10 years) with HIV infection, but without opportunistic infections of the CNS. All patients underwent MRI and CSF analysis. The global pattern of white matter signal intensity abnormalities, the index of atrophy, the severity of periventricular white matter abnormalities, and the severity of basal ganglia signal changes were analyzed. We measured CSF markers of neurodegeneration (total tau, phospho‐tau, beta‐amyloid). The findings of this evaluation were correlated with demographic and infection parameters of the patients in blood and CSF.

Results

We found a highly significant correlation between the severity of global brain atrophy, basal ganglia signal changes, and cognitive impairment in HIV‐infected patients. Furthermore, cognitive impairment was significantly correlated with total tau, but not with phospho‐tau or A‐beta‐amyloid in CSF analysis.

Conclusions

Our results confirm the significant correlation between MRI changes and cognitive impairment in HIV infection. Furthermore, we could show that global brain atrophy and signal changes in basal ganglia are the typical MRI pattern in HAND. The correlation between cognitive impairment and total tau, but not phospho‐tau, supports the hypothesis that HAND are not a subtype of Alzheimer's dementia.
Prevalence and prognostic impact of comorbidities in amyotrophic lateral sclerosis
Authors: Körner S. , Kollewe K. , Ilsemann J. , Müller‐Heine A. , Dengler R. , Krampfl K. , Petri S.
Published: October 2012

Background and purpose

Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive paralysis of striated muscles due to the loss of upper and lower motor neurons. The disease leads to death within 2–5 years, mainly due to respiratory failure. The pathogenesis of ALS is still unexplained for the most part. In this study, we aimed to determine the prevalence of different cardiovascular, metabolic, and neuropsychiatric comorbidities in a large ALS cohort and to evaluate their influence on the disease course.

Methods

A cohort of 514 patients with ALS of our ALS outpatient clinic was investigated retrospectively with reference to known prognostic factors and comorbidities. The prevalence of concomitant diseases was compared with the data from the German general population. Uni‐ and multivariate survival analyses were performed using the Cox proportional hazards model and Kaplan–Meier analysis.

Results

The prevalence of cardiovascular diseases and cardiovascular risk factors was significantly lower in patients with ALS compared to the German general population, whilst the prevalence of dementia, parkinsonism, and depressive symptoms was significantly higher in the ALS cohort. None of the investigated comorbidities had an influence on the disease course or on the survival of patients.

Conclusions

Persons with cardiovascular diseases or risk factors seem to be at lower risk of ALS. Although these diseases are apparently somehow protective regarding ALS susceptibility, their presence did not modify disease progression and survival in patients with ALS. Our study further confirms the well‐known continuum between ALS and dementia. It also suggests a link with other neurodegenerative diseases such as Parkinson's disease.
Critical determinants of the epilepsy treatment gap: A cross‐national analysis in resource‐limited settings
Authors: Meyer Ana‐Claire L. , Dua Tarun , Boscardin W. John , Escarce José J. , Saxena Shekhar , Birbeck Gretchen L.
Published: October 2012

Purpose:  Epilepsy is one of the most common serious neurologic disorders worldwide. Our objective was to determine which economic, health care, neurology, and epilepsy‐specific resources were associated with untreated epilepsy in resource‐constrained settings.

Methods:  A systematic review of the literature identified community‐based studies in resource‐constrained settings that calculated the epilepsy treatment gap, the proportion with untreated epilepsy, from prevalent active epilepsy cases. Economic, health care, neurology, and epilepsy‐specific resources were taken from existing datasets. Poisson regression models with jackknifed standard errors were used to create bivariate and multivariate models comparing the association between treatment status and economic and health resource indicators. Relative risks were reported.

Key Findings:  Forty‐seven studies of 8,285 individuals from 24 countries met inclusion criteria. Bivariate analysis demonstrated that individuals residing in rural locations had significantly higher risks of untreated epilepsy (relative risk [RR] 1.63; 95% confidence interval [CI] 1.26–2.11). Significantly lower risks of untreated epilepsy were observed for higher physician density (RR 0.65, 95% CI 0.55–0.78), presence of a lay (RR 0.74, 95% CI 0.60–0.91) or professional association for epilepsy (RR 0.73, 95% CI 0.59–0.91), or postgraduate neurology training program (RR 0.67, 95% CI 0.55–0.82). In multivariate models, higher physician density maintained significant effects (RR 0.67; 95% CI 0.52–0.88).

Significance:  Even among resource‐limited regions, people with epilepsy in countries with fewer economic, health care, neurology, and epilepsy‐specific resources are more likely to have untreated epilepsy. Community‐based epilepsy care programs have improved access to treatment, but in order to decrease the epilepsy‐treatment gap, poverty and inequalities of health care, neurology, and epilepsy resources must be dealt with at the local, national, and global levels.
Frontal lobe function and structure in juvenile myoclonic epilepsy: A comprehensive review of neuropsychological and imaging data
Authors: Wandschneider Britta , Thompson Pamela J. , Vollmar Christian , Koepp Matthias J.
Published: October 2012

Juvenile myoclonic epilepsy is the most common idiopathic epilepsy syndrome and is considered a benign seizure disorder that responds well to antiepileptic drug treatment, in particular sodium valproate. By definition, routine brain imaging shows no abnormalities, but advanced imaging studies have identified functional and structural abnormalities in the frontal cortex and thalamus. Neuropsychological studies revealed subtle cognitive deficits in patients with JME, mainly implicating the frontal lobes. These findings are in keeping with anecdotal reports of behavioral problems in JME. Cognitive dysfunction in otherwise healthy siblings of patients with JME and a high heritability support the concept of a genetically determined thalamo‐frontocortical network dysfunction, accounting for the cognitive impairment and cognitively triggered “motor seizures.”
Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency
Authors: Arsov Todor , Mullen Saul A. , Damiano John A. , Lawrence Kate M. , Huh Linda L. , Nolan Melinda , Young Helen , Thouin Anaïs , Dahl Hans‐Henrik M. , Berkovic Samuel F. , Crompton Douglas E. , Sadleir Lynette G. , Scheffer Ingrid E.
Published: October 2012

Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike‐waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in‐frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.
Structural basis for dual inhibitory role of tamarind Kunitz inhibitor (TKI) against factor Xa and trypsin
Authors: Patil Dipak N. , Chaudhary Anshul , Sharma Ashwani K. , Tomar Shailly , Kumar Pravindra
Published: October 2012

A Kunitz type dual inhibitor (TKI) of factor Xa (FXa) and trypsin was found in tamarind. It also shows prolongation of blood coagulation time. The deduced 185 amino acid sequence of TKI by cDNA cloning and sequence analysis revealed that it belongs to the Kunitz type soybean trypsin inhibitor (STI) family; however, it has a distorted Kunitz signature sequence due to insertion of Asn15 in the motif. TKI exhibited a competitive inhibitory activity against both FXa (Ki = 220 nm) and porcine pancreatic trypsin (Ki = 3.2 nm). The crystal structure of TKI shows a β‐trefoil fold similar to Kunitz STI inhibitors; however, a distinct mobile reactive site, an inserted residue and loop β7β8 make it distinct from classical Kunitz inhibitors. The crystal structure of TKI‐trypsin and a 3D model of TKI‐FXa complex revealed that the distinct reactive site loop probably plays a role in dual inhibition. The reactive site of TKI interacts with an active site and two exosites (36 loop and autolysis loop) of FXa. Apart from Arg66 (P1), Arg64 (P3) is one of the most important residues responsible for the specificity of TKI towards FXa. Along with the reactive site loop (β4β5), loops β1 and β7β8 also interact with FXa and could further confer selectivity for FXa. We also present the role of inserted Asn15 in the stabilization of complexes. To the best of our knowledge, this is the first structure of FXa inhibitor belonging to the Kunitz type inhibitor family and its unique structural and sequence features make TKI a novel potent inhibitor.

Database

The complete nucleotide of TKI was deposited in the NCBI gene databank with accession no. HQ385502. The atomic coordinates and structure factor files for the structure of TKI and TKI:PPT complex have been deposited in the Protein Data Bank with accession numbers 4AN6 and 4AN7, respectively

Structured digital abstract

 TKI and TKI bind by x-ray crystallography (View interaction)

 TKI and PPT bind by x-ray crystallography (View interaction)
Active site analysis of yeast flavohemoglobin based on its structure with a small ligand or econazole
Authors: El Hammi Emna , Warkentin Eberhard , Demmer Ulrike , Marzouki Nejib M. , Ermler Ulrich , Baciou Laura
Published: October 2012

Flavohemoglobins (flavoHbs) serve various microorganisms as the major protective enzymes against NO˙‐mediated toxicity. FlavoHbs dominantly function as an NO˙ dioxygenase (), the required electron being shuttled from NAD(P)H via FAD to the heme iron. The X‐ray structures of the flavoHb from Saccharomyces cerevisae presented in complex with an unknown small ligand (Yhb) and with econazole (YhbE) at 2.1 and 3.0 Å resolutions, respectively, reveal a high architectural accordance between prokaryotic and eukaryotic family members. The active site is characterized by a proximal heme side with a strictly conserved histidine, glutamate and tyrosine triad and a highly variable distal heme side with helix shifts up to 10 Å mainly dependent on the presence/absence and size of the bound ligand. In yeast flavoHb, the small heme iron ligand adjusts a catalytically productive active site geometry that reliably suggests the NO and O2 binding site. O2 is activated by its ligation to an electron‐rich heme iron and a hydrogen bond to Tyr29 and Gln53. High active site similarities between eukaryotic Yhb and bacterial single‐domain globins argue for identical biochemical reactions. Binding of the bulky econazole implies a large‐scale induced‐fit process concerning, in particular, an outwards shift of helices B and E to increase the active site pocket. Yeast Yhb and Ralstonia eutropha flavoHb both structurally studied in complex with econazole indicate conformational differences between the inhibitors and the polypeptide primarily caused by stable binding of a phospholipid to the latter and by distinct loop D structures.

Database

Structural data and final coordinates of Yhb and Yhb‐econazole are available in the Protein Data Bank under the accession numbers 4G1V and 4G1B
The S100A6 calcium‐binding protein regulates endothelial cell‐cycle progression and senescence
Authors: Bao Leyuan , Odell Adam F. , Stephen Sam L. , Wheatcroft Stephen B. , Walker John H. , Ponnambalam Sreenivasan
Published: October 2012

Endothelial cells regulate many aspects of vascular physiology, including vasculogenesis and angiogenesis. The S100 family of calcium‐binding proteins regulates many aspects of cell function but their roles in vascular physiology are less well understood. Herein, we investigated the expression and function of S100‐related family members in endothelial cells. Analysis of total endothelial mRNAs using a human gene chip array revealed significant gene expression of the S100 calcium‐binding protein family members S100A6, S100A10, S100A11 and S100A13. We then examined the expression and functional properties of the major S100 family member, S100A6, in vascular endothelial cells. Comparison of primary and transformed human cells revealed significant differences in S100A6 protein levels in these cells. In primary human endothelial cells, S100A6 was present in both the nucleus and the cytoplasm. To assess the function of endothelial S100A6, we depleted protein levels using RNA interference and this caused increased cell‐cycle arrest in the G2/M phase under different conditions. S100A6 depletion caused a decrease in both cyclin‐dependent kinase 1 (CDK1) and phospho‐CDK1 levels, which are essential for eukaryote cell‐cycle progression. S100A6 depletion also decreased expression of CDK1, cyclin A1 (CCNA1) and cyclin B (CCNB1) genes with effects on cell‐cycle progression. Depletion of endothelial S100A6 levels also elevated β‐galactosidase expression, which is an important hallmark of cellular senescence and exit from the mammalian cell cycle. We thus propose that S100A6 has an important role in regulating endothelial commitment to, and progression through, the cell cycle.