Automatic retrieval of bone fracture knowledge using natural language processing.
Natural language processing (NLP) techniques to extract data from unstructured text into formal computer representations are valuable for creating robust, scalable methods to mine data in medical documents and radiology reports. As voice recognition (VR) becomes more prevalent in radiology practice, there is opportunity for implementing NLP in real time for decision-support applications such as context-aware information retrieval. For example, as the radiologist dictates a report, an NLP algorithm can extract concepts from the text and retrieve relevant classification or diagnosis criteria or calculate disease probability. NLP can work in parallel with VR to potentially facilitate evidence-based reporting (for example, automatically retrieving the Bosniak classification when the radiologist describes a kidney cyst). For these reasons, we developed and validated an NLP system which extracts fracture and anatomy concepts from unstructured text and retrieves relevant bone fracture knowledge. We implement our NLP in an HTML5 web application to demonstrate a proof-of-concept feedback NLP system which retrieves bone fracture knowledge in real time.


Genetic variation in SENP1 and ANP32D as predictors of chronic mountain sickness.
Chronic mountain sickness (CMS) is a serious illness that affects life-long high-altitude residents. A recent study analyzed whole genome sequence data from residents of Cerro de Pasco (Peru) in an effort to identify the genetic basis of CMS and reported SENP1 (rs7963934) and ANP32D (rs72644851) to show signatures consistent with natural selection and protective against CMS (Zhou et al. 2013 ). We set out to replicate these observations in two Andean cohorts from Cerro de Pasco, consisting of 84 CMS cases and 91 healthy controls in total. We report evidence of association for rs7963934 (SENP1) in the combined cohorts (meta-analysis p=8.8x10(-4) OR 2.91, CI 1.56-5.5, I=0). The direction of effect was the same as in the original publication. We did not observe any significant correlation between rs72644851 (ANP32D) and the CMS phenotype, within or across cohorts (meta-analysis p=0.204, OR 1.37, CI 0.84-2.241, I=0). Our results provide independent evidence in support of a role for SENP1 in CMS in individuals of Quechua ancestry and suggest the SENP1 and ANP32D signatures of selection are in tight linkage disequilibrium (LD).


Preoperative Risk Factors of C5 Nerve Root Palsy After Laminectomy and Fusion in Patients With Cervical Myelopathy: Analysis of 70 Consecutive Patients.
A retrospective study. To identify preoperative risk factors causing cervical fifth nerve root palsy (C5 palsy) after laminectomy and fusion (LF). It is well known that postoperative C5 palsy is not rare after cervical surgery. Although there remains controversy, C5 palsy is considered to be more common in patients who had LF than in those who had laminoplasty. However, the reason for the higher incidence of C5 palsy in patients with LF has been poorly understood. A total of 70 consecutive patients (mean age: 60.3 y) who had LF due to cervical myelopathy were reviewed. Patients were divided on the basis of the presence (group P) or absence (group N) of C5 palsy. Among various risk factors for C5 palsy from previous reports, 6 risk factors were selected as follows: (1) preoperative low Japanese Orthopedic Association score, (2) postoperatively increased lordosis, (3) low Pavlov ratio, (4) high signal intensity in the cord at C3-C5, (5) anterior protruding mass lesion compressing the spinal cord, and (6) presence of C4-C5 foraminal stenosis. With these factors, the 2 groups were compared by statistical analysis. C5 palsy occurred in 10 patients (14.3%). The mean onset time was 3.5 days (range, 1-8 d) and the mean recovery time was 3.4 months (range, 1-7 mo). There were no significant differences in the preoperative Japanese Orthopedic Association score, cervical lordosis, Pavlov ratio, high signal intensity, and anterior protruding mass between the 2 groups (P>0.05). However, C4-C5 foraminal stenosis was found in 80.0% (8/10) in group P and 21.7% (13/60) in group N. There were significant differences between the 2 groups in C4-C5 foraminal stenosis (P=0.004). In this study, a high occurrence rate and risk factor for C5 palsy were verified after LF. Among the various factors, C4-C5 foraminal stenosis was the only risk factor for C5 palsy. Preoperative warning for C5 palsy after LF seems to be imperatively necessary, especially in patients with C4-C5 foraminal stenosis.


Adolescent Repeated Alcohol Intoxication as a Predictor of Young Adulthood Alcohol Abuse: The Role of Socioeconomic Context.
Trajectories of alcohol abuse from adolescence onwards are not well known. We examined the relationship between repeated alcohol intoxication in adolescence and later alcohol abuse, testing whether this association varies depending on individuals' socioeconomic context. Study participants (n = 674, age 22-35 years in 2009) belong to the French TEMPO cohort study; their parents also participate in an epidemiological study-the GAZEL cohort. Repeated alcohol intoxication was assessed by questionnaire in adolescence (1999) (defined by ≥3 episodes of alcohol intoxication in the preceding 12 months). In young adulthood (2009), alcohol abuse was assessed by the WHO AUDIT questionnaire. Socioeconomic characteristic studied was childhood family income. Data were analyzed using logistic regression models controlling for age, sex, childhood temperament, parental history of alcohol use, and the quality of family relations. Among adolescents who reported repeated alcohol intoxication, 30.8% reported alcohol abuse in young adulthood (adjusted OR=4.27, 95%CI 2.21-8.27). This association appeared stronger in participants who grew up in families with low income (adjusted OR=11.86, 95%CI 3.35-41.94 vs. 2.49, 95%CI 1.09-5.68 for youths from families with intermediate or high income). In most adolescents (69.2%), alcohol abuse is a time-limited behavior. Nonetheless, in participants from low income families, the likelihood of persistent alcohol abuse beyond adolescence may be increased. Although some limitations are noted, a preliminary conclusion is that alcohol abuse trajectories over time need to be monitored, particularly in certain subgroups.


Possible factors influencing distribution and prevalence of Echinococcus granulosus in Utah.
A descriptive epidemiologic study was designed to test an impression that infections of Echinococcus granulosus in dogs, sheep, and human beings were concentrated in central Utah, and to determine when and how the parasite was introduced into the state, which factors were involved in the distribution of the cestode, and which factors increased either a person's risk of infection of the number of people at risk. Data were secured by review of available records, interviews, questionnaires, and field observations. It was found that 37 of 39 infections in human beings, and seven of eight counties with endemic hydatid disease in dogs and sheep, are located in central Utah. Possible factors responsible for the increasing number of people at risk were use of local people as herders, the existence of community herds, and specific dog management practices. Determinants such as trailing sheep between seasonal pastures, association of sheepmen from several counties on winter range, and sheep marketing practices undoubtedly influence distribution of infections in dogs and sheep.


Laser operation of diode-pumped Er,Yb co-doped YAG ceramics at 1.6 μm.
1.6 μm eye-safe emission of a diode pumped Er,Yb co-doped YAG ceramic laser is firstly demonstrated. Operation of the ceramic laser under different ceramic sample lengths, co-doping concentrations and control temperatures were experimentally investigated. A maximum output power of 222 mW was achieved at an absorbed pump power of 8.1 W, corresponding to a conversion efficiency of 2.74%. Laser emission at 1.05 μm for transition of the Yb(3+) ions was also studied on the same ceramic samples. The results clearly show the existence of resonantly energy transfer from the Yb(3+) ions to Er(3+) ions.


Genetic and morphological variability of the European mudminnow Umbra krameri (Teleostei, Umbridae) in Serbia and in Bosnia and Herzegovina, a basis for future conservation activities.
As a basis for future conservation activities, the genetic and external body morphology variability of the European mudminnow Umbra krameri, a highly endangered fish species in Serbia and in Bosnia and Herzegovina, was determined for existing populations with the use of molecular markers (mitochondrial and microsatellite DNA) and geometric morphometric methods. Mitochondrial DNA cytochrome b gene analysis revealed two previously undescribed haplotypes: Da1 (the Lugomir population from the Danube River basin) and Sa1 (the Bakreni Batar and the Gromiželj populations from the Sava River system), with a corresponding genetic distance of 0·7%. Paired values of FST and DAS distances for microsatellite marker data show that the difference between the Danube and the Sava populations is seven to nine times higher than the difference between the populations within the Sava River system. Geometric morphometric analyses also support a clear separation of the Lugomir population from the Bakreni Batar and the Gromiželj populations. The analysis of the body shape variation, however, indicates a significant difference between the two genetically indistinguishable Sava populations. The observed genetic and phenetic relationships of the analysed mudminnow populations most probably represent a consequence of historical, geographical and ecological factors. These results will offer guidelines for future protection, conservation and sustainable management of this species in the region.


Effect of intravenous iron use on hospitalizations in patients undergoing hemodialysis: a comparative effectiveness analysis from the DEcIDE-ESRD study.
Intravenous iron use in hemodialysis patients has greatly increased over the last decade, despite limited studies on the safety of iron. We studied the association of receipt of intravenous iron with hospitalizations in an incident cohort of hemodialysis patients. We examined 9544 patients from Dialysis Clinic, Inc. (DCI). We ascertained intravenous iron use from DCI electronic medical record and USRDS data files, and hospitalizations through Medicare claims. We examined the association between iron exposure accumulated over 1-, 3- or 6-month time windows and incident hospitalizations in the follow-up period using marginal structural models accounting for time-dependent confounders. We performed sensitivity analyses including recurrent events models for multiple hospitalizations and models for combined outcome of hospitalization and death. There were 22 347 hospitalizations during a median follow-up of 23 months. Higher cumulative dose of intravenous iron was not associated with all-cause, cardiovascular or infectious hospitalizations [HR 0.97 (95% CI: 0.77-1.22) for all-cause hospitalizations comparing >2100 mg versus 0-900 mg of iron over 6 months]. Findings were similar in models examining the risk of hospitalizations in 1- and 3-month windows [HR 0.88 (95% CI: 0.79-0.99) and HR 0.88 (95% CI: 0.74-1.03), respectively] or the risk of combined outcome of hospitalization and death in the 6-month window [HR 0.98 (95% CI: 0.78-1.23)]. Higher cumulative dose of intravenous iron may not be associated with increased risk of hospitalizations in hemodialysis patients. While clinical trials are needed, employing higher iron doses to reduce erythropoiesis-stimulating agents does not appear to increase morbidity in routine clinical care.


Microplastics in the crustaceans Nephrops norvegicus and Aristeus antennatus: Flagship species for deep-sea environments?
Ingestion of microplastics (MPs) has been documented in several marine organisms, but their occurrence in deep-sea species remains almost unknown. In this study, MPs were investigated in two economically and ecologically key crustaceans of the Mediterranean Sea, the Norwegian lobster Nephrops norvegicus and the shrimp Aristeus antennatus. Both the species were collected from 14 sites around Sardinia Island, at depths comprised between 270 and 660 m. A total of 89 and 63 stomachs were analysed for N. norvegicus and A. antennatus respectively, and more than 2000 MPs-like particles were extracted and sorted for identification and characterization by μFT-IR. In N. norvegicus, 83% of the specimens contained MPs, with an average abundance of 5.5 ± 0.8 MPs individual-1, while A. antennatus showed a lower frequency of ingestion (67%) and a lower mean number of MPs (1.66 ± 0.1 MPs individual-1). Composition and size of particles differed significantly between the two species. The non-selective feeding strategy of N. norvegicus could explain the 3-5 folds higher numbers of MPs in its stomach, which were mostly composed of films and fragments derived by polyethylene and polypropylene single-use plastic items. Contrarily, most MPs in the stomachs of A. antennatus were polyester filaments. The MPs abundance observed in N. norvegicus is among the highest detected in Mediterranean species considering both fish and invertebrates species, and provides novel insights on MPs bioavailability in deep-sea habitats. The overall results suggest that both N. norvegicus and A. antennatus, easily available in common fishery markets, could be valuable bioindicators and flagship species for plastic contamination in the deep-sea.


Tubers are neither static nor discrete: Evidence from serial diffusion tensor imaging.
To assess the extent and evolution of tissue abnormality of tubers, perituber tissue, and normal-appearing white matter (NAWM) in patients with tuberous sclerosis complex using serial diffusion tensor imaging. We applied automatic segmentation based on a combined global-local intensity mixture model of 3T structural and 35 direction diffusion tensor MRIs (diffusion tensor imaging) to define 3 regions: tuber tissue, an equal volume perituber rim, and the remaining NAWM. For each patient, scan, lobe, and tissue type, we analyzed the averages of mean diffusivity (MD) and fractional anisotropy (FA) in a generalized additive mixed model. Twenty-five patients (mean age 5.9 years; range 0.5-24.5 years) underwent 2 to 6 scans each, totaling 70 scans. Average time between scans was 1.2 years (range 0.4-2.9). Patient scans were compared with those of 73 healthy controls. FA values were lowest, and MD values were highest in tubers, next in perituber tissue, then in NAWM. Longitudinal analysis showed a positive (FA) and negative (MD) correlation with age in tubers, perituber tissue, and NAWM. All 3 tissue types followed a biexponential developmental trajectory, similar to the white matter of controls. An additional qualitative analysis showed a gradual transition of diffusion values across the tissue type boundaries. Similar to NAWM, tuber and perituber tissues in tuberous sclerosis complex undergo microstructural evolution with age. The extent of diffusion abnormality decreases with distance to the tuber, in line with known extension of histologic, immunohistochemical, and molecular abnormalities beyond tuber pathology.


TRPV4 channels activity in bovine articular chondrocytes: regulation by obesity-associated mediators.
Turnover of the cartilage extracellular matrix depends exclusively on chondrocytes and varies in response to load and osmolarity fluctuations. Obesity can affect chondrocyte physiology; adipokines, insulin and proinflammatory cytokines levels are all altered in the obese and are related to matrix turnover impairments and thus to osteoarthritis. TRPV4, a mechanosensitive cation channel, is responsible for reacting to hypotonic variations. In this study, the presence and activity of TRPV4 channels in bovine chondrocytes were evaluated using the whole-cell patch-clamp technique and fluorescence measurements to perform characterisations of these channels and to determine intracellular calcium responses. The expression of TRPV4 was determined by RT-PCR. The TRPV4 regulation by hypotonic shock, insulin and adipokines were analysed. Hypoosmolarity induced a Gd(3+)-, ruthenium red-, and HC-067047-sensitive current, predominantly inward, an intracellular Ca(2+) concentration increase and a membrane depolarisation. The current had a reversal potential of +28±4mV and exhibited preferential permeability to Ca(2+); 4αPDD, a specific TRPV4 agonist, evoked the same response. TNFα, IL-1β, insulin, and, to a lesser degree, leptin and resistin attenuated the TRPV4-mediated effects; in contrast, adiponectin did not affect them. These results confirm the function of TRPV4 in bovine articular chondrocytes and its regulation by obesity-associated mediators.


Sensitizing the insensitive.
Lithium is still the treatment of choice in bipolar affective disorder. The patient presented here represents an example of the possible severity of metabolic defects resulting from lithium use. In this case, it caused severe intractable nephrogenic diabetes insipidus (NDI). Our case report draws attention to 2 important messages. The first is the complexity in treating psychiatric patients that is often not borne out in the medical literature. The second is the role and power of pharmacological augmentation. While the role of these agents has been appreciated for some time, the use of carbamazepine and of drug combinations is not as well recognized. We emphasize the clinical features of NDI, lithium's metabolic sequelae and furthermore collate the most up-to-date account of the signalling effects conferred by these agents in a summary diagram.


High displacement sensitivity in asymmetric plasmonic nanostructures.
The strong couplings between two asymmetric plasmonic nanostructures can lead to ultra-sensitive optical responses when their separation changes. We employ electromagnetic numerical simulations to study the displacement sensitivity of two kinds of plasmonic systems: (1) a split-ring resonator and a metal rod; (2) two metal rods of asymmetric lengths. Structural asymmetry makes antiparallel current interactions possible and greatly enhances the sensitivity to 5%/nm for normalized frequency changes and 29%/nm for normalized transmittance changes. These are the highest displacement sensitivity among all physical systems investigated so far. In addition, we also find that these systems display a universal scaling curve independent of their shapes or dimensions. These asymmetric plasmonic nanostructures will open widespread applications from strain mapping, surface wave or heat wave imaging, optomechanical sensing, to environmental detections.


Depleting components of the THO complex causes increased telomere length by reducing the expression of the telomere-associated protein Rif1p.
Telomere length is regulated mostly by proteins directly associated with telomeres. However, genome-wide analysis of Saccharomyces cerevisiae mutants has revealed that deletion of Hpr1p, a component of the THO complex, also affects telomere length. The THO complex comprises four protein subunits, namely, Tho2p, Hpr1p, Mft1p, and Thp2p. These subunits interplay between transcription elongation and co-transcriptional assembly of export-competent mRNPs. Here we found that the deletion of tho2 or hpr1 caused telomere lengthening by ∼50-100 bps, whereas that of mft1 or thp2 did not affect telomere length. Since the THO complex functions in transcription elongation, we analyzed the expression of telomere-associated proteins in mutants depleted of complex components. We found that both the mRNA and protein levels of RIF1 were decreased in tho2 and hpr1 cells. RIF1 encodes a 1917-amino acid polypeptide that is involved in regulating telomere length and the formation of telomeric heterochromatin. Hpr1p and Tho2p appeared to affect telomeres through Rif1p, as increased Rif1p levels suppressed the telomere lengthening in tho2 and hpr1 cells. Moreover, yeast cells carrying rif1 tho2 or rif1 hpr1 double mutations showed telomere lengths and telomere silencing effects similar to those observed in the rif1 mutant. Thus, we conclude that mutations of components of the THO complex affect telomere functions by reducing the expression of a telomere-associated protein, Rif1p.


Conditional fetal and infant killing by male baboons.
Sexually selected feticide-the death of infants in utero as a result of male behaviour-has only rarely been described or analysed, although it is presumed to be favoured by the same selective pressures that favour sexually selected infanticide. To test this hypothesis, we measured the frequency of feticide and infanticide by male baboons of the Amboseli basin in Kenya, and examined which characteristics of a male and his environment made him more likely to commit feticide and/or infanticide. We found a dramatic increase in fetal and infant death rates, but no increase in death rates of 1- to 2-year-old individuals, following the immigration of males who stood to benefit from feticide and infanticide. Specifically, fetal and infant death rates were highest following immigrations in which: (i) the immigrant male rapidly attained high rank, (ii) that male remained consistently resident in the group for at least three months, (iii) food availability and social group range overlap was relatively low and (iv) relatively many pregnant females and/or dependent infants were present. Together, these results provide strong evidence for the existence of both sexually selected feticide and infanticide in our population, and they indicate that feticide and infanticide are conditional male behavioural strategies employed under particular circumstances.


Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian.
Dietary supplements are widely used for desired effects on memory, insomnia, mood and anxiety. This review focuses on supplements which have anxiolytic or mild relaxation properties and enhance mood. For example, Kava (Piper methysticum) is reported to have anaxiolytic actions and to reduce tension through skeletal muscle relaxation. Dried passion flower (genus Passiflora) is reported to reduce insomnia and hysteria. Skullcap (genus Scutellaria), hops (Humulus lupulus), lemon balm (Melissa officinalis) and Valerian (Valeriana officinalis) root are all herbs reported as anaxiolytic calming agents. Further, extracts of Magnolia and Phellondendron bark are mild sedatives. Supplements such as gamma-aminobutyric acid (GABA), theanine, tryptophan and 5-hydroxytryptophan (5-HTP) are reported to promote relaxation. In general, these supplements appear to act as GABA receptor agonists or to boost GABA levels, although Kava inhibits both norephinephrine uptake and sodium and potassium channels and 5-HTP may act through elevation of serotonin. While questions remain in the literature regarding the medicinal value of these supplements in treating mood and anxiety disorders, based on cellular and animal studies as well as human clinical trials the literature supports a role for these preparations as useful alternatives in the management of the stress and anxiety of everyday life.


Role of vitamin D in endothelial function and endothelial repair in clinically stable systemic lupus erythematosus.
Patients with systemic lupus erythematosus (SLE) have endothelial dysfunction and increased risk of cardiovascular disease. Endothelium-dependent dilatation (ED) is abnormal in patients with SLE, and endothelial repair mechanisms are also impaired. Myeloid angiogenic cells (MACs) promote angiogenesis to restore damaged vessels. Vitamin D deficiency is associated with cardiovascular disease in the general population and is prevalent in SLE. We aimed to assess the effect of vitamin D on endothelial repair and function. Vitamin D deficient (<20 ng/mL) patients with SLE were treated with cholecalciferol by their physician. Vitamin D replete patients (>30 ng/mL) and healthy controls (>20 ng/mL) were also recruited. Endothelial function was determined by the ratio of ED to independent dilatation (EI). MACs from patients were cultured with and without 10 nM calcitriol, and function determined by migration and angiogenesis assays. Endothelial nitric oxide synthase (eNOS) expression was studied in human aortic endothelial cells treated with tumour necrosis factor α (TNFα) and MAC-conditioned media. We studied 22 vitamin D deficient and 18 replete patients. Vitamin D deficient patients had an increased number of MACs compared with controls (p=0·04) but impaired migratory capacity (p=0·001) and reduced angiogenic capacity, although this was not statistically significant (p=0·13). Media from calcitriol-treated MACs significantly increased angiogenesis compared with untreated MACs (p=0·01). Calcitriol reduced IP-10 expression by MACs (p<0·0006), and blockade of IP-10 restored the angiogenic capacity of MACs from patients with SLE. In cholecalciferol-treated patients, change in 25-hydroxyvitamin D was strongly correlated with change in ED:EI (r=0·650, p=0·006) after adjustment for age (odds ratio 1·12, 95% CI 1·02-1·24; p=0·02). Media from calcitriol-treated MACs more strongly attenuated TNFα-mediated downregulation of eNOS in human aortic endothelial cells than did untreated MACs from patients with SLE (p=0·01). In this small experimental study, calcitriol improved endothelial function in patients with stable SLE. This improvement was associated with an increase in MAC number and function. The improved angiogenic capacity in MACs might be mediated via downregulation of IP-10 and changes in ED:EI by MAC regulation of eNOS in endothelial cells. The findings suggest that vitamin D could be a novel therapy to reduce cardiovascular disease in this patient group. North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics (funding from UK Medical Research Council (grant number G1000417/94909), ICON, Astra Zeneca, GlaxoSmithKline, Medicines Evaluation Unit).


A dipicolinic acid tag for rigid lanthanide tagging of proteins and paramagnetic NMR spectroscopy.
A new lanthanide tag was designed for site-specific labeling of proteins with paramagnetic lanthanide ions. The tag, 4-mercaptomethyl-dipicolinic acid, binds lanthanide ions with nanomolar affinity, is readily attached to proteins via a disulfide bond, and avoids the problems of diastereomer formation associated with most of the conventional lanthanide tags. The high lanthanide affinity of the tag opens the possibility to measure residual dipolar couplings in a single sample containing a mixture of paramagnetic and diamagnetic lanthanides. Using the DNA-binding domain of the E. coli arginine repressor as an example, it is demonstrated that the tag allows immobilization of the lanthanide ion in close proximity of the protein by additional coordination of the lanthanide by a carboxyl group of the protein. The close proximity of the lanthanide ion promotes accurate determinations of magnetic susceptibility anisotropy tensors. In addition, the small size of the tag makes it highly suitable for studies of intermolecular interactions.


Total scalp irradiation using helical tomotherapy.
Homogeneous irradiation of the scalp poses technical and dosimetric challenges due to the extensive, superficial, curved treatment volume. Conventional treatments on a linear accelerator use multiple matched electron fields or a combination of electron and photon fields. Problems with these techniques include dose heterogeneity in the target due to varying source-to-skin distance (SSD) and angle of beam incidence, significant dose to the brain, and the potential for overdose or underdose at match lines between the fields. Linac-based intensity-modulated radiation therapy (IMRT) plans have similar problems. This work presents treatment plans for total scalp irradiation on a helical tomotherapy machine. Helical tomotherapy is well-suited for scalp irradiation because it has the ability to deliver beamlets that are tangential to the scalp at all points. Helical tomotherapy also avoids problems associated with field matching and use of more than one modality. Tomotherapy treatment plans were generated and are compared to plans for treatment of the same patient on a linac. The resulting tomotherapy plans show more homogeneous target dose and improved critical structure dose when compared to state-of-the-art linac techniques. Target equivalent uniform dose (EUD) for the best tomotherapy plan was slightly higher than for the linac plan, while the volume of brain tissue receiving over 30 Gy was reduced by two thirds. Furthermore, the tomotherapy plan can be more reliably delivered than linac treatments, because the patient is aligned prior to each treatment based on megavoltage computed tomography (MVCT).


[Sorafenib and radiotherapy association for hepatocellular carcinoma].
Conformal radiotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC), producing local control rates above 90% within the radiation beam. However, survival after radiotherapy remains limited by the high frequency of intra- and extra-hepatic recurrences, which occurs in 40-50 and 20-30% of cases, respectively. Sorafenib (BAY43-9006, Nexavar; Bayer, West Haven, CT) is a small-molecule inhibitor that demonstrated potent activity to target v-raf murine sarcoma oncogene homolog B1 (BRAF) and VEGFR tyrosine kinases. Sorafenib is the only drug that demonstrated effectiveness to increase overall survival in advanced or metastatic hepatocellular carcinoma. The rationale to combine radiotherapy with sorafenib is the following: (1) targeting RAS-RAF-MAPK and VEGFR signaling pathways, which are specifically activated after exposure to radiation, and responsible for radio-resistance phenomenon; (2) enhancing the oxygen effect through normalization of the surviving tumor vasculature; and (3) synchronization of the cell cycle. Sorafenib and radiotherapy represent complementary strategies, as radiotherapy may be useful to prolong the effect of sorafenib through control of the macroscopic disease, when sorafenib may target latent microscopic disease. Sorafenib and radiotherapy associations are thus based on a relevant biological and clinical rationale and are being evaluated in ongoing phase I-II trials.


PCSK6 is associated with handedness in individuals with dyslexia.
Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)]. The most highly associated marker, rs11855415 (P = 4.7 × 10(-7)), is located within PCSK6. Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill. Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 2.0 × 10(-8)). Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 0.0020). These results provide molecular evidence that cerebral asymmetry and dyslexia are linked. Furthermore, PCSK6 is a protease that cleaves the left-right axis determining protein NODAL. Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia.


Fast frequency-guided sequential demodulation of a single fringe pattern.
Fast frequency-guided sequential demodulation (FFSD) for demodulating a single closed-fringe pattern is proposed as an improvement of frequency-guided sequential demodulation (FSD). Instead of using optimization to estimate the local frequencies for determining the sign of the phase, the FFSD estimates the local frequencies by directly calculating the gradient of the obtained phase with an undetermined sign. This improvement considerably reduces the computational complexity of the FSD and leads to a faster and simpler method. Simulated and experimental fringe patterns are used to test the proposed method and show that the demodulation speed of FFSD is about 150 times faster than that of the FSD, while the robustness and accuracy remain almost the same.


Beneficial effects of the treatment of iron deficiency on clinical condition, left ventricular function, and quality of life in patients with chronic heart failure.
Anemia is now considered as an important contributing factor to the deterioration of chronic heart failure. The present study aimed to assess the effects of intravenous iron therapy on clinical condition, left ventricular function and also quality of life in patients who suffered of chronic heart failure and concomitant iron deficiency. In this clinical trial, 25 consecutive patients with concomitant chronic heart failure and iron deficiency referred to Shariati hospital in Isfahan, Iran in 2013. After initial clinical, laboratory, and echocardiography assessments, the patients administered 200 mg intravenous Iron per week until compensating iron deficit. Then, all study parameters were assessed again and compared to parameters before the therapeutic intervention. The NYHA class showed a significant improvement after the therapeutic approach. The prevalence of heart failure-related edema was also significantly reduced from 60% before treatment to 48% after that (p = 0.036). The rate of hospitalization was considerably reduced from 42% to 16% (P < 0.001). Moreover, mean 6 minute walk test (6MWT) was increased from 155.18 m to 187.40 m (P < 0.001). Comparing Left Ventricular Ejection Fraction (LVEF) after treatment to figures before the test indicated a significant improvement in this parameter (27.5% versus 33.0%, P = 0.007). The treatment of iron deficiency in this group of subjects got a significant improvement in SF36 total score. In patients with chronic heart failure, the treatment of iron deficiency results in a marked improvement in functional status, ejection fraction, and also quality of life as well as a reduction in need to re-hospitalization, however renal function was deteriorated and thus more pay attention to renal function is necessary.


Two-step self-assembly of liposome-multidomain peptide nanofiber hydrogel for time-controlled release.
Progress in self-assembly and supramolecular chemistry has been directed toward obtaining macromolecular assemblies with higher degrees of complexity, simulating the highly structured environment in natural systems. One approach to this type of complexity are multistep, multicomponent, self-assembling systems that allow approaches comparable to traditional multistep synthetic organic chemistry; however, only a few examples of this approach have appeared in the literature. Our previous work demonstrated nanofibrous mimics of the extracellular matrix. Here we demonstrate the ability to create a unique hydrogel, developed by stepwise self-assembly of multidomain peptide fibers and liposomes. The two-component system allows for controlled release of bioactive factors at multiple time points. The individual components of the self-assembled gel and the composite hydrogel were characterized by TEM, SEM, and rheometry, demonstrating that peptide nanofibers and lipid vesicles both retain their structural integrity in the composite gel. The rheological robustness of the hydrogel is shown to be largely unaffected by the presence of liposomes. Release studies from the composite gels loaded with different growth factors EGF, MCP-1, and PlGF-1 showed delay and prolongation of release by liposomes entrapped in the hydrogel compared to more rapid release from the hydrogel alone. This bimodal release system may have utility in systems where timed cascades of biological signals may be valuable, such as in tissue regeneration.


Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes.
Two of the major cancerous diseases associated with asbestos exposure are malignant pleural mesothelioma (MPM) and lung cancer (LC). In addition to asbestos exposure, genetic factors have been suggested to be associated with asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM were reported, to date the influence of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron (Fe) homeostasis are hallmarks of asbestos exposure affecting the pulmonary tissue, this study aimed at investigating the association between Fe-metabolism and inflammasome gene variants and susceptibility to develop LC or MPM, by comparing an asbestos-exposed population affected by LC with an "asbestos-resistant exposed population". A retrospective approach similar to our previous autopsy-based pilot study was employed in a novel cohort of autoptic samples, thus giving us the possibility to corroborate previous findings obtained on MPM by repeating the analysis in a novel cohort of autoptic samples. The protective role of HEPH coding SNP was further confirmed. In addition, the two non-coding SNPs, either in FTH1 or in TF, emerged to exert a similar protective role in a new cohort of LC exposed individuals from the same geographic area of MPM subjects. No association was found between NLRP1 and NLRP3 polymorphisms with susceptibility to develop MPM and LC. Further research into a specific MPM and LC "genetic signature" may be needed to broaden our knowledge of the genetic landscape attributed to result in MPM and LC.


Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study.
The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors. We measured 8 circulating biomarkers reflecting inflammation (C-reactive protein), hemostasis (plasminogen activator inhibitor-1, fibrinogen), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide), and endothelial dysfunction (homocysteine) in 2292 Framingham Offspring Study participants (mean age, 57 years; 56% women). We related the biomarker panel to incidence of MetS on follow-up initially and then related biomarkers associated with incident MetS to longitudinal change in its components. On follow-up (mean, 2.9 years), 282 participants (of 1473 participants without prevalent MetS at baseline) developed MetS. After adjustment for clinical risk factors, the biomarker panel was associated with incident MetS (P=0.008). On backward elimination, plasminogen activator inhibitor-1 and aldosterone remained associated with incident MetS (multivariable-adjusted odds ratio per 1-SD increment log marker, 1.31 [P=0.004] and 1.21 [P=0.015], respectively). In multivariable analyses evaluating longitudinal change in MetS components (analyzed as continuous variables), plasminogen activator inhibitor-1 was significantly and positively associated with changes in fasting glucose, systolic blood pressure, and triglycerides (all P<0.05). Serum aldosterone was associated positively with change in systolic blood pressure (P=0.023) and inversely with change in high-density lipoprotein cholesterol (P=0.001). Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk.


Antioxidant supplements and semen parameters: An evidence based review.
Many studies have focused on male infertility. There is limited evidence about the influence of nutrition on quality of semen. Approximately, 30-80% of infertility cases are caused by oxidative stress and decreased level of seminal total antioxidant capacity. This study was aimed to review the effects of oral antioxidant supplements on improving major semen parameters such as sperm concentration, motility, morphology, DNA damage, and fertility rate. Data were extracted from PubMed and Google scholar database by using the terms "antioxidant", "multivitamin", "carnitine", "CoQ10", "vitamin C", "vitamin E", "zinc", "folic acid", "N-acetyl cysteine" and "selenium" combined with "male infertility", "semen", and "sperm" to generate a set of relevant citations. Supplements such as CoQ10 and alpha-tocopherol significantly improve sperm count. Also, carnitine has positive effects on sperm motility and morphology. Simultaneous administration of vitamin E and vitamin C reduces the sperm DNA damage. However, in some studies, one or more factors have not changed substantially. In most of the studies, antioxidant supplementation improved the number, motility, morphology and sometimes DNA integrity of sperm. The present study showed that antioxidant supplements, especially a combination of antioxidants such as vitamin C, vitamin E, and CoQ10 intake can effectively improve semen parameters in infertile men.


Dentoskeletal and soft-tissue changes in growing class II malocclusion patients during nonextraction orthodontic treatment.
An investigation was conducted to determine the outcome of nonextraction edgewise orthodontic treatment of thirty-five caucasian patients with Class II molar relationships (13 division 1 and 22 division 2 cases). Twenty-three females and 12 males aged between 10 and 16 years old were treated using Class II intermaxillary elastics worn with 0.016" x 0.022" stainless steel archwires and without extra-oral traction. Thirty cephalometric landmarks were identified and digitized, and used to calculate 41 parameters. Space analyses were conducted on pretreatment study models. Most of the cases had between 0-4 mm space shortage in both maxillary and mandibular dentitions. Results of this study indicated that the mean SNA angle decreased by 1.580 degrees, and that this change was largely due to posterior movement of point A. The mean pre-treatment ANB value was 4.490 degrees which decreased to a mean posttreatment value of 2.810 degrees (p<0.05). No significant changes in the growth direction of the jaws were found, showing that the use of Class II intermaxillary elastics in this sample had no detrimental effect on this parameter (p<0.05). The SNB angle increased by a mean of 0.110 degrees, which can be attributed to anterior mandibular growth. The dentoalveolar changes included a mean overjet reduction of 3.816mm (mean posttreatment overjet was 2.2mm) and proclination of the lower incisors relative to the APo line and the mandibular plane, probably caused by the use of Class II intermaxillary elastics. The lower lip advanced relatively more than the upper lip, and this contributed to an improvement of the lip relationship. The amount of nose growth observed during the study was normal for this age group, and compared favourably with other data in the literature.


Aromatherapy: Using Essential Oils as a Supportive Therapy.
Essential oils can be a great adjunct to cancer care, aiding in the management of side effects, such as insomnia and nausea. Healthcare professionals should be knowledgeable about the quality and safety of essential oils when using them for clinical purposes. Using lesser quality essential oils and not understanding safety guidelines can negatively affect clinical outcomes. This article provides an overview of how nurses can help patients with cancer safely use essential oils as a supportive therapy.


Single dose oral lumiracoxib for postoperative pain in adults.
Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors were developed to avoid COX-1-related gastrointestinal (GI) problems while maintaining the analgesic and anti-inflammatory activity of traditional non-steriodal anti-inflammatory drugs (NSAIDs). To review the analgesic efficacy, duration of analgesia, and adverse effects of a single oral dose of lumiracoxib for moderate to severe postoperative pain in adults. We searched Cochrane CENTRAL, MEDLINE, and EMBASE to February 2010. Single oral dose, randomised, double-blind, placebo-controlled trials of lumiracoxib for relief of established moderate to severe postoperative pain in adults. Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Numbers of participants using rescue medication, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. In this updated review four studies met the inclusion criteria. In total 366 participants were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 212 with placebo. Active comparators were naproxen 500 mg, rofecoxib 50 mg, celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 400 mg. With lumiracoxib 400 mg 50% of participants had at least 50% pain relief over six hours, compared with 8% given placebo; RB 6.9 (95% CI 4.1 to 12), NNT 2.4 (2.1 to 2.8).Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than placebo (>12 hours). Fewer participants needed rescue medication with lumiracoxib (64%) than with placebo (91%) over 12 to 24 hours; NNT to prevent remedication 3.7 (2.9 to 5.0). The weighted median time to use of rescue medication was 9.4 hours for lumiracoxib 400 mg and 1.7 hours for placebo.Adverse events were generally mild to moderate in severity, with one serious event reported in a placebo patient. Lumiracoxib 400 mg given as a single oral dose is an effective analgesic for acute postoperative pain, and has a relatively long duration of action. Adverse events with lumiracoxib did not differ from placebo.


Molecular dynamics study of the structure, flexibility and dynamics of thermostable l1 lipase at high temperatures.
Molecular Dynamics (MD) simulations have been used to understand how protein structure, dynamics, and flexibility are affected by adaptation to high temperature for several years. We report here the results of the high temperature MD simulations of Bacillus stearothermophilus L1 (L1 lipase). We found that the N-terminal moiety of the enzyme showed a high flexibility and dynamics during high temperature simulations which preceded and followed by clear structural changes in two specific regions; the small domain and the main catalytic domain or core domain of the enzyme. These two domains interact with each other through a Zn(2+)-binding coordination with Asp-61 and Asp-238 from the core domain and His-81 and His-87 from the small domain. Interestingly, the His-81 and His-87 were among the highly fluctuated and mobile residues at high temperatures. The results appear to suggest that tight interactions of Zn(2+)-binding coordination with specified residues became weak at high temperature which suggests the contribution of this region to the thermostability of the enzyme.


Short-term outcomes for preterm infants with surgical necrotizing enterocolitis.
To characterize the population and short-term outcomes in preterm infants with surgical necrotizing enterocolitis (NEC). Preterm infants with surgical NEC were identified from 27 hospitals over 3 years using the Children's Hospitals Neonatal Database; infants with gastroschisis, volvulus, major congenital heart disease or surgical NEC that resolved prior to referral were excluded. Patient characteristics and pre-discharge morbidities were stratified by gestational age (<28 vs 28(0/7) to 36(6/7) weeks' gestation). Of the 753 eligible infants, 60% were born at <28 weeks' gestation. The median age at referral was 14 days; only 2 infants were inborn. Male gender (61%) was overrepresented, whereas antenatal steroid exposure was low (46%). Although only 11% had NEC totalis, hospital mortality (<28 weeks' gestation: 41%; 28(0/7) to 36(6/7) weeks' gestation: 32%, P=0.02), short bowel syndrome (SBS)/intestinal failure (IF) (20% vs 26%, P=0.06) and the composite of mortality or SBS/IF (50% vs 49%, P=0.7) were prevalent. Also, white matter injury (11.7% vs 6.6%, P=0.02) and grade 3 to 4 intraventricular hemorrhages (23% vs 2.7%, P<0.01) were commonly diagnosed. After referral, the median length of hospitalization was longer for survivors (106 days; interquartile range (IQR) 79, 152) relative to non-survivors (2 days; IQR 1,17; P<0.001). These survivors were prescribed parenteral nutrition infrequently after hospital discharge (<28 weeks': 5.2%; 28(0/7) to 36(6/7) weeks': 9.9%, P=0.048). After referral for surgical NEC, the short-term outcomes are grave, particularly for infants born <28 weeks' gestation. Although analyses to predict outcomes are urgently needed, these data suggest that affected infants are at a high risk for lengthy hospitalizations and adverse medical and neuro-developmental abnormalities.


Prevalence and correlates of psychotropic drug use in Dutch nursing-home patients with dementia.
Neuropsychiatric symptoms in dementia patients are common and are often treated with psychotropic drugs. The aim of this study was to determine the prevalence and correlates of psychotropic drug use in Dutch nursing home patients with dementia. Psychotropic drug use of 1322 patients on 59 dementia special care units (SCUs) in 25 nursing homes was registered. Drugs were categorized according to the Anatomical Therapeutical Chemical classification (ATC). The influence of age, gender, dementia stage measured by the Global Deterioration Scale (GDS), and type of neuropsychiatric symptoms on psychotropic drug use was analyzed using binomial logistic regression analysis. 63% of the patients used at least one psychotropic drug. Psychotropics in general and antipsychotics in particular were most frequently prescribed in GDS stage 6, and in patients aged between 65 and 75 years. Psychotropics in general were positively associated with depression, night-time behavior and agitation. Antipsychotic drug use was positively associated with psychosis, agitation and night-time behavior and was negatively associated with apathy. Anxiolytics were associated with age, psychosis, agitation and night-time behavior. Antidepressants were most frequently prescribed in GDS stage 6 and associated with female gender, agitation and depression. Sedatives were only associated with night-time behavior. Nursing home patients with dementia have a high prevalence of psychotropic drug use. In particular, the association with neuropsychiatric symptoms raises questions of efficacy of these drugs and the risk of chronic use.


Inhibition of aldehyde dehydrogenase-1 and p-glycoprotein-mediated multidrug resistance by curcumin and vitamin D3 increases sensitivity to paclitaxel in breast cancer.
Treatment of breast cancer by paclitaxel (PAX) often encounters therapeutic failure most likely caused by innate/acquired resistance. Cancer stem cells (CSCs) and multidrug resistance complex (MDR-1 or P-glycoprotein) overexpression are main mechanisms implicated in chemoresistance. Increased aldehyde dehrogenase-1 (ALDH-1) was previously correlated with the stemness features of CSCs and hence is used as a marker for identification and CSCs targeting. The present study, therefore, aimed at investigating the effect of both curcumin (CUR) and vitamin D3 (D3) on MDR-1 and ALDH-1 expression and consequently the resistance to PAX both in vitro and in vivo. CUR was isolated from Turmeric rhizomes and identified using UPLC-ESI-MS/MS. For in vitro studies, the antiproliferative effect of PAX, CUR, 1,25(OH)2D3 (the active form of D3, also known as calcitriol) was determined, each alone and combined (PAX+CUR, PAX+1,25(OH)2D3, and PAX+CUR+1,25(OH)2D3) on MCF-7 breast cancer cells. Ehrlich ascites carcinoma solid tumor animal model was also used for in vivo studies. Combining CUR and/or 1,25(OH)2D3 to PAX showed synergistic cytotoxic interaction on MCF-7 cells. The apoptotic potential was also enhanced, as evidenced by a significant increase in caspase-7 and -9 as well as the pro-apoptotic Bax whereas a decrease in Bcl-2 levels was reported. Combining CUR and 1,25(OH)2D3 to PAX caused a downregulation in both MDR-1 and ALDH-1 gene expression in MCF-7 besides a decrease in their protein levels. In vivo, the triple therapy group (PAX+CUR+D3) showed the least tumor size. It also showed the lowest levels of MDR-1 and ALDH-1. PAX alone, however, showed increased levels of MDR-1 and ALDH-1 compared to control. Overall, the present study showed that PAX, as a monotherapy, demonstrated acquired resistance possibly by increasing MDR-1 expression and enriching CSCs population, as evidenced by increased ALDH-1. However, using CUR and D3 enhanced tumor response to PAX.


Wilms tumour gene 1 overexpression in bone marrow as a marker for minimal residual disease in acute myeloid leukaemia.
Wilms tumour gene 1 (WT1) is overexpressed in leucocytes of most acute myeloid leukaemia (AML) patients. However, the clinical relevance of WT1 gene expression as minimal residual disease (MRD) marker in AML has been questioned. We determined the expression of WT1 gene in bone marrow (BM) mononuclear cells of 100 AML patients at diagnosis and compared it with other MRD markers during follow up in 16 patients using quantitative reverse transcription-polymerase chain reaction. The median WT1 gene expression was 9.7% of K562 cell line WT1 expression (lower quartile 1.5%, upper quartile 29.9%, n = 100) at diagnosis and, 0.053% (lower quartile 0.022%, upper quartile 0.125%, n = 87) in molecular or immunophenotypic remission. Median WT1 expression in control BM was 0.029% (lower quartile 0.013%, upper quartile 0.061%, n = 22). The upper 99% percentile of remission samples was 0.3%, which was regarded as the cut-off of increased WT1 gene expression in AML and was exceeded in 87% of all AML patients at diagnosis. WT1 and the other MRD markers showed only minor differences in profiles during follow-up. WT1 expression at diagnosis with median value 9.7% as the cut-off level or as a continuous variable had no prognostic significance for 2-yr survival. The sensitivity of WT1 as a MRD marker was low due to the relatively high background WT1 gene expression in BM cells at remission and in subjects without haematological malignancies. Therefore, WT1 gene expression analysis would be beneficial only in those patients who do not have a more specific and sensitive MRD marker.


Analysis of Urine, Oral fluid and Fingerprints by Liquid Extraction Surface Analysis Coupled to High Resolution MS and MS/MS - Opportunities for Forensic and Biomedical Science.
Liquid Extraction Surface Analysis (LESA) is a new, high throughput tool for ambient mass spectrometry. A solvent droplet is deposited from a pipette tip onto a surface and maintains contact with both the surface and the pipette tip for a few seconds before being re-aspirated. The technique is particularly suited to the analysis of trace materials on surfaces due to its high sensitivity and low volume of sample removal. In this work, we assess the suitability of LESA for obtaining detailed chemical profiles of fingerprints, oral fluid and urine, which may be used in future for rapid medical diagnostics or metabolomics studies. We further show how LESA can be used to detect illicit drugs and their metabolites in urine, oral fluid and fingerprints. This makes LESA a potentially useful tool in the growing field of fingerprint chemical analysis, which is relevant not only to forensics but also to medical diagnostics. Finally, we show how LESA can be used to detect the explosive material RDX in contaminated artificial fingermarks.


Residues in the alphaH and alphaI helices of the HIV-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer.
During retrovirus replication, reverse transcriptase (RT) must specifically interact with the polypurine tract (PPT) to generate and subsequently remove the RNA primer for plus-strand DNA synthesis. We have investigated the role that human immunodeficiency virus-1 RT residues in the alphaH and alphaI helices in the thumb subdomain play in specific RNase H cleavage at the 3'-end of the PPT; an in vitro assay modeling the primer removal step was used. Analysis of alanine-scanning mutants revealed that a subgroup exhibits an unusual phenotype in which the PPT is cleaved up to seven bases from its 3'-end. Further analysis of alphaH mutants (G262A, K263A, N265A, and W266A) with changes in residues in or near a structural motif known as the minor groove binding track showed that the RNase H activity of these mutants is more dramatically affected with PPT substrates than with non-PPT substrates. Vertical scan mutants at position 266 were all defective in specific RNase H cleavage, consistent with conservation of tryptophan at this position among lentiviral RTs. Our results indicate that residues in the thumb subdomain and the minor groove binding track in particular, are crucial for unique interactions between RT and the PPT required for correct positioning and precise RNase H cleavage.


Further investigations on fixed abrasive diamond pellets used for diminishing mid-spatial frequency errors of optical mirrors.
As further application investigations on fixed abrasive diamond pellets (FADPs), this work exhibits their potential capability for diminishing mid-spatial frequency errors (MSFEs, i.e., periodic small structure) of optical surfaces. Benefitting from its high surficial rigidness, the FADPs tool has a natural smoothing effect to periodic small errors. Compared with the previous design, this proposed new tool employs more compliance to aspherical surfaces due to the pellets being mutually separated and bonded on a steel plate with elastic back of silica rubber adhesive. Moreover, a unicursal Peano-like path is presented for improving MSFEs, which can enhance the multidirectionality and uniformity of the tool's motion. Experiments were conducted to validate the effectiveness of FADPs for diminishing MSFEs. In the lapping of a Φ=420 mm Zerodur paraboloid workpiece, the grinding ripples were quickly diminished (210 min) by both visual inspection and profile metrology, as well as the power spectrum density (PSD) analysis, RMS was reduced from 4.35 to 0.55 μm. In the smoothing of a Φ=101 mm fused silica workpiece, MSFEs were obviously improved from the inspection of surface form maps, interferometric fringe patterns, and PSD analysis. The mid-spatial frequency RMS was diminished from 0.017λ to 0.014λ (λ=632.8 nm).


Acute bone crises in sickle cell disease: the T1 fat-saturated sequence in differentiation of acute bone infarcts from acute osteomyelitis.
To prove the hypothesis that acute bone infarcts in sickle cell disease are caused by sequestration of red blood cells (RBCs) in bone marrow, and to evaluate the unenhanced T1 fat-saturated (fs) sequence in the differentiation of acute bone infarction from acute osteomyelitis in patients with sickle-cell disease. Two studies were undertaken: an experimental study using in-vitro packed red blood cells and normal volunteers, and a retrospective clinical study of 86 magnetic resonance imaging (MRI) studies. For the experimental study containers of packed RBCs were placed between the knees of four healthy volunteers with a saline bag under the containers as an additional control, and were scanned with the pre-contrast T1-fs sequence. Signal intensity (SI) ratios were obtained for packed RBCs:skeletal muscle and packed RBCs:saline. For the clinical study, the SIs of normal bone marrow, packed RBCs, bone and/or soft-tissue lesions, and normal skeletal muscle of 74 patients (86 MRI studies) were measured using unenhanced, T1 fat-saturated MRI. The ratios of the above SIs to normal skeletal muscle were calculated and subjected to statistical analysis. Fifty-one of 86 MRI studies were included in the final analysis. The ratios of SIs for normal bone marrow, packed red cells, bone infarction, acute osteomyelitis, and soft-tissue lesions associated with bone infarct, compared with normal skeletal muscle were (mean+/-SD) 0.9+/-0.2, 2.1+/-0.7, 1.7+/-0.5, 1.0+/-0.3, and 2.2+/-0.7, respectively. The difference in the ratio of SIs of bone infarcts and osteomyelitis was significant (p=0.003). The final diagnoses were bone infarction (n=50), acute osteomyelitis (n=1), and co-existent bone infarction and osteomyelitis (n=2). Seven patients who had suspected osteomyelitis underwent image-guided aspiration. Acute bone infarcts in sickle cell disease are caused by sequestration of red blood cells in the bone marrow. The unenhanced, T1-fat-saturated sequence alone is diagnostic for acute bone infarcts. Contrast enhancement aids in the diagnosis of acute osteomyelitis. MRI can thus help in early diagnosis, specific treatment, and preventing empirical antibiotic therapy.


p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility.
To determine the clinical utility of p63 expression, which has been identified in several cohorts as a predictor of poorer prognosis in Merkel cell carcinoma (MCC). Immunohistochemistry was used to determine p63 expression on MCC tumors from 128 patients. Of the patients, 33% had detectable p63 expression. p63 Positivity was associated with an increased risk of death from MCC (hazard ratio, 2.05; P = .02) in a multivariate Cox regression model considering stage at presentation, age at diagnosis, and sex. Although p63 expression correlated with diminished survival in this largest cohort reported thus far, the effect was weaker than that observed in prior studies. Indeed, within a given stage, p63 status did not predict survival in a clinically or statistically significant manner. It remains unclear whether this test should be integrated into routine MCC patient management.


Ibandronate treatment decreases the effects of tumor-associated lesions on bone density and strength in the rat.
Bisphosphonate treatment is beneficial against symptoms of metastatic bone disease, although less is known about the effect of preventative treatment schedules. We investigated the effect of various treatment regimens of the bisphosphonate, ibandronate (IB), on the preservation of bone quality in a rat model of tumor-induced osteolysis. Osteolytic Walker 256 (W256) carcinosarcoma cells were implanted into the left femur of female Sprague-Dawley rats, resulting in a 10% reduction in bone mineral density (BMD), a 16% reduction in bone density (BD), and a 26% reduction in failure load compared with the right femur 28 days after implantation. IB was administered subcutaneously in five different treatment schedules: (1) IB PRE-POST received IB for 26 days, prior to implantation of W256 cells in the medullary canal of the femur, and for 28 additional days after surgery; (2) IB PRE-POST SHAM received the same IB administration, but with a sham operation; (3) IB PRE received IB injections before W256 cell insertion only; (4) IB PRE-0 received IB injections for 26 days and was then killed to serve as a time zero control; and (5) IB POST received sham injection with saline before W256 cell insertion, and then received IB injections for 28 days until killing. Controls (TUMOR ONLY) received sham injections with saline prior to W256 cell insertion, and then for 28 additional days until killing. We used dual-energy X-ray absorptiometry (DXA) to measure distal femur BMD and bone mineral content (BMC), peripheral quantitative computed tomography (pQCT) to measure distal femur BD, and torsion testing to obtain torsional failure load. Combined preventative and interventional IB treatment best preserved bone mass and strength, although all treatment schedules resulted in significant improvement compared with untreated controls (TUMOR ONLY). The possibility of reducing or even preventing skeletal morbidity in cancer patients with a high risk of developing metastatic spreading to bone is exciting, and warrants further exploration.


Mortality in Individuals with Subjective Cognitive Decline: Results of the Leipzig Longitudinal Study of the Aged (LEILA75+).
Studies have shown that dementia and cognitive impairment can increase mortality, but less is known about the association between subjectively perceived cognitive deficits (subjective cognitive decline, SCD) and mortality risk. In this study, we analyzed mortality in non-demented individuals with SCD in a general population sample aged 75+ years. Data were derived from the Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan-Meier survival method to estimate survival times of individuals with and without SCD and multivariable Cox proportional hazards regression to assess the association between SCD and mortality risk, controlled for covariates. Out of 953 non-demented individuals at baseline, 117 (12.3% ) expressed SCD. Participants with SCD showed a significantly higher case-fatality rate per 1,000 person-years (114.8, 95% CI = 90.5-145.7 versus 71.7, 95% CI = 64.6-79.5) and a significantly shorter mean survival time than those without (5.4 versus 6.9 years, p < 0.001). The association between SCD and mortality remained significant in the Cox analysis; SCD increased mortality risk by about 50% (adjusted Hazard Ratio = 1.51) during the study period. Besides SCD, older age, male gender, diabetes mellitus, stroke, and lower global cognitive functioning were also significantly associated with increased mortality. Our findings suggest an increased mortality risk in non-demented older individuals with SCD. Even though further studies are required to analyze potential underlying mechanisms, subjective reports on cognitive deficits may be taken seriously in clinical practice not only for an increased risk of developing dementia and AD but also for a broader range of possible adverse health outcomes.


Better off dead: suicidal thoughts in cancer patients.
Cancer is associated with an increased risk of suicide and attempted suicide. However, we do not know how many cancer patients have thoughts that they would be better off dead or thoughts of hurting themselves. This study aimed to determine the prevalence of such thoughts in cancer outpatients and which patients are most likely to have them. A survey of consecutive patients who attended the outpatient clinics of a regional cancer center in Edinburgh, United Kingdom. Patients completed the Patient Health Questionnaire-9 (PHQ-9), which included Item 9 that asks patients if they have had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Those who reported having had such thoughts for at least several days in this period were labeled as positive responders. Patients also completed the Hospital Anxiety and Depression Scale (HADS) and a pain scale. The participating patients' cancer diagnoses and treatments were obtained from the cancer center clinical database. Data were available on 2,924 patients; 7.8% (229 of 2,924; 95% CI, 6.9% to 8.9%) were positive responders. Clinically significant emotional distress, substantial pain, and--to a lesser extent--older age, were associated with a positive response. There was strong evidence of interactions between these effects, and emotional distress played the most important role. A substantial number of cancer outpatients report thoughts that they would be better off dead or thoughts of hurting themselves. Management of emotional distress and pain should be a central aspect of cancer care.


Identifying nutritional, functional, and quality of life correlates with male hypogonadism in advanced cancer patients.
With the availability of a potential treatment to reverse male hypogonadism (MH), the primary aim of this case series study was to determine independent relationships between this condition and the nutritional, functional, and quality of life characteristics of advanced cancer patients (ACP). Free testosterone levels were measured in 100 male patients with advanced lung and gastrointestinal (GI) cancer. Routine blood markers of nutrition and inflammation, self-reporting questionnaires for symptom, nutrition, and functional status along with handgrip dynamometry were assessed for all patients at bedside. Almost half of this cohort underwent further assessments (body composition, lower body strength, in depth quality of life and fatigue questionnaires) at the McGill Nutrition and Performance Laboratory (mnupal.mcgill.ca). Multiple regression analyses were performed to identify independent correlations between free testosterone and the above measures. Seventy-six percent of patients were diagnosed with MH. Using multiple linear regression, low free testosterone (31.2 pmol/L) was independently associated with lower albumin (B = -3.8 g/L; 95% confidence interval CI -6.8:-0.8), muscle strength (-11.7 lbs; -20.4: -3.0) and mass in upper limbs (-0.8 kg; -1.4: -0.1), overall performance status (Eastern Cooperative Oncology Group Performance Scale, ECOG PS 0.6; 0.1:1.1), cancer-related fatigue (Brief Fatigue Inventory, BFI 16.7; 2.0: 31.3), and overall quality of life (MQoL total score -1.42; -2.5: -0.3). Thus MH seems to be highly prevalent in ACP, and it is independently associated with important nutritional, functional, and quality of life characteristics in this patient population.


An overview of female genital mutilation in Nigeria.
Nigeria, due to its large population, has the highest absolute number of female genital mutilation (FGM) worldwide, accounting for about one-quarter of the estimated 115-130 million circumcised women in the world. The objective of this review is to ascertain the current status of FGM in Nigeria. Pertinent literature on FGM retrieved from internet services [Google search on FGM in Nigeria, www.online Nigeria, PubMed of the national library of medicine www.medconsumer. Info/tropics/fgm.htm, Biomedcentral and African Journal Online (AJOL) (FGM)] and textbooks, journals, and selected references for proper understanding of the topic was included in this review. The national prevalence rate of FGM is 41% among adult women. Evidence abound that the prevalence of FGM is declining. The ongoing drive to eradicate FGM is tackled by World Health Organization, United Nations International Children Emergency Fund, Federation of International Obstetrics and Gynecology (FIGO), African Union, The economic commission for Africa, and many women organizations. However, there is no federal law banning FGM in Nigeria. There is need to eradicate FGM in Nigeria. Education of the general public at all levels with emphasis on the dangers and undesirability of FGM is paramount.


Subglottic stenosis and endobronchial disease in granulomatosis with polyangiitis.
To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease. Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways. Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia. SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.


Early and small changes in serum creatinine concentrations are associated with mortality in mechanically ventilated patients.
Emerging evidence suggests that minor changes in serum creatinine concentrations are associated with increased hospital mortality rates. However, whether serum creatinine concentration (SCr) on admission and its change are associated with an increased mortality rate in mechanically ventilated patients is not known. We have conducted an international, prospective, observational cohort study enrolling adult intensive care unit patients under mechanical ventilation (MV). Recursive partitioning was used to determine the values of SCr at the start of MV (SCr0) and the change in SCr ([DeltaSCr] defined as the maximal difference between the value at start of MV [day 0] and the value on MV day 2 at 8:00 am) that best discriminate mortality. In-hospital mortality, adjusted by a proportional hazards model, was the primary outcome variable. A total of 2,807 patients were included; median age was 59 years and median Simplified Acute Physiology Score II was 44. All-cause in-hospital mortality was 44%. The variable that best discriminated outcome was a SCr0 greater than 1.40 mg/dL (mortality, 57% vs. 36% for patients with SCr0 <or=1.40 mg/dL, P < 0.001). Among patients with SCr0 less than or equal to 1.40 mg/dL, DeltaSCr greater than 0.31 discriminated mortality (56% vs. 34%, P < 0.001). In multivariate analysis, geographic area, advanced age, severity of illness, reason for MV, and cardiovascular and hepatic failure were also associated with mortality. Our study suggests that SCr0 greater than 1.40 mg/dL and, in patients with low baseline SCr, a DeltaSCr greater than 0.31 are predictors of in-hospital mortality in mechanically ventilated patients.


The future of surgery: autonomy or employment?
History has shown that the professions of medicine and surgery have been in constant evolution. Physicians, including the historical barber surgeons, often remained focused only on medical practice and patient care. As a result, the medical profession had a reactionary response to the financial and political circumstances that developed over time. Subsequently, physicians have worked in environments designed by nonphysicians lacking the benefit of medical insight. The most poignant example of this in the U.S. was the rapid development of private insurance and Medicare. Due to the surrounding financial and political forces, these programs rapidly changed the practice environment of medicine. Physicians found that they needed to participate in these programs to remain financially solvent. Various countries around the world have faced similar challenges of increasing health care cost. As populations expand, the need for care increases, but is limited by available resources. These global experiences can lend insight into the effects of different models and how variations may or may not work within the U.S. The effects of those systems demonstrate the importance of physician input into the development of new models. A long-standing unwritten rule in medicine has taught generations of physicians to avoid discussing reimbursement and health care politics. Yet, in order to recruit the brightest minds with a compassionate bedside manner, excellent judgment, and high vigilance toward patient care, medical professionals need to discuss topics related to reimbursement. The government, insurance company administrations, and other lobby interest groups freely express their interests in these issues. Physicians must engage in health care politics to ensure an adequate physician pool in the future to take care of patients. By influencing the structure of the health care system, including physician reimbursement, all patient care can be positively influenced.


Effects of unsaturated fat dietary supplements on blood lipids, and on markers of malnutrition and inflammation in hemodialysis patients.
We examined the effects of commercially available unsaturated fat dietary supplements on blood lipids, and on markers of malnutrition and inflammation, in an adult population of hemodialysis (HD) patients. This was a restricted, randomized (equal blocks), investigator-blinded 2x6 week crossover trial, without a washout interval. This study was conducted at the Department of Nephrology, Copenhagen University Hospital Herlev, Herlev, Denmark, in spring 2007. Participants included 40 (30 males and 10 females) stable, adult patients undergoing regular HD, with a mean age of 64.6 years and a mean body mass index of 23.3kg/m(2). In addition to patients' habitual diets, oral unsaturated fat supplements (90mL of Calogen [SHS International, Ltd., Liverpool, UK] and 4 capsules of Pikasol [Dansk Droge, Ishoej, Denmark]) were given in one period, whereas no supplements were given in the other. Dietary supplements contributed 1.8 MJ (430kcal), 47g fat, 26.5g monounsaturated fatty acids, and 3g marine n-3 polyunsaturated fatty acids per day. Blood sampling and nutritional assessments were performed at baseline, after 6 weeks, and after 12 weeks. Dietary intakes, blood lipids, dry body weight, serum albumin, and serum C-reactive protein comprised our main outcome measures. According to a per-protocol analysis of 14 study completers, fat supplementation resulted in significantly increased total energy intake (+1.6 MJ/day, or 380kcal/day) and an increased dietary fat energy percentage (+9%). We observed no significant changes in blood lipids. Dry body weight (+0.49kg, P=.04) increased, and serum C-reactive protein concentration fell (-1.69mg/L, P=.01), with fat supplementation. Intention-to-treat analysis of 39 participants confirmed the absence of adverse blood-lipid changes. Unsaturated fat supplementation increased total dietary energy intake to recommended levels, had no adverse impact on blood lipids, improved nutritional status as assessed according to dry body weight, and reduced systemic inflammation as assessed according to C-reactive protein serum concentrations. Adding unsaturated fat to the diet seems to be a safe and effective way to prevent and treat malnutrition in hemodialysis patients.


Sequence and localization of a partial cDNA encoding the human alpha 3 chain of type IV collagen.
A novel type IV collagen, alpha 3(IV), has recently been identified in human and bovine basement membranes. Here we describe the cloning and sequencing of a cDNA encoding 218 residues of the NC1 domain of the human alpha 3(IV) chain. Of interest is the possible role of abnormalities of the alpha 3(IV) chain in Alport syndrome, as suggested by the failure to detect the NC1 domain of alpha 3(IV) in the basement membranes of some Alport syndrome patients. To determine whether the alpha 3(IV) gene (COL4A3) may be mutated in Alport syndrome, we localized it, by somatic cell hybrid analysis and in situ hybridization of metaphase chromosomes, to chromosome 2q35-2q37. Mutations in alpha 3(IV) cannot therefore be responsible for the vast majority of cases of Alport syndrome, which have been shown to be X linked. One explanation for the immunochemical data implicating alpha 3(IV) in Alport syndrome pathogenesis is that mutations of the alpha 5(IV) chain, which has been localized to Xq22 and found to be mutated in at least three kindreds with Alport syndrome, lead to failure to incorporate the alpha 3(IV) chains into the multimeric structure of glomerular basement membrane in a stable fashion.


CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.
Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.


The Problem of Female Genital Cutting: Bridging Secular and Islamic Bioethical Perspectives.
Recent events, including the arrest of physicians in Michigan, have renewed bioethical debates surrounding the practice of female genital cutting (FGC). The secular discourse remains divided between zero-tolerance activists and harm-reduction strategists, while Islamic bioethical debates on FGC similarly comprise two camps. "Traditionalists" find normative grounds for a minor genital procedure in statements from the Prophet Muhammad and in classical law manuals. "Reformers" seek to decouple FGC from Islam by reexamining its ethico-legal status in light of the deficiencies within narrations ascribed to the Prophet, the health risks posed by FGC, and contemporary perspectives on human rights, and thereby delegitimize the practice. This paper argues that alignment between secular and Islamic views can be found in a harm-reduction strategy by demonstrating that the impetus to reduce harms is found within Prophetic statements on FGC. From an Islamic ethico-legal standpoint, it is justified to acknowledge the permitted status of FGC procedures that do not harm-in other words, the ritual nick-and at the same time the prohibited status of procedures that lead to credible medical and psychological harms. Bringing these multiple perspectives and data points into conversation forges a common ground to delegitimize and eradicate harmful genital procedures among Muslim communities.


The Involvement of the Myelin-Associated Inhibitors and Their Receptors in CNS Plasticity and Injury.
The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair. For example, in the injured adult CNS, there are various inhibitory factors that impede the outgrowth of neurites from damaged neurons. One of the most potent of these neurite outgrowth inhibitors is the group of proteins known as the myelin-associated inhibitors (MAIs), present mainly on the membranes of oligodendroglia. Several studies have shown that interfering with these proteins can have positive outcomes in CNS injury models by promoting neurite outgrowth and improving functional recovery. As such, the MAIs, their receptors, and downstream effectors are valid drug targets for the treatment of CNS injury. This review will discuss the current literature on MAIs in the context of CNS development, plasticity, and injury. Molecules that interfere with the MAIs and their receptors as potential candidates for the treatment of CNS injury will additionally be introduced in the context of preclinical and clinical trials.


Metabolic alterations after a two-hour nocturnal interruption of a continuous subcutaneous insulin infusion.
In order to evaluate the metabolic consequences of a 2-h nocturnal interruption of continuous subcutaneous insulin infusion (CSII), seven insulin-dependent diabetic patients without residual insulin secretion were investigated. The changes in blood glucose, plasma free insulin, glucagon, free fatty acids, and 3-hydroxybutyrate (3 OH-B) concentrations have been compared during two randomized tests carried out either during the normal functioning of a Mill-Hill pump from 10 p.m. to 8 a.m. (1.00 +/- 0.06 U insulin/h, keeping adequate metabolic control) or during the same conditions but with a deliberate arrest of the pump between 11 p.m. and 1 a.m. Considering the value recorded at 11 p.m. as reference, interruption of the insulin infusion resulted in: (1) a rapid (already significant after 1 h) and sustained (maximal fall: --12.5 +/- 2.5 mU/L at 3 a.m.) decrease in plasma free insulin; (2) a delayed (significant after 4 h) and linear rise in blood glucose (maximal increase: + 4.0 +/- 1.3 mmol/L at 5 a.m.); (3) an early (significant at midnight) and prolonged rise in plasma free fatty acids (+ 387 +/- 148 mumol/L at 3 a.m.); (4) a delayed (significant after 3 h) and sustained increase in plasma 3 OH-B (+ 347 +/- 88 mumol/L at 3 a.m.); and (5) no significant changes in plasma glucagon. Thus, a 2-h interruption of CSII in resting nocturnal conditions is sufficient to induce significant, delayed, and sustained metabolic alterations in C-peptide-negative patients despite good baseline blood glucose control. Resetting the pump at its basal rate is insufficient to quickly restore adequate circulating insulin levels and effectively counteract the metabolic disturbances. The efficacy of a bolus insulin injection in these conditions should be evaluated.


Full-mouth minimally invasive adhesive rehabilitation to treat severe dental erosion: a case report.
Dental erosion is increasing, and only recently are clinicians starting to acknowledge the problem. A prospective clinical trial investigating which therapeutic approach must be undertaken to treat erosion and when is under way at the University of Geneva (Geneva Erosion Study). All patients affected by dental erosion who present with signs of dentin exposure are immediately treated using only adhesive techniques. In this article, the full-mouth adhesive rehabilitation of one of these patients affected by severe dental erosion (ACE class IV) is illustrated. By the end of the therapy, a very pleasing esthetic outcome had been achieved (esthetic success), all of the patient's teeth maintained their vitality, and the amount of tooth structure sacrificed to complete the adhesive full-mouth rehabilitation was negligible (biological success).


A major invasion of transposable elements accounts for the large size of the Blumeria graminis f.sp. tritici genome.
Powdery mildew of wheat (Triticum aestivum L.) is caused by the ascomycete fungus Blumeria graminis f.sp. tritici. Genomic approaches open new ways to study the biology of this obligate biotrophic pathogen. We started the analysis of the Bg tritici genome with the low-pass sequencing of its genome using the 454 technology and the construction of the first genomic bacterial artificial chromosome (BAC) library for this fungus. High-coverage contigs were assembled with the 454 reads. They allowed the characterization of 56 transposable elements and the establishment of the Blumeria repeat database. The BAC library contains 12,288 clones with an average insert size of 115 kb, which represents a maximum of 7.5-fold genome coverage. Sequencing of the BAC ends generated 12.6 Mb of random sequence representative of the genome. Analysis of BAC-end sequences revealed a massive invasion of transposable elements accounting for at least 85% of the genome. This explains the unusually large size of this genome which we estimate to be at least 174 Mb, based on a large-scale physical map constructed through the fingerprinting of the BAC library. Our study represents a crucial step in the perspective of the determination and study of the whole Bg tritici genome sequence.


Joint analysis of left ventricular expression and circulating plasma levels of Omentin after myocardial ischemia.
Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia. A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies. mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p < 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression. Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia. Trial Registration Clinicaltrials.gov ID: NCT00985049.


Lipid and lipoprotein biomarkers and the risk of ischemic stroke in postmenopausal women.
Few studies simultaneously investigated lipids and lipoprotein biomarkers as predictors of ischemic stroke. The value of these biomarkers as independent predictors of ischemic stroke remains controversial. We conducted a prospective nested case-control study among postmenopausal women from the Women's Health Initiative Observational Study to assess the relationship between fasting lipids (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), lipoproteins (LDL, HDL, and very low-density lipoprotein [VLDL] particle number and size, intermediate-density lipoprotein [IDL] particle number, and lipoprotein (a)), and risk of ischemic stroke. Among women free of stroke at baseline, 774 ischemic stroke patients were matched according to age and race to control subjects, using a 1:1 ratio. In bivariate analysis, baseline triglycerides (P<0.001), IDL particles (P<0.01), LDL particles (P<0.01), VLDL triglyceride (P<0.001), VLDL particles (P<0.01), VLDL size (P<0.001), LDL size (P=0.03), and total/HDL cholesterol ratio (P<0.01) were significantly higher among women with incident ischemic stroke, whereas levels of HDL-C (P<0.01) and HDL size (P<0.01) were lower. No significant baseline difference for total cholesterol (P=0.15), LDL-C (P=0.47), and lipoprotein (a) (P=0.11) was observed. In multivariable analysis, triglycerides (odds ratio for the highest versus lowest quartile, 1.56; 95% confidence interval, 1.13-2.17; P for trend=0.02), VLDL size (odds ratio, 1.59; 95% confidence interval, 1.10-2.28; P for trend=0.03), and IDL particle number (odds ratio, 1.46; 95% confidence interval, 1.04-2.04; P for trend=0.02) were significantly associated with ischemic stroke. Among a panel of lipid and lipoprotein biomarkers, baseline triglycerides, VLDL size, and IDL particle number were significantly associated with incident ischemic stroke in postmenopausal women.


Predictors of diagnosis of child psychiatric disorder in adult-infant social-communicative interaction at 12 months.
To establish which social interactive behaviours predict later psychiatric diagnosis, we examined 180 videos of a parent-infant interaction when children were aged one year, from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Sixty of the videos involved infants who were later diagnosed with a psychiatric disorder at seven years, and 120 were a randomly selected sex-matched control group. Interactive behaviours for both the caregiver and the one year old infant were coded from the videos according to eight holistic categories of interpersonal engagement: Well-being, Contingent Responsiveness, Cooperativeness, Involvement, Activity, Playfulness, Fussiness, and Speech. Lower levels of adult activity and speech in interaction at one year significantly predicted overall diagnosis of child psychiatric disorder.


Development of inhibition and switching: A longitudinal study of the maturation of interference suppression and reversal processes during childhood.
Inhibition and switching are executive functions (EFs) that have different developmental trajectories across childhood. The development of specific processes unique to each EF may contribute to these trajectories. Interference suppression and reversal were examined in a large sample of children aged 7 and 9 years (n = 120) and followed-up after two-years to investigate developmental trajectories of inhibition and switching. The N2 and P3b components provided neural correlates of conflict monitoring and attentional processing of conflict involved in interference suppression and reversal. Interference suppression improved over time, however, switching performance did not significantly change between 7 and 11 years. Improvements in correct RT with age and time indicated increased efficiency of stimulus evaluation, response preparation and execution. N2 amplitude decreased with both age and time, indicating less reliance on conflict monitoring to signal cognitive control to manage stimulus and response conflict. P3b amplitude modulations indicated that different amounts of attention were allocated to updating mental representations of interference suppression and reversal task features. These data indicated different developmental trajectories of specific processes unique to inhibition and switching across the childhood period of 7-11 years, providing further empirical evidence that 7-11 years is a critical period for cognitive development.