bluuebunny/crossref_metadata_2025_split huggingface dataset:
The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias
Authors: Hesson Luke B , Dunwell Thomas L , Cooper Wendy N , Catchpoole Daniel , Brini Anna T , Chiaramonte Raffaella , Griffiths Mike , Chalmers Andrew D , Maher Eamonn R , Latif Farida 
Published: July 2009

Abstract

Background
The Ras-assocation family (RASSF) of tumour suppressor genes (TSGs) contains 10 members that encode proteins containing Ras-assocation (RA) domains. Several members of the RASSF family are frequently epigenetically inactivated in cancer, however, their role in leukaemia has remained largely uninvestigated. Also, RASSF10 is a predicted gene yet to be experimentally verified. Here we cloned, characterised and demonstrated expression of RASSF10 in normal human bone marrow. We also determined the methylation status of CpG islands associated with RASSF1–10 in a series of childhood acute lymphocytic leukaemias (ALL) and normal blood and bone marrow samples.

Results
COBRA and bisulphite sequencing revealed RASSF6 and RASSF10 were the only RASSF members with a high frequency of leukaemia-specific methylation. RASSF6 was methylated in 94% (48/51) B-ALL and 41% (12/29) T-ALL, whilst RASSF10 was methylated in 16% (8/51) B-ALL and 88% (23/26) T-ALL. RASSF6 and RASSF10 expression inversely correlated with methylation which was restored by treatment with 5-aza-2'deoxycytidine (5azaDC).

Conclusion
This study shows the hypermethylation profile of RASSF genes in leukaemias is distinct from that of solid tumours and represents the first report of inactivation of RASSF6 or RASSF10 in cancer. These data show epigenetic inactivation of the candidate TSGs RASSF6 and RASSF10 is an extremely frequent event in the pathogenesis of childhood leukaemia. This study also warrants further investigation of the newly identified RASSF member RASSF10 and its potential role in leukaemia.
Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study
Authors: Lindkvist Annica , Edén Arvid , Norström Melissa M , Gonzalez Veronica D , Nilsson Staffan , Svennerholm Bo , Karlsson Annika C , Sandberg Johan K , Sönnerborg Anders , Gisslén Magnus 
Published: July 2009

AbstractBackgroundThe latency of HIV-1 in resting CD4+T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective.MethodsNine subjects on effective ART were included in the study and treated with high dosage intravenous immunoglobulin (IVIG) for five consecutive days. Seven of those had detectable levels of replication-competent virus in the latent reservoir and were thus possible to evaluate. Highly purified resting memory CD4+T-cells were activated and cells containing replication-competent HIV-1 were quantified. HIV-1 from plasma and activated memory CD4+T-cells were compared with single genome sequencing (SGS) of thegagregion. T-lymphocyte activation markers and serum interleukins were measured.ResultsThe latent HIV-1 pool decreased with in median 68% after IVIG was added to effective ART. The reservoir decreased in five, whereas no decrease was found in two subjects with detectable virus. Plasma HIV-1 RNA ≥ 2 copies/mL was detected in five of seven subjects at baseline, but in only one at follow-up after 8–12 weeks. The decrease of the latent HIV-1 pool and the residual plasma viremia was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool and SGS of thegagregion showed that viral clones from plasma clustered together with virus from activated memory T-cells, pointing to the latent reservoir as the source of HIV-1 RNA in plasma.ConclusionThe findings from this uncontrolled proof-of-concept study suggest that the reservoir became accessible by IVIG treatment through activation of HIV-1 gene expression in latently-infected resting CD4+T-cells. We propose that IVIG should be further evaluated as an adjuvant to effective ART.
Resveratrol exhibits a strong cytotoxic activity in cultured cells and has an antiviral action against polyomavirus: potential clinical use
Authors: Berardi Valerio , Ricci Francesca , Castelli Mauro , Galati Gaspare , Risuleo Gianfranco 
Published: July 2009

Abstract

Background
Resveratrol is a non flavonoid polyphenol compound present in many plants and fruits and, at especially high concentrations, in the grape berries of Vitis vinifera. This compound has a strong bioactivity and its cytoprotective action has been demonstrated, however at high concentrations the drug exhibits also an effective anti-proliferative action. We recently showed its ability to abolish the effects of oxidative stress in cultured cells. In this work we assayed the bioactivity of resveratrol as antiproliferative and antiviral drug in cultured fibroblasts. Studies by other Authors showed that this natural compound inhibits the proliferation of different viruses such as herpes simplex, varicella-zoster and influenza A. The results presented here show an evident toxic activity of the drug at high concentrations, on the other hand at sub-cytotoxic concentrations, resveratrol can effectively inhibit the synthesis of polyomavirus DNA. A possible interpretation is that, due to the damage caused by resveratrol to the plasma membrane, the transfer of the virus from the endoplasmic reticulum to the nucleus, may be hindered thus inhibiting the production of viral DNA.

Methods
The mouse fibroblast line 3T6 and the human tumor line HL60 were used throughout the work. Cell viability and vital cell count were assessed respectively, by the MTT assay and Trypan Blue staining. Cytotoxic properties and evaluation of viral DNA production by agarose gel electrophoresis were performed according to standard protocols.

Results
Our results show a clear dose dependent both cytotoxic and antiviral effect of resveratrol respectively at high and low concentrations. The cytotoxic action is exerted towards a stabilized cell-line (3T6) as well as a tumor-line (HL60). Furthermore the antiviral action is evident after the phase of virion entry, therefore data suggest that the drug acts during the synthesis of the viral progeny DNA.

Conclusion
Resveratrol is cytotoxic and inhibits, in a dose dependent fashion, the synthesis of polyomavirus DNA in the infected cell. Furthermore, this inhibition is observed at non cytotoxic concentrations of the drug. Our data imply that cyto-toxicity may be attributed to the membrane damage caused by the drug and that the transfer of polyomavirus from the endoplasmic reticulum to the cytoplasm may be hindered. In conclusion, the cytotoxic and antiviral properties of resveratrol make it a potential candidate for the clinical control of proliferative as well as viral pathologies.
Differences in resistance mutations among HIV‐1 non‐subtype B infections: a systematic review of evidence (1996–2008)
Authors: Martinez‐Cajas Jorge L , Pai Nitika P , Klein Marina B , Wainberg Mark A 
Published: July 2009

Ninety percent of HIV‐1‐infected people worldwide harbour non‐subtype B variants of HIV‐1. Yet knowledge of resistance mutations in non‐B HIV‐1 and their clinical relevance is limited. Although a few reviews, editorials and perspectives have been published alluding to this lack of data among non‐B subtypes, no systematic review has been performed to date.With this in mind, we conducted a systematic review (1996–2008) of all published studies performed on the basis of non‐subtype B HIV‐1 infections treated with antiretroviral drugs that reported genotype resistance tests. Using an established search string, 50 studies were deemed relevant for this review.These studies reported genotyping data from non‐B HIV‐1 infections that had been treated with either reverse transcriptase inhibitors or protease inhibitors. While most major resistance mutations in subtype B were also found in non‐B subtypes, a few novel mutations in non‐B subtypes were recognized. The main differences are reflected in the discoveries that: (i) the non‐nucleoside reverse transcriptase inhibitor resistance mutation, V106M, has been seen in subtype C and CRF01_AE, but not in subtype B, (ii) the protease inhibitor mutations L89I/V have been reported in C, F and G subtypes, but not in B, (iii) a nelfinavir selected non‐D30N containing pathway predominated in CRF01_AE and CRF02_AG, while the emergence of D30N is favoured in subtypes B and D, (iv) studies on thymidine analog‐treated subtype C infections from South Africa, Botswana and Malawi have reported a higher frequency of the K65R resistance mutation than that typically seen with subtype B.Additionally, some substitutions that seem to impact non‐B viruses differentially are: reverse transcriptase mutations G196E, A98G/S, and V75M; and protease mutations M89I/V and I93L.Polymorphisms that were common in non‐B subtypes and that may contribute to resistance tended to persist or become more frequent after drug exposure. Some, but not all, are recognized as minor resistance mutations in B subtypes. These observed differences in resistance pathways may impact cross‐resistance and the selection of second‐line regimens with protease inhibitors. Attention to newer drug combinations, as well as baseline genotyping of non‐B isolates, in well‐designed longitudinal studies with long duration of follow up are needed.
Broad-range PCR, cloning and sequencing of the full 16S rRNA gene for detection of bacterial DNA in synovial fluid samples of Tunisian patients with reactive and undifferentiated arthritis
Authors: Siala Mariam , Gdoura Radhouane , Fourati Hela , Rihl Markus , Jaulhac Benoit , Younes Mohamed , Sibilia Jean , Baklouti Sofien , Bargaoui Naceur , Sellami Slaheddine , Sghir Abdelghani , Hammami Adnane 
Published: July 2009

Abstract
Introduction
Broad-range rDNA PCR provides an alternative, cultivation-independent approach for identifying bacterial DNA in reactive and other form of arthritis. The aim of this study was to use broad-range rDNA PCR targeting the 16S rRNA gene in patients with reactive and other forms of arthritis and to screen for the presence of DNA from any given bacterial species in synovial fluid (SF) samples.

Methods
We examined the SF samples from a total of 27 patients consisting of patients with reactive arthritis (ReA) (n = 5), undifferentiated arthritis (UA) (n = 9), rheumatoid arthritis (n = 7), and osteoarthritis (n = 6) of which the latter two were used as controls. Using broad-range bacterial PCR amplifying a 1400 bp fragment from the 16S rRNA gene, we identified and sequenced at least 24 clones from each SF sample. To identify the corresponding bacteria, DNA sequences were compared to the EMBL (European Molecular Biology Laboratory) database.

Results
Bacterial DNA was identified in 20 of the 27 SF samples (74, 10%). Analysis of a large number of sequences revealed the presence of DNA from more than one single bacterial species in the SF of all patients studied. The nearly complete sequences of the 1400 bp were obtained for most of the detected species. DNA of bacterial species including Shigella species, Escherichia species, and other coli-form bacteria as well as opportunistic pathogens such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans were shared in all arthritis patients. Among pathogens described to trigger ReA, DNA from Shigella sonnei was found in ReA and UA patients. We also detected DNA from rarely occurring human pathogens such as Aranicola species and Pantoea ananatis. We also found DNA from bacteria so far not described in human infections such as Bacillus niacini, Paenibacillus humicus, Diaphorobacter species and uncultured bacterium genera incertae sedis OP10.

Conclusions
Broad-range PCR followed by cloning and sequencing the entire 16S rDNA, allowed the identification of the bacterial DNA environment in the SF samples of arthritic patients. We found a wide spectrum of bacteria including those known to be involved in ReA and others not previously associated with arthritis.
Motifs and cis-regulatory modules mediating the expression of genes co-expressed in presynaptic neurons
Authors: Liu Rui , Hannenhalli Sridhar , Bucan Maja 
Published: July 2009

Abstract
Background
Hundreds of proteins modulate neurotransmitter release and synaptic plasticity during neuronal development and in response to synaptic activity. The expression of genes in the pre- and post-synaptic neurons is under stringent spatio-temporal control, but the mechanism underlying the neuronal expression of these genes remains largely unknown.

Results
Using unbiased in vivo and in vitro screens, we characterized the cis elements regulating the Rab3A gene, which is expressed abundantly in presynaptic neurons. A set of identified regulatory elements of the Rab3A gene corresponded to the defined Rab3A multi-species conserved elements. In order to identify clusters of enriched transcription factor binding sites, for example, cis-regulatory modules, we analyzed intergenic multi-species conserved elements in the vicinity of nine presynaptic genes, including Rab3A, that are highly and specifically expressed in brain regions. Sixteen transcription factor binding motifs were over-represented in these multi-species conserved elements. Based on a combined occurrence for these enriched motifs, multi-species conserved elements in the vicinity of 107 previously identified presynaptic genes were scored and ranked. We then experimentally validated the scoring strategy by showing that 12 of 16 (75%) high-scoring multi-species conserved elements functioned as neuronal enhancers in a cell-based assay.

Conclusions
This work introduces an integrative strategy of comparative genomics, experimental, and computational approaches to reveal aspects of a regulatory network controlling neuronal-specific expression of genes in presynaptic neurons.
Prenatal risk factors for autism: comprehensive meta-analysis
Authors: Gardener Hannah , Spiegelman Donna , Buka Stephen L. 
Published: July 2009

BackgroundThe aetiology of autism is unknown, although prenatal exposures have been the focus of epidemiological research for over 40 years.AimsTo provide the first quantitative review and meta-analysis of the association between maternal pregnancy complications and pregnancy-related factors and risk of autism.MethodPubMed, Embase and PsycINFO databases were searched for epidemiological studies that examined the association between pregnancy-related factors and autism. Forty studies were eligible for inclusion in the meta-analysis. Summary effect estimates were calculated for factors examined in multiple studies.ResultsOver 50 prenatal factors have been examined. The factors associated with autism risk in the meta-analysis were advanced parental age at birth, maternal prenatal medication use, bleeding, gestational diabetes, being first born v. third or later, and having a mother born abroad. The factors with the strongest evidence against a role in autism risk included previous fetal loss and maternal hypertension, proteinuria, pre-eclampsia and swelling.ConclusionsThere is insufficient evidence to implicate any one prenatal factor in autism aetiology, although there is some evidence to suggest that exposure to pregnancy complications may increase the risk.
Effect of feedback of treatment outcome in specialist mental
healthcare: meta-analysis
Authors: Knaup Carina , Koesters Markus , Schoefer Dorothea , Becker Thomas , Puschner Bernd 
Published: July 2009

BackgroundFeedback of treatment outcome during the course of therapy (outcome
management) is increasingly considered to be beneficial for improving the
quality of mental healthcare.AimsTo review the impact of feedback of outcome to practitioners and/or
patients in specialist mental health services.MethodA systematic search and meta-analysis of controlled trials using outcome
management in mental health services published in English or German
language.ResultsTwelve studies met inclusion criteria. Feeding back outcome showed a
small, but significant (d = 0.10; 95% CI 0.01–0.19) positive short-term
effect on the mental health of individuals that did not prevail in the
long run. Subgroup analysis revealed no significant differences regarding
feedback modalities. Outcome management did not contribute to a reduction
of treatment duration.ConclusionsEvidence on the effects of outcome management in mental healthcare is
promising. More targeted research is needed in order to identify the
effective ingredients of outcome feedback and to assess its
cost-effectiveness.
Clinical effectiveness of online computerised
cognitive–behavioural therapy without support for depression in primary
care: randomised trial
Authors: de Graaf L. E. , Gerhards S. A. H. , Arntz A. , Riper H. , Metsemakers J. F. M. , Evers S. M. A. A. , Severens J. L. , Widdershoven G. , Huibers M. J. H. 
Published: July 2009

BackgroundComputerised cognitive–behavioural therapy (CCBT) might offer a solution
to the current undertreatment of depression.AimsTo determine the clinical effectiveness of online, unsupported CCBT for
depression in primary care.MethodThree hundred and three people with depression were randomly allocated to
one of three groups: Colour Your Life; treatment as usual (TAU) by a
general practitioner; or Colour Your Life and TAU combined. Colour Your
Life is an online, multimedia, interactive CCBT programme. No assistance
was offered. We had a 6-month follow-up period.ResultsNo significant differences in outcome between the three interventions
were found in the intention-to-treat and per protocol analyses.ConclusionsOnline, unsupported CCBT did not outperform usual care, and the
combination of both did not have additional effects. Decrease in
depressive symptoms in people with moderate to severe depression was
moderate in all three interventions. Online CCBT without support is not
beneficial for all individuals with depression.
Shooting the messenger: the science and politics of ethnicity
research
Authors: Singh Swaran P. 
Published: July 2009

SummaryScientific arguments showing ‘how the world is’ are fundamentally different
from political assertions about ‘how the world should be’. Ideologically
motivated political attacks can hamper our understanding of mental disorders
by preventing academics from pursuing research in contentious areas.
Evidence should be countered by better evidence, not by shooting the
messenger.
Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept
Authors: Hamshere M. L. , Green E. K. , Jones I. R. , Jones L. , Moskvina V. , Kirov G. , Grozeva D. , Nikolov I. , Vukcevic D. , Caesar S. , Gordon-Smith K. , Fraser C. , Russell E. , Breen G. , Clair D. St , Collier D. A. , Young A. H. , Ferrier I. N. , Farmer A. , McGuffin P. , Holmans P. A. , Owen M. J. , O'Donovan M. C. , Craddock N. ,   Wellcome Trust Case Control Consortium
Published: July 2009

BackgroundPsychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological–genetic research.AimsTo use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case–control bipolar disorder sample.MethodWe analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant atP<0.00001 as a metric for the overall genetic signal in the sample. We next compared this metric with that obtained using each of seven diagnostic subsets of the group with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder; manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type; DSM–IV: bipolar I disorder; bipolar II disorder; schizoaffective disorder, bipolar type.ResultsThe RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (P<0.003) compared with that expected in samples of the same size selected randomly from the total bipolar disorder group data-set. The strongest association in this subset of participants with bipolar disorder was at rs4818065 (P= 2.42 × 10–7). Biological systems implicated included gamma amniobutyric acid (GABA)Areceptors. Genes having at least one associated polymorphism atP<10–4includedB3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2andCDH12.ConclusionsOur findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes.
The rise and fall of the biopsychosocial model
Authors: Ghaemi S. Nassir 
Published: July 2009

SummaryThe biopsychosocial model is the conceptual status quo of contemporary psychiatry. Although it has played an important role in combatting psychiatric dogmatism, it has devolved into mere eclecticism. Other non-reductionistic approaches to medicine and psychiatry such as William Osler's medical humanism or Karl Jaspers' method-based psychiatry should be reconsidered.
Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes
Authors: Salgin Burak , Marcovecchio Maria L. , Williams Rachel M. , Jackson Sarah J. , Bluck Leslie J. , Humphreys Sandy M. , Acerini Carlo L. , Dunger David B. 
Published: July 2009

Context: Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D.
Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit.
Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P &lt; 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity.
Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis.
Growth hormone decreases insulin sensitivity through increases in free fatty acid levels.