Y-chromosome R-M343 African lineages and sickle cell disease reveal structured assimilation in Lebanon. We have sought to identify signals of assimilation of African male lines in Lebanon by exploring the association of sickle cell disease (SCD) in Lebanon with Y-chromosome haplogroups that are informative of the disease origin and its exclusivity to the Muslim community. A total of 732 samples were analyzed, including 33 SCD patients from Lebanon genotyped for 28 binary markers and 19 short tandem repeats on the non-recombinant segment of the Y chromosome. Genetic organization was identified using populations known to have influenced the genetic structure of the Lebanese population, in addition to African populations with high incidence of SCD. Y-chromosome haplogroup R-M343 sub-lineages distinguish between sub-Saharan African and Lebanese Y chromosomes. We detected a limited penetration of SCD into Lebanese R-M343 carriers, restricted to Lebanese Muslims. We suggest that this penetration brought the sickle cell gene along with the African R-M343, probably with the Saharan caravan slave trade.


Association of serotonin transporter gene variation with smoking, chronic obstructive pulmonary disease, and its depressive symptoms. A serotonin transporter gene, SLC6A4, is thought to be related to nicotine dependence and depression, one of the comorbidities of chronic obstructive pulmonary disease (COPD). To investigate the association between SLC6A4 variation and tobacco consumption, susceptibility to COPD, and depression status. In all, 247 patients with COPD and 119 control subjects were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) of SLC6A4. We analyzed the correlation between these genotypes and COPD, using the results of a pulmonary function test or chest computed tomography; data on tobacco consumption (pack-years); and the depression score based on the hospital anxiety and depression scale (HADS) after adjusting for age, gender, and smoking status (and pack-years, when appropriate). The rare allele rs2020936 was significantly associated with COPD incidence in the trend model (P = 0.003; odds ratio, 2.20; 95% confidence interval, 1.31-3.74). This allele was also associated with the number of pack-years (P = 0.026). The major allele of another SNP of SLC6A4, namely rs3794808, correlated with the HADS depression score (P = 0.016). We conclude that SLC6A4 variation affects COPD pathogenesis, and this effect depends partly on tobacco consumption. SLC6A4 variation also affects depressive symptoms. SLC6A4 could be modified to prevent COPD and treat the depressive symptoms of COPD.


Regional disaster planning for neonatology.


Chromosome 17q21 SNP and severe asthma.

Chromosome 17q21 SNP and severe asthma.


Lacrimal gland choristoma in a preterm infant, presenting with spontaneous hyphema and increased intraocular pressure. We report a case of intraocular lacrimal gland choristoma presenting very early in a preterm infant with hyphema, a mass lesion and raised intraocular pressure. Enucleation of the involved eye, which is the treatment in most cases, was performed and prosthesis was fitted successfully. An interesting additional finding in our patient was a choroidal defect, not reported to date with other cases in the literature.


Prenatally diagnosed left ventricular diverticulum with thoracoabdominal wall defect: a case and review of the literature.


Volatile accretion history of the Earth. It has long been thought that the Earth had a protracted and complex history of volatile accretion and loss. Albarède paints a different picture, proposing that the Earth first formed as a dry planet which, like the Moon, was devoid of volatile constituents. He suggests that the Earth's complement of volatile elements was only established later, by the addition of a small veneer of volatile-rich material at ∼100 Myr (here and elsewhere, ages are relative to the origin of the Solar System). Here we argue that the Earth's mass balance of moderately volatile elements is inconsistent with Albarède's hypothesis but is well explained by the standard model of accretion from partially volatile-depleted material, accompanied by core formation.


Preventing mother-to-child transmission of HIV in urban Zimbabwe.


Not quite assured.

Not quite assured.


The innovation game.

The innovation game.


Space hitch-hiker.

Space hitch-hiker.


Glimpsing a comet's heart.

Glimpsing a comet's heart.


Spending review leaves research in the lurch.


Verbal autopsy methods questioned.

Verbal autopsy methods questioned.


UK scientists celebrate budget reprieve.


Quake threat looms over Haiti.

Quake threat looms over Haiti.


Mystery fraud accusations.

Mystery fraud accusations.


Mountaintop mining plans close to defeat.


Human genome: Genomes by the thousand.

Human genome: Genomes by the thousand.


Space science: The telescope that ate astronomy.


Long shadow of the stem-cell ruling.

Long shadow of the stem-cell ruling.


Fate of 'retired' research chimps.

Fate of 'retired' research chimps.


Marine stewardship: catalysing change.

Marine stewardship: catalysing change.


Pakistan: the brain drain dilemma.

Pakistan: the brain drain dilemma.


Pakistan: why the reforms need work.

Pakistan: why the reforms need work.


Safaris can help conservation.

Safaris can help conservation.


Georges Charpak (1924-2010).

Georges Charpak (1924-2010).


Genomics: In search of rare human variants.


Drug development: Longer-lived proteins.


Biogeochemistry: Phosphorus and the gust of fresh air.


Cancer: Genomic evolution of metastasis.


Stem cells: The intestinal-crypt casino.


Astrophysics: Weighing in on neutron stars.


Structural biology: A peep through anion channels.


A two-solar-mass neutron star measured using Shapiro delay. Neutron stars are composed of the densest form of matter known to exist in our Universe, the composition and properties of which are still theoretically uncertain. Measurements of the masses or radii of these objects can strongly constrain the neutron star matter equation of state and rule out theoretical models of their composition. The observed range of neutron star masses, however, has hitherto been too narrow to rule out many predictions of 'exotic' non-nucleonic components. The Shapiro delay is a general-relativistic increase in light travel time through the curved space-time near a massive body. For highly inclined (nearly edge-on) binary millisecond radio pulsar systems, this effect allows us to infer the masses of both the neutron star and its binary companion to high precision. Here we present radio timing observations of the binary millisecond pulsar J1614-2230 that show a strong Shapiro delay signature. We calculate the pulsar mass to be (1.97 ± 0.04)M(⊙), which rules out almost all currently proposed hyperon or boson condensate equations of state (M(⊙), solar mass). Quark matter can support a star this massive only if the quarks are strongly interacting and are therefore not 'free' quarks.


Homologue structure of the SLAC1 anion channel for closing stomata in leaves. The plant SLAC1 anion channel controls turgor pressure in the aperture-defining guard cells of plant stomata, thereby regulating the exchange of water vapour and photosynthetic gases in response to environmental signals such as drought or high levels of carbon dioxide. Here we determine the crystal structure of a bacterial homologue (Haemophilus influenzae) of SLAC1 at 1.20 Å resolution, and use structure-inspired mutagenesis to analyse the conductance properties of SLAC1 channels. SLAC1 is a symmetrical trimer composed from quasi-symmetrical subunits, each having ten transmembrane helices arranged from helical hairpin pairs to form a central five-helix transmembrane pore that is gated by an extremely conserved phenylalanine residue. Conformational features indicate a mechanism for control of gating by kinase activation, and electrostatic features of the pore coupled with electrophysiological characteristics indicate that selectivity among different anions is largely a function of the energetic cost of ion dehydration.


Detecting excitation and magnetization of individual dopants in a semiconductor. An individual magnetic atom doped into a semiconductor is a promising building block for bottom-up spintronic devices and quantum logic gates. Moreover, it provides a perfect model system for the atomic-scale investigation of fundamental effects such as magnetism in dilute magnetic semiconductors. However, dopants in semiconductors so far have not been studied by magnetically sensitive techniques with atomic resolution that correlate the atomic structure with the dopant's magnetism. Here we show electrical excitation and read-out of a spin associated with a single magnetic dopant in a semiconductor host. We use spin-resolved scanning tunnelling spectroscopy to measure the spin excitations and the magnetization curve of individual iron surface-dopants embedded within a two-dimensional electron gas confined to an indium antimonide (110) surface. The dopants act like isolated quantum spins the states of which are governed by a substantial magnetic anisotropy that forces the spin to lie in the surface plane. This result is corroborated by our first principles calculations. The demonstrated methodology opens new routes for the investigation of sample systems that are more widely studied in the field of spintronics-that is, Mn in GaAs (ref. 5), magnetic ions in semiconductor quantum dots, nitrogen-vacancy centres in diamond and phosphorus spins in silicon.


Deformation of the lowermost mantle from seismic anisotropy. The lowermost part of the Earth's mantle-known as D″-shows significant seismic anisotropy, the variation of seismic wave speed with direction. This is probably due to deformation-induced alignment of MgSiO(3)-post-perovskite (ppv), which is believed to be the main mineral phase present in the region. If this is the case, then previous measurements of D″ anisotropy, which are generally made in one direction only, are insufficient to distinguish candidate mechanisms of slip in ppv because the mineral is orthorhombic. Here we measure anisotropy in D″ beneath North and Central America, where material from subducting oceanic slabs impinges on the core-mantle boundary, using shallow as well as deep earthquakes to increase the azimuthal coverage in D″. We make more than 700 individual measurements of shear wave splitting in D″ in three regions from two different azimuths in each case. We show that the previously assumed case of vertical transverse isotropy (where wave speed shows no azimuthal variation) is not possible, and that more complicated mechanisms must be involved. We test the fit of different MgSiO(3)-ppv deformation mechanisms to our results and find that shear on (001) is most consistent with observations and the expected shear above the core-mantle boundary beneath subduction zones. With new models of mantle flow, or improved experimental determination of the dominant ppv slip systems, this method will allow us to map deformation at the core-mantle boundary and link processes in D″, such as plume initiation, to the rest of the mantle.


The evolution of the marine phosphate reservoir. Phosphorus is a biolimiting nutrient that has an important role in regulating the burial of organic matter and the redox state of the ocean-atmosphere system. The ratio of phosphorus to iron in iron-oxide-rich sedimentary rocks can be used to track dissolved phosphate concentrations if the dissolved silica concentration of sea water is estimated. Here we present iron and phosphorus concentration ratios from distal hydrothermal sediments and iron formations through time to study the evolution of the marine phosphate reservoir. The data suggest that phosphate concentrations have been relatively constant over the Phanerozoic eon, the past 542 million years (Myr) of Earth's history. In contrast, phosphate concentrations seem to have been elevated in Precambrian oceans. Specifically, there is a peak in phosphorus-to-iron ratios in Neoproterozoic iron formations dating from ∼750 to ∼635 Myr ago, indicating unusually high dissolved phosphate concentrations in the aftermath of widespread, low-latitude 'snowball Earth' glaciations. An enhanced postglacial phosphate flux would have caused high rates of primary productivity and organic carbon burial and a transition to more oxidizing conditions in the ocean and atmosphere. The snowball Earth glaciations and Neoproterozoic oxidation are both suggested as triggers for the evolution and radiation of metazoans. We propose that these two factors are intimately linked; a glacially induced nutrient surplus could have led to an increase in atmospheric oxygen, paving the way for the rise of metazoan life.


Late middle Eocene epoch of Libya yields earliest known radiation of African anthropoids. Reconstructing the early evolutionary history of anthropoid primates is hindered by a lack of consensus on both the timing and biogeography of anthropoid origins. Some prefer an ancient (Cretaceous) origin for anthropoids in Africa or some other Gondwanan landmass, whereas others advocate a more recent (early Cenozoic) origin for anthropoids in Asia, with subsequent dispersal of one or more early anthropoid taxa to Africa. The oldest undoubted African anthropoid primates described so far are three species of the parapithecid Biretia from the late middle Eocene Bir El Ater locality of Algeria and the late Eocene BQ-2 site in the Fayum region of northern Egypt. Here we report the discovery of the oldest known diverse assemblage of African anthropoids from the late middle Eocene Dur At-Talah escarpment in central Libya. The primate assemblage from Dur At-Talah includes diminutive species pertaining to three higher-level anthropoid clades (Afrotarsiidae, Parapithecidae and Oligopithecidae) as well as a small species of the early strepsirhine primate Karanisia. The high taxonomic diversity of anthropoids at Dur At-Talah indicates either a much longer interval of anthropoid evolution in Africa than is currently documented in the fossil record or the nearly synchronous colonization of Africa by multiple anthropoid clades at some time during the middle Eocene epoch.


Fine-scale recombination rate differences between sexes, populations and individuals. Meiotic recombinations contribute to genetic diversity by yielding new combinations of alleles. Recently, high-resolution recombination maps were inferred from high-density single-nucleotide polymorphism (SNP) data using linkage disequilibrium (LD) patterns that capture historical recombination events. The use of these maps has been demonstrated by the identification of recombination hotspots and associated motifs, and the discovery that the PRDM9 gene affects the proportion of recombinations occurring at hotspots. However, these maps provide no information about individual or sex differences. Moreover, locus-specific demographic factors like natural selection can bias LD-based estimates of recombination rate. Existing genetic maps based on family data avoid these shortcomings, but their resolution is limited by relatively few meioses and a low density of markers. Here we used genome-wide SNP data from 15,257 parent-offspring pairs to construct the first recombination maps based on directly observed recombinations with a resolution that is effective down to 10 kilobases (kb). Comparing male and female maps reveals that about 15% of hotspots in one sex are specific to that sex. Although male recombinations result in more shuffling of exons within genes, female recombinations generate more new combinations of nearby genes. We discover novel associations between recombination characteristics of individuals and variants in the PRDM9 gene and we identify new recombination hotspots. Comparisons of our maps with two LD-based maps inferred from data of HapMap populations of Utah residents with ancestry from northern and western Europe (CEU) and Yoruba in Ibadan, Nigeria (YRI) reveal population differences previously masked by noise and map differences at regions previously described as targets of natural selection.


On-line, voluntary control of human temporal lobe neurons. Daily life continually confronts us with an exuberance of external, sensory stimuli competing with a rich stream of internal deliberations, plans and ruminations. The brain must select one or more of these for further processing. How this competition is resolved across multiple sensory and cognitive regions is not known; nor is it clear how internal thoughts and attention regulate this competition. Recording from single neurons in patients implanted with intracranial electrodes for clinical reasons, here we demonstrate that humans can regulate the activity of their neurons in the medial temporal lobe (MTL) to alter the outcome of the contest between external images and their internal representation. Subjects looked at a hybrid superposition of two images representing familiar individuals, landmarks, objects or animals and had to enhance one image at the expense of the other, competing one. Simultaneously, the spiking activity of their MTL neurons in different subregions and hemispheres was decoded in real time to control the content of the hybrid. Subjects reliably regulated, often on the first trial, the firing rate of their neurons, increasing the rate of some while simultaneously decreasing the rate of others. They did so by focusing onto one image, which gradually became clearer on the computer screen in front of their eyes, and thereby overriding sensory input. On the basis of the firing of these MTL neurons, the dynamics of the competition between visual images in the subject's mind was visualized on an external display.


The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.


Genomics: The tough new variants.

Genomics: The tough new variants.


Genomics: The search for association.

Genomics: The search for association.


Genomics: Seeing more SNPs.

Genomics: Seeing more SNPs.


Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.


A map of human genome variation from population-scale sequencing. The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.


Adenovirus-mediated human paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon. Human paraoxonase1 (hPON1) is a potential therapeutic against the toxicity of organophosphorus (OP) pesticides and chemical warfare nerve agents. We tested whether PON1 gene transfer using adenovirus provides protection against the toxicity of the OP diazoxon. Using an adenovirus construct containing hPON1 gene, we showed elevated levels of recombinant hPON1 in vitro in 293A cells and in vivo in mice. The recombinant enzyme was secreted by 293A cells into culture medium and into the systemic circulation of mice. Western blotting revealed that the virally expressed hPON1 had the expected molecular weight of 45 kDa. Recombinant hPON1 in mice was in complex with mouse high-density lipoprotein (HDL) and migrated more slowly than endogenous hPON1 in the human HDL complex. Mice injected with adenovirus expressed PON1 at 600-3480 U ml(-1) on day 5 post-treatment, which is 8-50-fold above endogenous. Six mice expressing hPON1 survived 2LD(50) doses of diazoxon. Four of the six mice survived a second dose of diazoxon (for a total of 4LD(50)) administered 24 h later. In contrast, none of the three mice in the control group survived one 2LD(50) dose. These results show that hPON1 in mice functions as a prophylactic and offers significant protection against lethal doses of diazoxon.


Irritant activation of epithelial cells is mediated via protease-dependent EGFR activation. Although numerous studies have examined in vivo and in vitro effects of irritants, most focused on events developing hours to days after exposure. Molecular events occurring immediately after skin contact remain incompletely defined. Characterization of early events could lead to the identification of key molecular signals necessary for the production of inflammatory mediators responsible for the signs and symptoms of irritant contact dermatitis (ICD). HaCaT cells treated with sodium lauryl sulfate (SLS), a model irritant, were used to examine early molecular events of ICD. Western analysis showed SLS-mediated induction of early growth response-1 (egr-1), a transcription factor capable of regulating hallmarks of ICD such as angiogenesis, hyperproliferation, and inflammation. Additionally, de novo egr-1 expression was commensurate with transcriptional activation of egr-1 mRNA and heteronuclear RNA. Use of pharmacological inhibitors demonstrated that SLS-induced egr-1 was dependent on MEK1/p44/42 ERK, but not on p38 or JNK signaling. The EGFR inhibitor PD168393 and the metalloprotease inhibitor TAPI-2 both inhibited SLS-induced egr-1. Finally, small interfering RNA silencing of the EGFR diminished SLS-induced egr-1 mRNA. These studies suggest a role of the EGFR in SLS signaling as well as a, to our knowledge, previously unreported association between ICD and EGFR induction of egr-1.


Transient expression of OCT4 is sufficient to allow human keratinocytes to change their differentiation pathway. In this study, we describe a simple system in which human keratinocytes can be redirected to an alternative differentiation pathway. We transiently transfected freshly isolated human skin keratinocytes with the single transcription factor OCT4. Within 2 days these cells displayed expression of endogenous embryonic genes and showed reduced genomic methylation. More importantly, these cells could be specifically converted into neuronal and contractile mesenchymal cell types. Redirected differentiation was confirmed by expression of neuronal and mesenchymal cell mRNA and protein, and through a functional assay in which the newly differentiated mesenchymal cells contracted collagen gels as efficiently as authentic myofibroblasts. Thus, to generate patient-specific cells for therapeutic purposes, it may not be necessary to completely reprogram somatic cells into induced pluripotent stem cells before altering their differentiation and grafting them into new tissues.


Innovative DNA vaccine for human papillomavirus (HPV)-associated head and neck cancer. Human papillomavirus (HPV), particularly type 16, has been associated with a subset of head and neck cancers. The viral-encoded oncogenic proteins E6 and E7 represent ideal targets for immunotherapy against HPV-associated head and neck cancers. DNA vaccines have emerged as attractive approaches for immunotherapy due to its simplicity, safety and ease of preparation. Intradermal administration of DNA vaccine by means of gene gun represents an efficient method to deliver DNA directly into dendritic cells for priming antigen-specific T cells. We have previously shown that a DNA vaccine encoding an invariant chain (Ii), in which the class II-associated Ii peptide (CLIP) region has been replaced by a Pan-DR-epitope (PADRE) sequence to form Ii-PADRE, is capable of generating PADRE-specific CD4+ T cells in vaccinated mice. In the current study, we hypothesize that a DNA vaccine encoding Ii-PADRE linked to E6 (Ii-PADRE-E6) will further enhance E6-specific CD8+ T cell immune responses through PADRE-specific CD4+ T-helper cells. We found that mice vaccinated with Ii-PADRE-E6 DNA generated comparable levels of PADRE-specific CD4+ T-cell immune responses, as well as significantly stronger E6-specific CD8+ T-cell immune responses and antitumor effects against the lethal challenge of E6-expressing tumor compared with mice vaccinated with Ii-E6 DNA. Taken together, our data indicate that vaccination with Ii-E6 DNA with PADRE replacing the CLIP region is capable of enhancing the E6-specific CD8+ T-cell immune response generated by the Ii-E6 DNA. Thus, Ii-PADRE-E6 represents a novel DNA vaccine for the treatment of HPV-associated head and neck cancer and other HPV-associated malignancies.


Chronic kidney disease: the effect of CKD therapies on serum potassium levels.


Spatial organization of intestinal microbiota in the mouse ascending colon. Complex microbial populations are organized in relation to their environment. In the intestine, the inner lining (mucosa) is a potential focal point for such organization. The proximal murine colon contains mucosal folds that are known to be associated with morphologically distinct microbes. To identify these microbes, we used the technique of laser capture microdissection (LCM) to sample microbes associated with these folds (interfold region) and within the central lumen (digesta region). Using 16S rRNA gene tag pyrosequencing, we found that microbes in the interfold region were highly enriched for the phylum Firmicutes and, more specifically, for the families Lachnospiraceae and Ruminococcaceae. Other families such as Bacteroidaceae, Enterococcaceae and Lactobacillaceae were all enriched in the digesta region. This high-resolution system to capture and examine spatial organization of intestinal microbes should facilitate microbial analysis in other mouse models, furthering our understanding of host-microbial interactions.


The effectiveness of sildenafil citrate in patients with erectile dysfunction and lower urinary system symptoms and the significance of asymptomatic inflammatory prostatitis. We evaluated the effectiveness of sildenafil citrate on lower urinary system symptoms (LUTS) by using symptom score scales. We also evaluated whether or not the presence of asymptomatic inflammatory prostatitis had an effect on the alteration in the symptom scores. A total of 36 male patients were included in the study. For all the cases, 'International Prostate Symptom Score' (IPSS), 'National Health Institute Chronic Prostatitis Symptom Index' (NIH-CPSI) and 'International Index of Erectile Function' (IIEF-5) were investigated and the scores were calculated in the first visit. Sildenafil citrate was given for 30 days and at the second visit IPSS, NIH-CPSI and IIEF-5 scores were once more analyzed. Afterwards, the alterations of the scores between visits were statistically compared. Mean age of the 36 cases included in the study was 59.03±1.35. When the alterations in parameters of first visit and second visit were evaluated, we found a statistically significant increase in IIEF-5 and a statistically significant decrease in IPSS, IPSS-QOL (Quality of Life). In addition, when the cases were divided into two groups with and without asymptomatic inflammatory prostatitis, in the cases with asymptomatic inflammatory prostatitis, sildenafil citrate caused improvement only in ED, but had no effect on LUTS. Sildenafil citrate use in cases with LUTS and ED has an improving effect on LUTS as well as ED. However, in cases with asymptomatic inflammatory prostatitis, sildenafil citrate did not lead to an improvement in LUTS.


Recovery of methanotrophs from disturbance: population dynamics, evenness and functioning. Biodiversity is claimed to be essential for ecosystem functioning, but is threatened by anthropogenic disturbances. Prokaryotes have been assumed to be functionally redundant and virtually inextinguishable. However, recent work indicates that microbes may well be sensitive to environmental disturbance. Focusing on methane-oxidizing bacteria as model organisms, we simulated disturbance-induced mortality by mixing native with sterilized paddy soil in two ratios, 1:4 and 1:40, representing moderate and severe die-offs. Disturbed microcosms were compared with an untreated control. Recovery of activity and populations was followed over 4 months by methane uptake measurements, pmoA-qPCR, pmoA-based terminal restriction fragment length polymorphism and a pmoA-based diagnostic microarray. Diversity and evenness of methanotrophs decreased in disturbed microcosms, but functioning was not compromised. We consistently observed distinctive temporal shifts between type I and type II methanotrophs, and a rapid population growth leading to even higher cell numbers comparing disturbed microcosms with the control. Overcompensating mortality suggested that population size in the control was limited by competition with other bacteria. Overall, methanotrophs showed a remarkable ability to compensate for die-offs.


Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy. We had previously reported that transduction of the channelrhodopsin-2 (ChR2) gene into retinal ganglion cells restores visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats. In this study, we attempted to reveal the safety and influence of exogenous ChR2 gene expression. Adeno-associated virus (AAV) type 2 encoding ChR2 fused to Venus (rAAV-ChR2V) was administered by intra-vitreous injection to dystrophic RCS rats. However, rAAV-ChR2 gene expression was detected in non-target organs (intestine, lung and heart) in some cases. ChR2 function, monitored by recording visually evoked potentials, was stable across the observation period (64 weeks). No change in retinal histology and no inflammatory marker of leucocyte adhesion in the retinal vasculature were observed. Although antibodies to rAAV (0.01-12.21 μg ml(-1)) and ChR2 (0-4.77 μg ml(-1)) were detected, their levels were too low for rejection. T-lymphocyte analysis revealed recognition by T cells and a transient inflammation-like immune reaction only until 1 month after the rAAV-ChR2V injection. In conclusion, ChR2, which originates from Chlamydomonas reinhardtii, can be expressed without immunologically harmful reactions in vivo. These findings will help studies of ChR2 gene transfer to restore vision in progressed retinitis pigmentosa.


Acute kidney injury: kidney injury after contrast media: marker or mediator?


Chronic kidney disease: implications of the AURORA and JUPITER results.


Pathology: Oxford IgA nephropathy classification: valid for children?


Transplantation: can sirolimus prevent skin cancer in transplant recipients?


Acute kidney injury: defining prerenal azotemia in clinical practice and research.


Genetics: How to validate a breast cancer prognostic signature.


Chemotherapy: Effectiveness of adjuvant chemotherapy for resected NSCLC.


Radiotherapy: Accelerated radiotherapy for HNSCC in developing countries.


Targeted therapies: Tyrosine-kinase inhibitors--new standard for NSCLC therapy.


Chemotherapy: Lo and behold, a role for lomustine in acute myeloid leukemia?


Clinical utility of image-guided peritoneal and omental biopsy. Image-guided core biopsy of the omentum and peritoneum was described a decade ago and has since been validated in a number of large studies as a safe and effective means of providing a tissue diagnosis in patients with undiagnosed peritoneal disease. Some studies have addressed its ability for determining whether peritoneal infiltration and/or omental masses in patients with prior malignancy represent recurrent disease or a new disease process. Others have focused on the specific issue of women suspected to have advanced peritoneal carcinomatosis from ovarian or primary peritoneal cancer where the primary management of the patient is directed by the tissue diagnosis. The initial management of many of these women, especially those with advanced disease or substantial comorbidity, is with primary chemotherapy. With current clinical trials for ovarian cancer directed to specific morphological subtypes of the disease, image-guided core biopsy offers a rapid and well tolerated nonsurgical means of providing this information. In this Review, we discuss the technique and its clinical applications, and critically examine the currently available alternative options.


Sudden infant death syndrome and left ventricular hypertrabeculation-hidden arrhythmogenic entity? Left ventricular noncompaction/hypertrabeculation is a condition which is characterized by a highly trabeculated, "spongy" myocardium.It can present at any age with heart failure, arrhythmia and/or thromboembolic events.A wide variety of mutations have been found to be a cause of hypertrabeculation and it is possible that there is a continuum of hypertrophic cardiomyopathy, dilated cardiomyopathy and hypertrabeculation/noncompaction.We present a case of left ventricular hypertrabeculation which presented as sudden infant death syndrome and we propose that this entity may be a hidden cause of arrhythmic death in some infants presenting as sudden infant death syndrome.


The Double U Wave-Should the Electrocardiogram be Interpreted Echocardiographically? The U wave is still an electrocardiographic deflection of enigmatic origin. Numerous hypotheses on its origin have been formulated, but to date none has been conclusively proven. Recently, a report described the first case of bifid (or notched) U waves. Until then this phenomenon has only been described in the T wave. This is the first report of double U waves-two separate deflections, ascribed to an accessory papillary muscle. The presence of a double U wave will be associated with an accessory papillary muscle (s). This is a retrospective analysis of 4729 patient files of patients who were evaluated at a cardiology practice. The 12-lead surface electrocardiogram was evaluated for the possible presence of a double U wave. In cases where a double U wave was found, the transthoracic echocardiogram was then scrutinized for the presence of an accessory papillary muscle. A total of 3 cases of a double U wave were found. In every case an accessory papillary muscle was clearly seen on the transthoracic echocardiogram. A double U wave is a new variant of an old electrocardiographic deflection of enigmatic origin. This variant may be associated with an accessory papillary muscle.


Expression of toll-like receptor 4, tumor necrosis factor- alpha, matrix metalloproteinase-9 and effects of benazepril in patients with acute coronary syndromes. The study aims to explore the relationship between expressions of toll-like receptor 4 (TLR4) on peripheral blood monocytes, serum tumor necrosis factor-alpha (TNF-α) and matrix metalloproteinase-9 (MMP-9) in patients with acute coronary syndromes(ACS), and to investigate the possible mechanisms of Benazepril stabilizing atherosclerosis plaques. 70 patients selected were randomly divided into Benazepril treatment group (35 patients) and regular treatment group (35 patients). Meanwhile, Stable angina pectoris (SAP) group of 32 patients and control group of 22 patients were also set up. With the help of flow-cytometry, expressions of TLR4 on peripheral blood monocytes of the four groups were analyzed and compared to show differences, correlations and changes of the above mentioned indicators. The concentration of TNF-α and MMP-9 in serum were measured by enzyme linked immunosorbent assay (ELISA). (1) Expressions of TLR4, levels of TNF-α and MMP-9 were increased and the rate was rising from the control group, to SAP group and then to ACS group. All these indicators in ACS group are significantly higher than those in other groups (P < 0.05). (ACS versus SAP, control; all (P < 0.05). (2) Multi-linear regression analysis indicates that there was a positive correlation between the expression level of TLR4 and serum levels of TNF-α and MMP-9 in patients with ACS (P < 0.01). (3) There is no significant differences between the expression level of TLR4 and serum levels of TNF-α and MMP-9 in Benazepril treatment group and regular treatment group before treatment (P > 0.05) while they all fell after treatment (P < 0.05). In addition, all the indicators decreased more greatly than the regular treatment group. TLR4 on peripheral blood monocytes and serum TNF-α and MMP-9 in patients with coronary arteriosclerosis disease may be effective markers of the vulnerable plaque. Benazepril can inhibit over-expression of TLR4 and reduce serum levels of TNF-α and MMP-9, thus stabilize the vulnerable plaques and improve the condition of the patients with ACS.


Targeted therapies: Molecular selection for 'smart' study design in lung cancer.


Paclitaxel as neoadjuvant therapy for high grade angiosarcoma of the spleen: a brief report and literature review. Splenic angiosarcoma is a rare tumor with only a few cases reported in the literature. Surgical resection offers the best chance of cure for this aggressive neoplasm but is often precluded by infiltration of the tumor to surrounding critical structures. We report a case of a locally advanced angiosarcoma rendered operable by treatment with Paclitaxel monotherapy. A 69 year old female presented with a high grade splenic angiosarcoma, considered inoperable due to the extent of local spread. She received three cycles of single agent Paclitaxel and underwent a successful resection of the tumor. Chemotherapy options for splenic angiosarcoma are not well studied. Paclitaxel as monotherapy is a useful therapeutic option in down staging tumors, facilitating surgical resection and merits further study in clinical trials.


Pazopanib for the treatment of patients with advanced renal cell carcinoma. Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years, including insights into the molecular pathogenesis of this disease, that have now been translated into paradigm-changing therapeutic strategies. Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements. Pazopanib is a novel small molecule tyrosine kinase inhibitor that targets VEGFR-1, -2, and -3; PDGFR-α, PDGFR-β; and c-kit tyrosine kinases. This agent exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of VEGF signaling pathway inhibitors. This review will discuss the scientific rationale for the development of pazopanib, as well as preclinical and clinical trials that led to approval of pazopanib for patients with advanced renal cell carcinoma. The most recent information, including data from 2010 national meeting of the American Society of Clinical Oncology, and the design of ongoing Phase III trials, will be discussed. Finally, an algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed.


HO1 mRNA and Protein do not Change in Parallel in Bronchial Biopsies of Patients After Long Term Exposure to Sulfur Mustard. Sulfur mustard (SM), is an alkylating agent and has been emerged as a chemical weapon in various battlefields. More recently, SM was employed in the Iraq conflict against Iranian military forces and civilians. Nowadays there are more than 40,000 people suffering from pulmonary lesions special chronic obstructive pulmonary disease (COPD) due to mustard gas in Iran. SM causes the endogenous production of reactive oxygen species (ROS).Heme oxygenases (HOs) are the rate-limiting enzyme for heme metabolism. Numerous studies have confirmed that HOs are concerned in diverse biological processes such as anti-oxidation.The present study was undertaken to consider the regulation of HO-1 and HO-2 n the human airway wall, and to suggest a probable role that HOs may play in cellular defense against oxidative stress due to SM.In this research ten unexposed SM individuals and twenty SM exposed patients were included. Evaluation of HO-1& HO -2 expressions in unexposed and SM exposed patients samples was performed by semiquantitative RT-PCR, real-time RT-PCR and Immunohistochemistry analysis.While unexposed SM samples expressed same levels of HOs, expression level of HO-1 was upregulated about 3.58 ± 1.93 folds in SM exposed patients in comparison with unexposed ones, we could not find any difference in expression of HO-2 n two groups. In contrast, Immunohistochemistry results showed negative HO-1 protein expression in SM injured patients.Our results revealed that HO1 may plays an important role in cellular protection against oxidative stress due to mustard gas toxicity in airway wall of SM exposed patients at mRNA level, but translational modifications might cause decrease in the amount of HO1 protein.


The effect of the gravitation of the moon on frequency of births. The purpose of this study was to examine the influence of the gravitation of the Moon on the frequency of births in Kyoto, Japan. A retrospective cohort analysis of 1007 consecutive births without the use of the induction agents was conducted on a population of births in a private midwife hospital from January, 1966 to December, 2000. There was a significant increase in the cases of births, when the gravitation of the Moon to the Earth was less than 31.5 N. Results of this study suggest that the gravitation of the Moon has an influence on the frequency of births.


BeadDataPackR: A Tool to Facilitate the Sharing of Raw Data from Illumina BeadArray Studies. Microarray technologies have been an increasingly important tool in cancer research in the last decade, and a number of initiatives have sought to stress the importance of the provision and sharing of raw microarray data. Illumina BeadArrays provide a particular problem in this regard, as their random construction simultaneously adds value to analysis of the raw data and obstructs the sharing of those data.We present a compression scheme for raw Illumina BeadArray data, designed to ease the burdens of sharing and storing such data, that is implemented in the BeadDataPackR BioConductor package (http://bioconductor.org/packages/release/bioc/html/BeadDataPackR.html). It offers two key advantages over off-the-peg compression tools. First it uses knowledge of the data formats to achieve greater compression than other approaches, and second it does not need to be decompressed for analysis, but rather the values held within can be directly accessed.


Heterogeneity Between Ducts of the Same Nuclear Grade Involved by Duct Carcinoma In Situ (DCIS) of the Breast. Nuclear grade of breast DCIS is considered during patient management decision-making although it may have only a modest prognostic association with therapeutic outcome. We hypothesized that visual inspection may miss substantive differences in nuclei classified as having the same nuclear grade. To test this hypothesis, we measured subvisual nuclear features by quantitative image cytometry for nuclei with the same grade, and tested for statistical differences in these features. EXPERIMENTAL DESIGN AND STATISTICAL ANALYSIS: Thirty-nine nuclear digital image features of about 100 nuclei were measured in digital images of H&E stained slides of 81 breast biopsy specimens. One field with at least 5 ducts was evaluated for each patient. We compared features of nuclei with the same grade in multiple ducts of the same patient with ANOVA (or Welch test), and compared features of nuclei with the same grade in two ducts of different patients using 2-sided t-tests (P ≤ 0.05). Also, we compared image features for nuclei in patients with single grade to those with the same grade in patients with multiple grades using t-tests. Statistically significant differences were detected in nuclear features between ducts with the same nuclear grade, both in different ducts of the same patient, and between ducts in different patients with DCIS of more than one grade. Nuclei in ducts visually described as having the same nuclear grade had significantly different subvisual digital image features. These subvisual differences may be considered additional manifestations of heterogeneity over and above differences that can be observed microscopically. This heterogeneity may explain the inconsistency of nuclear grading as a prognostic factor.


Assessment of mRNA and microRNA Stabilization in Peripheral Human Blood for Multicenter Studies and Biobanks. In this study we evaluate the suitability of two methods of RNA conservation in blood samples, PAXgene and RNAlater, in combination with variable shipping conditions for their application in multicenter studies and biobanking. RNA yield, integrity, and purity as well as levels of selected mRNA and microRNA species were analyzed in peripheral human blood samples stabilized by PAXgene or RNAlater and shipped on dry ice or at ambient temperatures from the study centers to the central analysis laboratory. Both examined systems were clearly appropriate for RNA stabilization in human blood independently of the shipping conditions. The isolated RNA is characterized by good quantity and quality and well suited for downstream applications like quantitative RT-PCR analysis of mRNA and microRNA. Superior yield and integrity values were received using RNAlater. It would be reasonable to consider the production and approval of blood collection tubes prefilled with RNAlater to facilitate the use of this excellent RNA stabilization system in large studies.


Recovery of Visual Function in a Patient with an Onodi Cell Mucocele Compressive Optic Neuropathy Who Had a 5-Week Interval between Onset and Surgical Intervention: A Case Report. Purpose. To report on a patient with compressive optic neuropathy secondary to an Onodi cell mucocele, who fully recovered visual function following surgery. Method. Case report. Results. A 28-year-old male was admitted with a right visual acuity of 20/100 following treatment for an initial diagnosis of optic neuritis. Subsequent examination suggested compressive optic neuropathy, and neuroimaging confirmed the presence of an Onodi mucocele compressing the optic nerve. The patient underwent a right endonasal sphenoethmoidectomy with decompression 5 weeks after the initial onset of symptoms. Three weeks following surgery, the visual acuity was 20/20, and there was complete resolution of the visual field defect, which has remained stable at 1 year. Conclusion. Onodi cell mucocele should be included in the differential diagnosis of a young patient with compressive optic neuropathy. Surgical decompression should be considered even when symptoms have been present for over a month.


Factors influencing the one- and two-year growth response in children treated with growth hormone: analysis from an observational study. To assess gender-, pubertal-, age-related differences in change from baseline height standard deviation score (ΔHSDS), data from 5,797 growth hormone (GH) naïve pediatric patients (<18 years) with growth hormone deficiency (GHD), multiple pituitary hormone deficiency (MPHD), Turner syndrome (TS), small for gestational age (SGA), Noonan syndrome (NS), and idiopathic short stature (ISS) were obtained from the ANSWER (American Norditropin Studies: Web-enabled Research) Program registry. For patients with SGA, ΔHSDS at year 1 was significantly greater for males versus females (P = .016), but no other gender differences were observed. For patients with GHD, ΔHSDS was greater in prepubertal than in pubertal patients. Younger patients for both genders (<11 years for boys; <10 years for girls) showed a greater ΔHSDS (P < .05 for GHD, MPHD, and ISS). Overall, positive ΔHSDSs were observed in all patients, with greater growth responses in younger prepubertal children, emphasizing the importance of starting GH treatment early.


Therapeutic Antibodies Targeting CSF1 Impede Macrophage Recruitment in a Xenograft Model of Tenosynovial Giant Cell Tumor. Tenosynovial giant cell tumor is a neoplastic disease of joints that can cause severe morbidity. Recurrences are common following local therapy, and no effective medical therapy currently exists. Recent work has demonstrated that all cases overexpress macrophage colony-stimulating factor (CSF1), usually as a consequence of an activating gene translocation, resulting in an influx of macrophages that form the bulk of the tumor. New anti-CSF1 drugs have been developed; however there are no preclinical models suitable for evaluation of drug benefits in this disease. In this paper, we describe a novel renal subcapsular xenograft model of tenosynovial giant cell tumor. Using this model, we demonstrate that an anti-CSF1 monoclonal antibody significantly inhibits host macrophage infiltration into this tumor. The results from this model support clinical trials of equivalent humanized agents and anti-CSF1R small molecule drugs in cases of tenosynovial giant cell tumor refractory to conventional local therapy.


Sex chromosome evolution in amniotes: applications for bacterial artificial chromosome libraries. Variability among sex chromosome pairs in amniotes denotes a dynamic history. Since amniotes diverged from a common ancestor, their sex chromosome pairs and, more broadly, sex-determining mechanisms have changed reversibly and frequently. These changes have been studied and characterized through the use of many tools and experimental approaches but perhaps most effectively through applications for bacterial artificial chromosome (BAC) libraries. Individual BAC clones carry 100-200 kb of sequence from one individual of a target species that can be isolated by screening, mapped onto karyotypes, and sequenced. With these techniques, researchers have identified differences and similarities in sex chromosome content and organization across amniotes and have addressed hypotheses regarding the frequency and direction of past changes. Here, we review studies of sex chromosome evolution in amniotes and the ways in which the field of research has been affected by the advent of BAC libraries.


Activation of PPARs α, β/δ, and γ Impairs TGF-β1-Induced Collagens' Production and Modulates the TIMP-1/MMPs Balance in Three-Dimensional Cultured Chondrocytes. Background and Purpose. We investigated the potency of Peroxisome Proliferators-Activated Receptors (PPARs) α, β/δ, and γ agonists to modulate Transforming Growth Factor-β1 (TGF-β1-) induced collagen production or changes in Tissue Inhibitor of Matrix Metalloproteinase- (TIMP-) 1/Matrix Metalloproteinase (MMP) balance in rat chondrocytes embedded in alginate beads. Experimental Approach. Collagen production was evaluated by quantitative Sirius red staining, while TIMP-1 protein levels and global MMP (-1, -2, -3, -7, and -9) or specific MMP-13 activities were measured by ELISA and fluorigenic assays in culture media, respectively. Levels of mRNA for type II collagen, TIMP-1, and MMP-3 & 13 were quantified by real-time PCR. Key Results. TGF-β1 increased collagen deposition and type II collagen mRNA levels, while inducing TIMP-1 mRNA and protein expression. In contrast, it decreased global MMP or specific MMP-13 activities, while decreasing MMP-3 or MMP-13 mRNA levels. PPAR agonists reduced most of the effects of TGF-β1 on changes in collagen metabolism and TIMP-1/MMP balance in rat in a PPAR-dependent manner, excepted for Wy14643 on MMP activities. Conclusions and Implications. PPAR agonists reduce TGF-β1-modulated ECM turnover and inhibit chondrocyte activities crucial for collagen biosynthesis, and display a different inhibitory profile depending on selectivity for PPAR isotypes.


Biochemical signatures of doppel protein in human astrocytomas to support prediction in tumor malignancy. Doppel (Dpl) is a membrane-bound glycoprotein mainly expressed in the testis of adult healthy people. It is generally absent in the central nervous system, but its coding gene sequence is ectopically expressed in astrocytoma specimens and in derived cell lines. In this paper, we investigated the expression and the biochemical features of Dpl in a panel of 49 astrocytoma specimens of different WHO malignancy grades. As a result, Dpl was expressed in the majority of the investigated specimens (86%), also including low grade samples. Importantly, Dpl exhibited different cellular localizations and altered glycan moieties composition, depending on the tumor grade. Most low-grade astrocytomas (83%) showed a membrane-bound Dpl, like human healthy testis tissue, whereas the majority of high-grade astrocytomas (75%) displayed a cytosolic Dpl. Deglycosylation studies with N-glycosidase F and/or neuraminidase highlighted defective glycan moieties and an unexpected loss of sialic acid. To find associations between glial tumor progression and Dpl biochemical features, predictive bioinformatics approaches were produced. In particular, Decision tree and Nomogram analysis showed well-defined Dpl-based criteria that separately clustered low-and high-grade astrocytomas. Taken together, these findings show that in astrocytomas, Dpl undergoes different molecular processes that might constitute additional helpful tools to characterize the glial tumor progression.


Effects of clofibrate on salt loading-induced hypertension in rats. The effects of clofibrate on the hemodynamic and renal manifestations of increased saline intake were analyzed. Four groups of male Wistar rats were treated for five weeks: control, clofibrate (240 mg/kg/day), salt (2% via drinking water), and salt + clofibrate. Body weight, systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, SBP, HR, and morphologic, metabolic, plasma, and renal variables were measured. Salt increased SBP, HR, urinary isoprostanes, NOx, ET, vasopressin and proteinuria and reduced plasma free T(4) (FT(4)) and tissue FT(4) and FT(3) versus control rats. Clofibrate prevented the increase in SBP produced by salt administration, reduced the sodium balance, and further reduced plasma and tissue thyroid hormone levels. However, clofibrate did not modify the relative cardiac mass, NOx, urinary ET, and vasopressin of saline-loaded rats. In conclusion, chronic clofibrate administration prevented the blood pressure elevation of salt-loaded rats by decreasing sodium balance and reducing thyroid hormone levels.


Isolation of specific clones from nonarrayed BAC libraries through homologous recombination. We have developed a new approach to screen bacterial artificial chromosome (BAC) libraries by recombination selection. To test this method, we constructed an orangutan BAC library using an E. coli strain (DY380) with temperature inducible homologous recombination (HR) capability. We amplified one library segment, induced HR at 42°C to make it recombination proficient, and prepared electrocompetent cells for transformation with a kanamycin cassette to target sequences in the orangutan genome through terminal recombineering homologies. Kanamycin-resistant colonies were tested for the presence of BACs containing the targeted genes by the use of a PCR-assay to confirm the presence of the kanamycin insertion. The results indicate that this is an effective approach for screening clones. The advantage of recombination screening is that it avoids the high costs associated with the preparation, screening, and archival storage of arrayed BAC libraries. In addition, the screening can be conceivably combined with genetic engineering to create knockout and reporter constructs for functional studies.


The Relationship between Physical Activity and Bone during Adolescence Differs according to Sex and Biological Maturity. This study examines the relationships between bone mass, physical activity, and maturational status in healthy adolescent boys and girls. Methods. Ninety-nine early high-school (Year 9) students were recruited. Physical activity and other lifestyle habits were recorded via questionnaire. Anthropometrics, muscle power, calcaneal broadband ultrasound attenuation (BUA), bone mineral content (BMC), and lean tissue mass were measured. Maturity was determined by Tanner stage and estimated age of peak height velocity (APHV). Results. Boys had greater APHV, weight, height, muscle power, and dietary calcium than girls (P < .05). Boys exhibited greater femoral neck BMC and trochanteric BMC while girls had higher BUA and spine BMAD (P < .05). Physical activity and vertical jump predicted BMAD and BUA most strongly for boys whereas years from APHV were the strongest predictor for girls. Conclusion. Sex-specific relationships exist between physical activity, maturity and bone mass during adolescence.


Revisiting estrogen: efficacy and safety for postmenopausal bone health. The rapid decline in endogenous estrogen production that occurs during menopause is associated with significant bone loss and increased risk for fragility fracture. While hormone therapy (HT) is an effective means to re-establish endogenous estrogen levels and reduce the risk of future fracture, its use can be accompanied by undesirable side effects such as stroke and breast cancer. In this paper, we revisit the issue of whether HT can be both safe and effective for the prevention of postmenopausal bone loss by examining standard and alternative doses and formulations of HT. The aim of this paper is to continue the dialogue regarding the benefits and controversies of HT with the goal of encouraging the dissemination of-up-to date evidence that may influence how HT is viewed and prescribed.


Molecular mechanisms of the whole DNA repair system: a comparison of bacterial and eukaryotic systems. DNA is subjected to many endogenous and exogenous damages. All organisms have developed a complex network of DNA repair mechanisms. A variety of different DNA repair pathways have been reported: direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and recombination repair pathways. Recent studies of the fundamental mechanisms for DNA repair processes have revealed a complexity beyond that initially expected, with inter- and intrapathway complementation as well as functional interactions between proteins involved in repair pathways. In this paper we give a broad overview of the whole DNA repair system and focus on the molecular basis of the repair machineries, particularly in Thermus thermophilus HB8.


Influence of Friction Resistance on Expression of Superelastic Properties of Initial NiTi Wires in "Reduced Friction" and Conventional Bracket Systems. Objectives. The aim of this study was to assess the influence of resistance to sliding on expression of superelastic properties of NiTi wires. Methods and Materials. A three-point bending test was performed for 0.014 NiTi wire engaged in self-ligating (Damon, SmartClip, In-Ovation) and conventional brackets (Victory) ligated with regular and reduced friction modules (Slide). The wire was deflected in the buccal direction and allowed to straighten. The maximum load, unloading plateau and unloading capacity were registered. Results. The lowest activation load was required in the active self-ligating group (In-Ovation 2.2 ± 0.4 N) and reduced friction module group (Victory/Slide 2.9 ± 0.4 N), followed by the passive self-ligating systems (Damon 3.6 ± 0.7 N, SmartClip 3.7 ± 0.4 N). Higher activation load was obtained in the conventionally ligated group (Victory/module 4.5 ± 0.4 N). Unloading plateau phase with the load magnitude ranging from 1.27 ± 0.4 N (In-Ovation) to 1.627 ± 0.4 N (Slide) was distinct in all groups but one (Victory). Conclusions. Higher friction at flanking points reduces the net force delivered by the wire. Unloading plateau phase of NiTi load-deflection curve disappears in the conventionally ligated group thus indicating to an incomplete expression of NiTi superelastic properties. A rigid passive bracket clip amplifies resistance to sliding in an active configuration and produces a permanent deflection of the wire.


A radiographic study on the associations of age and prevalence of vertebral fractures with abdominal aortic calcification in Japanese postmenopausal women and men. The purpose of the present study was to determine the associations of age and history of non- and low-traumatic fractures with the severity of abdominal aortic calcification in Japanese postmenopausal women and men. Four hundred and one Japanese persons (24 men and 377 postmenopausal women, mean age: 73.8 years) for whom thoracic and lumbar spine radiographs had been obtained to evaluate their posture prior to patient participation in a fall-prevention exercise program were enrolled. The associations of sex, age, history of hip fracture, prevalence of vertebral fracture, and spondylosis grade (the Nathan degree) with the severity of abdominal aortic calcification (length of calcification, as evaluated according to the number of vertebral bodies) were analyzed. Nine subjects (2.2%) had a history of hip fracture, and 221 (55.1%) had at least one prevalent vertebral fracture. Two hundred and sixty-seven subjects (66.6%) had first-degree spondylosis. Age and the number of prevalent vertebral fractures, but not sex, history of hip fracture, or spondylosis grade, were significantly associated with the severity of abdominal aortic calcification. The present study confirmed that age and the number of vertebral fractures were associated with the severity of abdominal aortic calcification in Japanese postmenopausal women and men.


A 10-month physical activity intervention improves body composition in young black boys. Objective. To determine if a 10-month after-school physical activity (PA) intervention could prevent deleterious changes in body composition and cardiovascular (CV) fitness in young black boys. Methods. Following baseline measures, 106 boys (8-12 yrs) were randomized to either a control group or an intervention group, further divided into attenders (ATT) and nonattenders (NATT), participating in ≥60% or <60% of the intervention, respectively. The daily intervention consisted of skills development (25 min), vigorous PA (VPA, 35 min), and strengthening/stretching (20 min) components. Body composition was measured by dual-energy X-ray absorptiometry. Results. Following the intervention, the ATT exhibited an increase in moderate-to-vigorous PA and a significant reduction in BMI, fat mass, and %BF compared to the control group. A significant association among the intervention energy expenditure and changes in body composition and CV fitness was observed only in the ATT group. Conclusion. An after-school PA program of sufficient length and intensity can promote healthy changes in body composition and fitness levels in black boys who attend at least 3 days/week.


Biomechanical Response in Mandibular Bone due to Mastication Loading on 3-Unit Fixed Partial Dentures. An understanding of functional responses in oral bone is a crucial component of dental biomechanics. The purpose of this study was to investigate the potential biological remodelling response during mastication on the mandibular pre- and post-insertion of a fixed partial denture (FPD). A series of three-dimensional (3D) finite element analysis (FEA) models were presented pre- and postextraction to determine the biomechanical responses to masticatory loading in the anterior mandible. Equivalent strains were analysed at lingual/buccal and mesial/distal areas of the premolar to molar region and quantified to anticipate bone remodelling response. Mandibular bone incorporating an FPD experienced substantially greater stress/strain magnitudes than that prior to placement of fixed prosthodontics, which is suggestive of engagements of bone remodelling. The results suggest similar outcomes to those reported clinically. Developing a simulation reflecting the outcomes of restorative treatment can provide meaningful insight into restorative treatment planning, clinical outcomes, and fixed prosthodontics designs.


Hodgkin's Lymphomas: A Tumor Recognized by Its Microenvironment. Thomas Hodgkin's and Samuel Wilks first recognized Hodgkin disease in the first half of the 19th century. Initially described as lymphogranulomatosis, it was later recognized to be a lymphoid neoplasm derived from B cells and was classified on the basis of its histopathological features. Hodgkin lymphomas are now regarded as encompassing two clearly defined entities according to the WHO classification: nodular lymphocyte-predominant Hodgkin Lymphoma (NLPHL) and classical Hodgkin Lymphoma (CHL). This paper focuses on the current knowledge about the biological features that characterize both NLPHL and CHL, highlighting those relevant to correct pathological diagnosis and those that might be associated with patient outcome.


The effects of forodesine in murine and human multiple myeloma cells. Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, characterized by a monoclonal proliferation of malignant cells in the bone marrow. Despite recent advances in treatment strategies, MM remains incurable and new therapeutical targets are needed. Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels. We therefore tested whether forodesine was able to inhibit proliferation and/or induce apoptosis in both murine and human MM cells through a similar pathway. We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis. When investigating the pathways leading to cell cycle arrest and apoptosis, we observed an upregulation of p27, caspase 3, and BIM. We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells. Forodesine might be however potentiating towards other established cytotoxic drugs in MM.


Role of Radiotherapy in Modern Treatment of Hodgkin's Lymphoma. Hodgkin's Lymphoma was incurable until the advent of effective therapeutic radiation around the first half of the 20th century. As survival rates improved, the long-term toxicities from radiotherapy began to emerge. This together with the availability of effective chemotherapy has encouraged a combined modality approach for early-staged disease and the omission of radiotherapy in advanced-staged disease. The differing toxicities of radiotherapy and chemotherapy has promoted ongoing research to identify the utility of each of these modalities in the modern management of Hodgkin's Lymphoma. This article will provide a critical review of the developments and indications for modern radiotherapy, in context with advances in chemotherapy, for the treatment of Hodgkin's Lymphoma.


The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients. Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15-20% of patients remain refractory to chemoradiotherapy, and 20-40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies.


Concentration-Dependent Protection by Ethanol Extract of Propolis against γ-Ray-Induced Chromosome Damage in Human Blood Lymphocytes. Radioprotection with natural products may be relevant to the mitigation of ionizing radiation-induced damage in mammalian systems; in this sense, propolis extracts have shown effects such as antioxidant, antitumoral, anti-inflammatory, and immunostimulant. We report for the first time a cytogenetic study to evaluate the radioprotective effect, in vitro, of propolis against radiation-induced chromosomal damage. Lymphocytes were cultured with increasing concentrations of ethanol extract of propolis (EEP), including 20, 40, 120, 250, 500, 750, 1000, and 2000 μg mL(-1) and then exposed to 2 Gy γ-rays. A significant and concentration-dependent decrease is observed in the frequency of chromosome aberrations in samples treated with EEP. The protection against the formation of dicentrics was concentration-dependent, with a maximum protection at 120 μg mL(-1) of EEP. The observed frequency of dicentrics is described as negative exponential function, indicating that the maximum protectible fraction of dicentrics is approximately 44%. Free radical scavenging and antioxidant activities are the mechanisms that these substances use to protect cells from ionizing radiation.


A Randomized Controlled Exploratory Evaluation of Standardized Ayurvedic Formulations in Symptomatic Osteoarthritis Knees: A Government of India NMITLI Project. The multidisciplinary "New Millennium Indian Technology Leadership Initiative" Arthritis Project was undertaken to validate Ayurvedic medicines. Herbal formulations in popular use were selected by expert consensus and standardized using modern tools. Our clinical strategy evolved from simple exploratory evaluations to better powered statistically designed drug trials. The results of the first drug trial are presented here. Five oral formulations (coded A, B, C, D and E), with a common base of Zingiber officinale and Tinospora cordifolia with a maximum of four plant extracts, were evaluated; with placebo and glucosamine as controls. 245 patients suffering from symptomatic OA knees were randomized into seven arms (35 patients per arm) of a double blind, parallel efficacy, multicentric trial of sixteen weeks duration. The groups matched well at baseline. There were no differences for patient withdrawals (17.5%) or adverse events (AE) of mild nature. Intention-to-treat efficacy analysis, demonstrated no significant differences (P < .05) for pain (weight bearing) and WOMAC questionnaire (knee function); placebo response was high. Based on better pain relief, significant (P < .05) least analgesic consumption and improved knee status, "C" formulation was selected for further development. Controlled exploratory drug trials with multiple treatment arms may be used to economically evaluate several candidate standardized formulations.


Gestational diabetes mellitus: why screen and how to diagnose. Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future. The global incidence of GDM is difficult to estimate, due to lack of uniform diagnostic criteria. Various diagnostic criteria have been proposed. The benefit of treating GDM has also been controversial. The clinical significance of treating maternal hyperglycemia was made evident in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The HAPO study demonstrated that there is a continuous association of maternal glucose levels with adverse pregnancy outcomes and served as the basis for a new set of diagnostic criteria, proposed in 2010 by the International Association of Diabetes and Pregnancy Groups (IADPSG). According to these criteria the diagnosis of GDM is made if there is at least one abnormal value (≥92, 180 and 153 mg/dl for fasting, one-hour and two-hour plasma glucose concentration respectively), after a 75 g oral glucose tolerance test (OGTT).


Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-1α in Skeletal Muscle. Electroacupuncture (EA) has been observed to reduce insulin resistance in obesity and diabetes. However, the biochemical mechanism underlying this effect remains unclear. This study investigated the effects of low-frequency EA on metabolic action in genetically obese and type 2 diabetic db/db mice. Nine-week-old db/m and db/db mice were randomly divided into four groups, namely, db/m, db/m + EA, db/db, and db/db + EA. db/m + EA and db/db + EA mice received 3-Hz electroacupuncture five times weekly for eight consecutive weeks. In db/db mice, EA tempered the increase in fasting blood glucose, food intake, and body mass and maintained insulin levels. In EA-treated db/db mice, improved insulin sensitivity was established through intraperitoneal insulin tolerance test. EA was likewise observed to decrease free fatty acid levels in db/db mice; it increased protein expression in skeletal muscle Sirtuin 1 (SIRT1) and induced gene expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), and acyl-CoA oxidase (ACOX). These results indicated that EA offers a beneficial effect on insulin resistance in obese and diabetic db/db mice, at least partly, via stimulation of SIRT1/PGC-1α, thus resulting in improved insulin signal.


Collagenous and non-collagenous biochemical markers of bone metastases from prostate cancer. The importance of the bone microenvironment to the pathophysiology and morbidity associated with prostate cancer bone metastasis is becoming increasingly apparent. Significant alterations take place in the microenvironment of bone, which disturb the normal coupling that exists between bone resorption and bone formation. Consequently, a better understanding of the mechanisms that interact at the molecular level will definitely result in more effective therapy for patients with this devastating complication of prostatic carcinoma. This review will discuss the diagnostic and predictive implications of various collagenous and non-collagenous bone markers, along with the novel markers of osteoclastogenesis and other matrix enzymes such as metalloproteinases and growth factors responsible for the complex biochemical mechanisms that upregulate bone resorption/formation during the development of metastasis. Further prospective studies are needed to determine whether any of these markers measured longitudinally in prostate cancer patients without bone scan evidence of skeletal disease will ultimately predict those patients who will develop bone metastases from their malignancy. Nonetheless, from the clinical point of view it is important to know that these novel markers carry the potential to provide meaningful information for daily practice by using upper normal reference values as cut-offs for identifying patients with an increased risk of developing progressive bone disease or skeletal related events.


Long-term outcome after implantation of prosthetic disc nucleus device (PDN) in lumbar disc disease. The prosthetic disc nucleus (PDN) device offers an adjunct treatment for patients with degenerative disc disease and herniation, who necessitate surgical intervention, avoiding total-disc replacement or fusion. This prospective, clinical study aimed to gauge the long-term effectiveness of microdiscectomy followed by PDN implantation in relieving pain and improving functional status in patients with symptomatic degenerative lumbar disc disease and herniation. Ten patients with a) at least 6 months low back pain and/or sciatica resistant to conservative treatment and b) radiologically documented degenerative lumbar disc disease and herniation have been selected. Follow-up at 6 weeks, 3, 12, 48, and 96 months postoperatively included physical examination, radiological investigation (plain and dynamic radiographs and magnetic resonance imaging), and self-completion of outcome scales (visual analogue, Oswestry, and Prolo functional status). Short Form-36 version 2 Health Survey patient profile at 96 months completed the image of health related quality of life. Patients' mean follow-up was 100.6 months. Significant improvements in Oswestry, Prolo, and VAS scores were documented (p: 0.004 in all scales at 48 months). Generic health status was rated within the average lumbar disease population (46.36.8 for physical component summary and 45.29.6 for mental component summary). Lumbar spine range of motion (20.211.8 at 96 months) was restricted in relation to normal, but maintained considerable mobility. Treated disc height increased postoperatively (p:0.002) and its maintenance could also be documented in all cases. Disc height at the level above did not show any significant modification. All postoperative MRI showed a non-clinically significant high signal of end-plate on T2 sequences. Clinically relevant complications included one case of pulmonary thrombosis and one case of device extrusion, which was subsequently explanted. After implantation, most patients continue to enjoy significant pain relief, a considerable amount of mobility is conserved and the disease specific functional outcome is excellent and remains for long, although it could not be supported that the generic health related quality of life is that of the general population.


P2X(7) receptor at the heart of disease. Purinergic signaling is a crucial component of disease whose pathophysiological basis is now well established. This review focuses on P2X(7), a unique bifunctional purinoreceptor that either opens a non selective cation channel or forms a large, cytolytic pore depending on agonist application and leading to membrane blebbing and to cell death either by necrosis or apoptosis.Activation of P2X(7) receptor has been shown to stimulate the release of multiple proinflammatory cytokines by activated macrophages, with the IL-1b to be the most extensively studied among them. These findings were verified by the use of knockout P2X(7) ((-/-)) mice.Update information coming from all fields of research implicate this receptor at the very heart of diseases such as rheumatoid arthritis, multiple sclerosis, depression, Alzheimer disease, and to kidney damage, in renal fibrosis and experimental nephritis.Clinical studies are currently underway with the newly developed selective antagonists for P2X(7) receptor, the results of which are eagerly anticipated. These studies together with data from in-vivo experiments with the P2X(7) knockout mice and in-vitro experiments will shed light in this exciting area.


Screening for prostate cancer: a controversy or fact. Adenocarcinoma of the prostate is the most frequent malignancy in men and the second leading cause of death in the male population worldwide. The screening for prostate cancer allows early diagnosis of prostate malignancy before the individual presents with symptoms. The early stage of the disease is easier to manage by different therapeutic modalities. The aim of this review is to evaluate the reasons and facts for enthusiasm and positive approach towards the clinical decision about whether to screen or not male patients for early detection of prostate cancer. We performed a computerized MEDLINE search followed by a manual bibliographic review of cross-references. These reports were analyzed and the important findings were summarized. We analyzed the methods and schedule of screening, as well as advantages and disadvantages of the prostate cancer screening. There were more than a hundred studies on prostate cancer screening performed but only a few are eligible for a decisive conclusion concerning the prostate cancer screening issue. We reviewed the screening methods, the schedule of screening, the advantages and disadvantages of prostate cancer screening. The role for prostate cancer screening is not established yet. Definite proof of screening should be assumed as a decrease in the death rate of that cancer due to screening activity.


Homocysteine and its relationship to deep venous thrombosis in patients undergoing total knee or hip arthroplasty. Backround: The role of hyperhomocysteinemia as an independent risk factor for venous thrombosis after lower limb arthroplasty remains questionable. The objective of this study is to determine the relationship between hyperhomocysteinemia and postoperative thromboembolic events in patients undergoing total hip or knee arthroplasty. Between September 2004 and June 2006, we studied 172 patients (41 male and 131 female) with mean age 70.2 years (48-85). Total plasma homocysteine as well as other thrombophilic agents (proteinC, protein S, Antithrombin III, Lupus anticoagulants, APC-Resistance) were measured preoperatively. Duplex sonography was performed twice postoperatively, on the 7(th) day (+/-2) and on the 42th day (+/- 2). Spiral CT was performed when pulmonary embolism was suspected. Four patients developed deep venous thrombosis from which two developed pulmonary embolism. Only one of these four patients had high levels of total plasma homocysteine. Total plasma homocysteine does not seem to affect the development of deep venous thrombosis in patients undergoing total knee or hip arthroplasty and receive low molecular weight heparine.


Correlation of depressive symptoms and olfactory dysfunction in patients on hemodialysis. A possible link between depression and olfactory dysfunction has been suggested in the literature, in research projects using the olfactory bulbectomy model. In human studies using a syndrome-oriented approach, such an association has not been reported consistently. The aim of the study was to test the association of olfactory dysfunction with depression using a symptom-oriented approach.Paients and methods: Twenty eight end-stage renal failure patients took part in this project. The patients olfactory identification ability was tested with the University of Pennsylvania Smell Identification Test (UPSIT). Immediately before olfactory testing, the subjects completed the Zung self-rating scale, which provides data on symptoms of depression in this group of patients. The mean value of the number of mistakes made in the olfactory identification ability (UPSIT test) by the total sample was 14.0±4.5, with a range 6-22. Half of the symptoms seem to bear an influence on the olfactory identification performance. Patients experiencing decreased libido and dissatisfaction exhibited significantly reduced olfactory function, as contrasted to those not experiencing these symptoms. The above results remain practically unaltered even after taking into account such probable confounding factors as age, sex, olfactory detection threshold and duration of illness. These findings support previous evidence indicating that olfactory dysfunction may be related to specific depressive symptoms in humans. The present findings also suggest that the symptom-oriented approach is an effective research tool for the elucidation of such clinical issues. The need for further research in this field is pointed out.


Nutrition parameters as hemodialysis adequacy markers. The nutritive status has significant role in improving the quality of life of dialysis' patients. The aim of this study was to find out if there is any correlation of the anthropometric parameters and markers of nutrition with the adequacy of HD. The investigation was organized as a clinical, cross sectional study. Demographic characteristics, co-morbid conditions, smoking, dialysis duration and blood pressure were recorded. Serum total protein, albumin, ferritin and blood-lipids were measured as biochemical markers of nutritional status.One hundred and forty patients, 82 (58.6%) male, and 58 (41.4%) female, 55±12.59 years, were dividied into two groups. Group A consisted of 44 patients (14 women and 30 men) received the recommended hemodialysis dose (Kt/V ≥ 1.2), while the Group B consisted of 96 patients (69 males and 27 females) received non-adequate hemodialysis dose (Kt/V < 1.2). Patients with adequate hemodialysis had been longer on dialysis in correlation with the group of patients with non-adequate hemodialysis (73 ± 56.4 vs. 44 ± 50.1 months; p: 0.004). Group A and group B presented significant differences in the number of leukocytes (p: 0.027), and hemoglobin (p: 0.047), potassium (p: 0.038) and C-reactive protein level (p: 0.048) as well as in serum total protein (69 ± 4.63 vs. 65 ± 5.74 g/L; p < 0.0001) and albumin (38 ± 2.99 vs. 29 ± 4.4 g/L; p: 0.047). Pearsons correlation of factors that may have impact on hemodialysis adequacy indicated a significant relation between serum total protein and the index of hemodialysis adequacy (r: 0.21; p: 0.0446). All investigated anthropometric parameters and protein status showed significantly higher values in patients with adequate hemodialysis quality (Group A). The Group B showed higher levels of CRP and lower values of hemoglobin.


First body fat percentiles for 607 children from Thessaloniki-Northern Greece. The purpose of this study was to establish for the first time reference curves for body fat levels in a Greek pediatric population aged 7-15y. Six hundred and seven (607) children randomly selected from 8 primary and secondary schools from Northern Greece. Percentage body fat was measured by bioelectrical impedance analysis and percentile curves were constructed using the LMS method. All children were measured twice in the morning and the mean number of the two measurements was considered as the percentage of body fat. The mean number of the percentage body fat for the age group (7-9) was 18.2 ± 5.1 and 18.4 ± 6.1 for boys and girls, respectively. In the second age group (10-12) the girls had higher mean fat levels than boys (22.6 ± 5.8 vs. 20.4 ± 6.2). This increase was continued also in the third age group (13-15) with the girls having higher mean body fat levels (24.2 ± 5.5 vs. 17 ± 5.9). The 85th and 95th percentiles represented the cut-off point for overweight and obesity and it was (26.3, 33.0 and 28.9%) and (34.0, 38.2 and 38.1) for boys for the three age groups (7-9, 10-12 and 13-15), respectively. On the other hand, the girls had higher 85th and 95th percentiles for the same age group (7-9, 10-12, 13-15y) and it was (34.5, 32.9 and 33.6%) and (39.0, 370 and 38.3%), respectively. Body fat level, which is the component of overweight that leads to pathology, is a better representative over body mass index. These first percentile curves will be at great assistance helping the medical community to identify obesity in these children at early stages and to prevent development at pathological diseases early in their lives.


The sural sensory/radial motor amplitude ratio for the diagnosis of peripheral neuropathy in type 2 diabetic patients. The diagnosis of peripheral diabetic neuropathy is based on clinical examination. Nerve conduction study (NCS) enables earlier diagnosis, but it is demanding and requires specialised personnel. In an attempt to simplify the procedure, this study aimed to identify a new electrophysiological index, which might correlate with results obtained on standardised NCS in patients with long-standing type 2 diabetes. Medical records of type 2 diabetic patients evaluated for neuropathy by NCS were reviewed retrospectively. This analysis included 104 patients (50 men, 54 women) with a mean age of 67.1±5.5 years and mean diabetes duration of 13.1±2.7 years. NCS was performed on radial, ulnar, sural, and peroneal nerves. Neuropathy was defined as impaired NCS. Ratios of neurophysiological parameters from these nerves were calculated and each of them was compared with diagnosis of neuropathy. The sural sensory/radial motor amplitude ratio had the best combination of sensitivity (85%) and specificity (71%) for neuropathy. It also remained the strongest independent predictor of neuropathy in multivariate regression analysis: low levels of this ratio yielded an odds ratio of 7.7 for neuropathy. The sural sensory/radial motor amplitude ratio has a high sensitivity and a moderately high specificity for the diagnosis of neuropathy, low levels being associated with a nearly eightfold increase in the risk for neuropathy. These results encourage further evaluation of this and other electrophysiological indices to enable wider availability of NCS.


Insomnia symptoms among Greek adolescent students with excessive computer use. The aim of the present study is to assess the intensity of computer use and insomnia epidemiology among Greek adolescents, to examine any possible age and gender differences and to investigate whether excessive computer use is a risk factor for developing insomnia symptoms. Cross-sectional study of a stratified sample of 2195 high school students. Demographic data were recorded and two specific questionnaires were used, the Adolescent Computer Addiction Test (ACAT) and the Athens Insomnia Scale (AIS). Females scored higher than males on insomnia complaints but lower on computer use and addiction. A dosemediated effect of computer use on insomnia complaints was recorded. Computer use had a larger effect size than sex on insomnia complaints. Duration of computer use was longer for those adolescents classified as suffering from insomnia compared to those who were not. Computer use can be a significant cause of insomnia complaints in an adolescent population regardless of whether the individual is classified as addicted or not.


Weaver syndrome associated with bilateral congenital hip and unilateral subtalar dislocation. Weaver syndrome is a congenital paediatric syndrome characterized by mental, respiratory and musculoskeletal manifestations. The coexisting deformities of the skull, the face, fingers and toes are typical. We report a case of a girl with Weaver syndrome associated with rare bilateral congenital dislocation of the hips associated with congenital hypoplastic talus and subtalar dislocation of her ankle joint. A 3-year old girl was admitted in our department with typical manifestations of Weaver syndrome, associated with congenital dislocation of bilateral hips, hypoplastic talus and subtalar dislocation of her right ankle. She was in pain while standing upright and incapable of independent walking. Both hips were treated operatively with open reduction and bilateral iliac osteotomy. Two years afterwards she had an open reduction of her talus and extraarticular arthrodesis of her subtalar joint in her right ankle. Six years postoperatively after the hip operations and four years after the ankle operation the girl is ambulant with a painless independent and unaided walking with a mild limp and full range of movements in all the operated joints. We suggest that children with Weaver syndrome and disabling musculosceletal deformities, particularly affecting their ability to stand up and walk should be treated early, before bone maturity, in order to achieve the best potential musculoskeletal as well as developmental outcome.


Effective treatment of antiphospholipid syndrome with plasmapheresis and rituximab. With the exception of the catastrophic antiphospholipid syndrome (APS), the management of patients with APS has been largely supportive aiming at avoiding a recurrent thrombotic event; it is noteworthy that data concerning therapy targeting the triggering factor (the antiphopsholipid antibodies) are scarce. We report a case of APS manifested as recurrent fetal losses, ischemic stroke and renal dysfunction with concomitant nephrotic syndrome successfully treated with the combination of plasmapheresis and anti-CD20 antibody.


Electrocardiographic findings compatible with Brugada syndrome in a patient with febrile respiratory infection. Brugada syndrome is an inherited autosomal dominant-type disease characterized by ST-segment abnormalities and increased fatal ventricular tachyarrhythmias. We hereby present a 57-years-old patient with no symptoms or history of cardiovascular disease, diagnosed with febrile respiratory infection (39℃). Electrocardiographic (ECG) findings were typical of Brugada-like type I syndrome that gradually turned to Brugada type II and III, following fever remission, and finally became normal. Other clinical evaluation tests (echocardiographic evaluation, treadmill stress test, Holter ECG, procainamide provocation test) did not relate to Brugada syndrome.


KAATSU: Rationale for application in Astronauts.


Unicystic ameloblastoma of the maxillary sinus: Pitfalls of diagnosis and management. Ameloblastoma is a common odontogenic tumor of the jaws that comprises 3 variants: conventional (solid), unicystic and peripheral ameloblastomas. Unicystic ameloblastoma (UA) in the maxillary sinus is very rare. With a secondary infection, the clinical features may lead to incorrect diagnosis and treatment. A 19-year-old man was referred for the management of sinusitis and a mass at the right cheek. A few weeks earlier, the patient presented with acute cellulitis at the same area and underwent an incision and drainage in a primary care unit without any appropriate investigation. A radiographic examination revealed a massive lesion in the right maxillary sinus. An unerupted tooth within the lesion was found at the level of the orbital floor. The patient was successfully treated by enucleation of the tumor and curettage. The specimen was sent for histopathological examination, and the definite diagnosis was UA. The patient has been followed-up periodically for 5 years without recurrence. This case report suggests that primary care doctors should pay attention to differential diagnosis of orofacial lesions. It is therefore of great benefit to organize continuing education for general physicians who initially meet oral disease patients as a 'gate keeper'. Errors of clinical diagnosis and management of orofacial lesions would be minimized. Pitfalls of diagnosis and management of UA in the maxillary sinus were briefly reviewed.


Tobacco consummation: Is it still a dilemma?