A phase II study of SGN-30 in cutaneous anaplastic large cell lymphoma and related lymphoproliferative disorders.
An open-label, multicenter, phase II study was conducted to define the safety and antitumor activity of the monoclonal antibody SGN-30 in patients with CD30(+) primary cutaneous anaplastic large cell lymphoma (pc-ALCL), lymphomatoid papulosis (LyP), or transformed mycosis fungoides (T-MF). In the initial course (six doses), patients received i.v. SGN-30 every 3 weeks; eligible patients could receive two additional courses. The initial dose level of 4 mg/kg was increased to 12 mg/kg by protocol amendment. The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days). Fifteen of 23 patients (65%) experienced at least one adverse event during the study, most of which were mild or moderate. SGN-30 was clinically active in 16 of 23 patients with heavily pretreated pc-ALCL, LyP, and T-MF and was well tolerated in this study.


In vitro cell-toxicity screening as an alternative animal model for coral toxicology: effects of heat stress, sulfide, rotenone, cyanide, and cuprous oxide on cell viability and mitochondrial function.
The logistics involved in obtaining and maintaining large numbers of corals hampers research on the toxicological effects of environmental contaminants for this ecologically and economically important taxon. A method for creating and culturing single-cell suspensions of viable coral cells was developed. Cell segregation/separation was based on specific cell densities and resulting cell cultures were viable for at least 2 mos. Low-density cells lacking symbiotic zooxanthallae and rich in mitochondria were isolated and cultured for toxicity studies. Cells were exposed to differing degrees or concentrations of heat stress, rotenone, cyanide, sulfide, and cuprous oxide. Cells were assayed for mitochondrial membrane potential using the fluorescent probe, JC-9, and for overall viability using the MTT/formazan spectrophotometric viability assay. Significant differences were observed between controls and treatments and the efficacy of this method was validated; only 2 cm(2) of tissue was required for a seven-point concentration-exposure series.


Transcranial direct current stimulation enhances foot sole somatosensation when standing in older adults.
Foot-sole somatosensation is critical for safe mobility in older adults. Somatosensation arises when afferent input activates a neural network that includes the primary somatosensory cortex. Transcranial direct current stimulation (tDCS), as a strategy to increase somatosensory cortical excitability, may, therefore, enhance foot-sole somatosensation. We hypothesized that a single session of tDCS would improve foot-sole somatosensation, and thus mobility, in older adults. Twenty healthy older adults completed this randomized, double-blinded, cross-over study consisting of two visits separated by one week. On each visit, standing vibratory threshold (SVT) of each foot and the timed-up-and-go test (TUG) of mobility were assessed immediately before and after a 20-min session of tDCS (2.0 mA) or sham stimulation with the anode placed over C3 (according to the 10/20 EEG placement system) and the cathode over the contralateral supraorbital margin. tDCS condition order was randomized. SVT was measured with a shoe insole system. This system automatically ramped up, or down, the amplitude of applied vibrations and the participant stated when they could or could no longer feel the vibration, such that lower SVT reflected better somatosensation. The SVTs of both foot soles were lower following tDCS as compared to sham and both pre-test conditions [F(1,76) > 3.4, p < 0.03]. A trend towards better TUG performance following tDCS was also observed [F(1,76) = 2.4, p = 0.07]. Greater improvement in SVT (averaged across feet) moderately correlated with greater improvement in TUG performance (r = 0.48, p = 0.03). These results suggest that tDCS may enhance lower-extremity somatosensory function, and potentially mobility, in healthy older adults.


Development and validation of a genotype 3 recombinant protein-based immunoassay for hepatitis E virus serology in swine.
Hepatitis E virus (HEV) is classified within the family Hepeviridae, genus Hepevirus. HEV genotype 3 (Gt3) infections are endemic in pigs in Western Europe and in North and South America and cause zoonotic infections in humans. Several serological assays to detect HEV antibodies in pigs have been developed, at first mainly based on HEV genotype 1 (Gt1) antigens. To develop a sensitive HEV Gt3 ELISA, a recombinant baculovirus expression product of HEV Gt3 open reading frame-2 was produced and coated onto polystyrene ELISA plates. After incubation of porcine sera, bound HEV antibodies were detected with anti-porcine anti-IgG and anti-IgM conjugates. For primary estimation of sensitivity and specificity of the assay, sets of sera were used from pigs experimentally infected with HEV Gt3. For further validation of the assay and to set the cutoff value, a batch of 1100 pig sera was used. All pig sera were tested using the developed HEV Gt3 assay and two other serologic assays based on HEV Gt1 antigens. Since there is no gold standard available for HEV antibody testing, further validation and a definite setting of the cutoff of the developed HEV Gt3 assay were performed using a statistical approach based on Bayes' theorem. The developed and validated HEV antibody assay showed effective detection of HEV-specific antibodies. This assay can contribute to an improved detection of HEV antibodies and enable more reliable estimates of the prevalence of HEV Gt3 in swine in different regions.


Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains.
In this work, we address the question of whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologous G domains of different stability: the mesophilic G domain of the elongation factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-1α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time scale, we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favorable for both systems, with the hyperthermophilic protein offering a slightly more favorable environment to host water molecules. We estimate that, under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that, at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that under extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.


Reconstruction of calcium silicate hydrates using multiple 2D and 3D imaging techniques: Light microscopy, μ-CT, SEM, FIB-nT combined with EDX.
This study demonstrates the application and combination of multiple imaging techniques [light microscopy, micro-X-ray computer tomography (μ-CT), scanning electron microscopy (SEM) and focussed ion beam - nano-tomography (FIB-nT)] to the analysis of the microstructure of hydrated alite across multiple scales. However, by comparing findings with mercury intrusion porosimetry (MIP), it becomes obvious that the imaged 3D volumes and 2D images do not sufficiently overlap at certain scales to allow a continuous quantification of the pore size distribution (PSD). This can be overcome by improving the resolution and increasing the measured volume. Furthermore, results show that the fibrous morphology of calcium-silicate-hydrates (C-S-H) phases is preserved during FIB-nT. This is a requirement for characterisation of nano-scale porosity. Finally, it was proven that the combination of FIB-nT with energy-dispersive X-ray spectroscopy (EDX) data facilitates the phase segmentation of a 11 × 11 × 7.7 μm3 volume of hydrated alite.


Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid.
Anti-laminin 332 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by predominant mucosal lesions and autoantibodies against laminin 332. The exact diagnosis of anti-laminin 332 MMP is important since nearly 30% of patients develop solid cancers. This study compared two independently developed diagnostic indirect immunofluorescence (IF) tests based on recombinant laminin 332 expressed in HEK239 cells (biochip mosaic assay) and the migration trails of cultured keratinocytes rich in laminin 332 (footprint assay). The sera of 54 anti-laminin 332 MMP, 35 non-anti-laminin 332 MMP, and 30 pemphigus vulgaris patients as well as 20 healthy blood donors were analyzed blindly and independently. Fifty-two of 54 and 54/54 anti-laminin 332 MMP sera were positive in the biochip mosaic and the footprint assay, respectively. In the 35 non-anti-laminin 332 MMP sera, 3 were positive in both tests and 4 others showed weak reactivity in the footprint assay. In conclusion, both assays are easy to perform, highly sensitive, and specific, which will further facilitate the diagnosis of anti-laminin 332 MMP.


Impact of HIV-related stigma on treatment adherence: systematic review and meta-synthesis.
Adherence to HIV antiretroviral therapy (ART) is a critical determinant of HIV-1 RNA viral suppression and health outcomes. It is generally accepted that HIV-related stigma is correlated with factors that may undermine ART adherence, but its relationship with ART adherence itself is not well established. We therefore undertook this review to systematically assess the relationship between HIV-related stigma and ART adherence. We searched nine electronic databases for published and unpublished literature, with no language restrictions. First we screened the titles and abstracts for studies that potentially contained data on ART adherence. Then we reviewed the full text of these studies to identify articles that reported data on the relationship between ART adherence and either HIV-related stigma or serostatus disclosure. We used the method of meta-synthesis to summarize the findings from the qualitative studies. Our search protocol yielded 14,854 initial records. After eliminating duplicates and screening the titles and abstracts, we retrieved the full text of 960 journal articles, dissertations and unpublished conference abstracts for review. We included 75 studies conducted among 26,715 HIV-positive persons living in 32 countries worldwide, with less representation of work from Eastern Europe and Central Asia. Among the 34 qualitative studies, our meta-synthesis identified five distinct third-order labels through an inductive process that we categorized as themes and organized in a conceptual model spanning intrapersonal, interpersonal and structural levels. HIV-related stigma undermined ART adherence by compromising general psychological processes, such as adaptive coping and social support. We also identified psychological processes specific to HIV-positive persons driven by predominant stigmatizing attitudes and which undermined adherence, such as internalized stigma and concealment. Adaptive coping and social support were critical determinants of participants' ability to overcome the structural and economic barriers associated with poverty in order to successfully adhere to ART. Among the 41 quantitative studies, 24 of 33 cross-sectional studies (71%) reported a positive finding between HIV stigma and ART non-adherence, while 6 of 7 longitudinal studies (86%) reported a null finding (Pearson's χ (2)=7.7; p=0.005). We found that HIV-related stigma compromised participants' abilities to successfully adhere to ART. Interventions to reduce stigma should target multiple levels of influence (intrapersonal, interpersonal and structural) in order to have maximum effectiveness on improving ART adherence.


An integrated experimental and theoretical reaction path search: analyses of the multistage reaction of an ionized diethylether dimer involving isomerization, proton transfer, and dissociation.
An ionization-induced multistage reaction of an ionized diethylether (DEE) dimer involving isomerization, proton transfer, and dissociation is investigated by combining infrared (IR) spectroscopy, tandem mass spectrometry, and a theoretical reaction path search. The vertically-ionized DEE dimer isomerizes to a hydrogen-bonded cluster of protonated DEE and the [DEE-H] radical through barrierless intermolecular proton transfer from the CH bond of the ionized moiety. This isomerization process is confirmed by IR spectroscopy and the theoretical reaction path search. The multiple dissociation pathways following the isomerization are analyzed by tandem mass spectrometry. The isomerized cluster dissociates stepwise into a [protonated DEE-acetaldehyde (AA)] cluster, protonated DEE, and protonated AA. The structure of the fragment ion is also analyzed by IR spectroscopy. The reaction map of the multistage processes is revealed through a harmony of these experimental and theoretical methods.


Architecture of a mammalian glomerular domain revealed by novel volume electroporation using nanoengineered microelectrodes.
Dense microcircuit reconstruction techniques have begun to provide ultrafine insight into the architecture of small-scale networks. However, identifying the totality of cells belonging to such neuronal modules, the "inputs" and "outputs," remains a major challenge. Here, we present the development of nanoengineered electroporation microelectrodes (NEMs) for comprehensive manipulation of a substantial volume of neuronal tissue. Combining finite element modeling and focused ion beam milling, NEMs permit substantially higher stimulation intensities compared to conventional glass capillaries, allowing for larger volumes configurable to the geometry of the target circuit. We apply NEMs to achieve near-complete labeling of the neuronal network associated with a genetically identified olfactory glomerulus. This allows us to detect sparse higher-order features of the wiring architecture that are inaccessible to statistical labeling approaches. Thus, NEM labeling provides crucial complementary information to dense circuit reconstruction techniques. Relying solely on targeting an electrode to the region of interest and passive biophysical properties largely common across cell types, this can easily be employed anywhere in the CNS.


Armored kinorhynch-like scalidophoran animals from the early Cambrian.
Morphology-based phylogenetic analyses support the monophyly of the Scalidophora (Kinorhyncha, Loricifera, Priapulida) and Nematoida (Nematoda, Nematomorpha), together constituting the monophyletic Cycloneuralia that is the sister group of the Panarthropoda. Kinorhynchs are unique among living cycloneuralians in having a segmented body with repeated cuticular plates, longitudinal muscles, dorsoventral muscles, and ganglia. Molecular clock estimates suggest that kinorhynchs may have diverged in the Ediacaran Period. Remarkably, no kinorhynch fossils have been discovered, in sharp contrast to priapulids and loriciferans that are represented by numerous Cambrian fossils. Here we describe several early Cambrian (~535 million years old) kinorhynch-like fossils, including the new species Eokinorhynchus rarus and two unnamed but related forms. E. rarus has characteristic scalidophoran features, including an introvert with pentaradially arranged hollow scalids. Its trunk bears at least 20 annuli each consisting of numerous small rectangular plates, and is armored with five pairs of large and bilaterally placed sclerites. Its trunk annuli are reminiscent of the epidermis segments of kinorhynchs. A phylogenetic analysis resolves E. rarus as a stem-group kinorhynch. Thus, the fossil record confirms that all three scalidophoran phyla diverged no later than the Cambrian Period.


Identification of a dimerization domain in the C-terminal segment of the IE110 transactivator protein from herpes simplex virus.
The 775-amino-acid IE110 (or ICP0) phosphoprotein of herpes simplex virus (HSV) functions as an accessory transcription factor during the lytic cycle and plays a critical role in reactivation from latent infection. By immunofluorescence analysis, IE110 localizes in a novel pattern consisting of several dozen spherical punctate granules in the nuclei of DNA-transfected cells. We constructed a hybrid version of IE110 that contained an epitope-tagged domain from the N terminus of the HSV IE175 protein and lacked the IE110 N-terminal domain that confers punctate characteristics. This hybrid IE175(N)/IE110(C) protein gave an irregular nuclear diffuse pattern on its own but was redistributed very efficiently into spherical punctate granules after cotransfection with the wild-type HSV-1 IE110 protein. Similar colocalization interactions occurred with internally deleted forms of IE110 that lacked the zinc finger region or large segments from the center of the protein, including both cytoplasmic and elongated punctate forms, but C-terminal truncated versions of IE110 did not interact. In all such interactions, the punctate phenotype was dominant. Evidence that C-terminal segments of IE110 could also form stable mixed-subunit oligomers in vitro was obtained by coimmunoprecipitation of in vitro-translated IE110 polypeptides with different-size hemagglutinin epitope-tagged forms of the protein. This occurred only when the two forms were cotranslated, not when they were simply mixed together. An in vitro-synthesized IE110 C-terminal polypeptide also gave immunoprecipitable homodimers and heterodimers when two different-size forms were cross-linked with glutaraldehyde and reacted specifically with a bacterial glutathione S-transferase/IE110 C-terminal protein in far-Western blotting experiments. The use of various N-terminal and C-terminal truncated forms of IE110 in the in vivo assays revealed that the outer boundaries of the interaction domain mapped between codons 617 and 711, although inclusion of adjacent codons on either side increased the efficiency severalfold in some assays. We conclude that the C-terminal region of IE110 contains a high-affinity self-interaction domain that leads to stable dimer and higher-order complex formation both in DNA-transfected cells and in in vitro assays. This segment of IE110 is highly conserved between HSV-1 and HSV-2 and appears to have the potential to play an important role in the interaction with the IE175 protein, as well as in correct intracellular localization, but it is not present in the equivalent proteins from varicella-zoster virus, pseudorabies virus, or equine abortion virus.


Light scattering by microscopic spheres behind a glass-air interface.
Scattering of light from single spheres placed behind a glass-air interface with light incident through the glass is examined. This scattering is investigated for both p- and s-polarized light incident at angles below the glass-air critical angle. The intensity of light scattered into the air half-space from each sphere is measured as a function of scattering angle, and this response is compared in situ with the background scatter produced by the planar substrate. A detailed comparison between data and established theory are thereby obtained. This system is of interest in the field of optical biosensing.


Active microorganisms in forest soils differ from the total community yet are shaped by the same environmental factors: the influence of pH and soil moisture.
Predicting the impact of environmental change on soil microbial functions requires an understanding of how environmental factors shape microbial composition. Here, we investigated the influence of environmental factors on bacterial and fungal communities across an expanse of northern hardwood forest in Michigan, USA, which spans a 500-km regional climate gradient. We quantified soil microbial community composition using high-throughput DNA sequencing on coextracted rDNA (i.e. total community) and rRNA (i.e. active community). Within both bacteria and fungi, total and active communities were compositionally distinct from one another across the regional gradient (bacteria P = 0.01; fungi P < 0.01). Taxonomically, the active community was a subset of the total community. Compositional differences between total and active communities reflected changes in the relative abundance of dominant taxa. The composition of both the total and active microbial communities varied by site across the gradient (P < 0.01) and was shaped by differences in soil moisture, pH, SOM carboxyl content, as well as C and N concentration. Our study highlights the importance of distinguishing between metabolically active microorganisms and the total community, and emphasizes that the same environmental factors shape the total and active communities of bacteria and fungi in this ecosystem.


Kir3.1/3.2 encodes an I(KACh)-like current in gastrointestinal myocytes.
Expression of the Kir3 channel subfamily in gastrointestinal (GI) myocytes was investigated. Members of this K(+) channel subfamily encode G protein-gated inwardly rectifying K(+) channels (I(KACh)) in other tissues, including the heart and brain. In the GI tract, I(KACh) could act as a negative feedback mechanism to temper the muscarinic response mediated primarily through activation of nonselective cation currents and inhibition of delayed-rectifier conductance. Kir3 channel subfamily isoforms expressed in GI myocytes were determined by performing RT-PCR on RNA isolated from canine colon, ileum, duodenum, and jejunum circular myocytes. Qualitative PCR demonstrated the presence of Kir3.1 and Kir3.2 transcripts in all smooth muscle cell preparations examined. Transcripts for Kir3.3 and Kir3.4 were not detected in the same preparations. Semiquantitative PCR showed similar transcriptional levels of Kir3.1 and Kir3.2 relative to beta-actin expression in the various GI preparations. Full-length cDNAs for Kir3.1 and Kir3.2 were cloned from murine colonic smooth muscle RNA and coexpressed in Xenopus oocytes with human muscarinic type 2 receptor. Superfusion of oocytes with ACh (10 microM) reversibly activated a Ba(2+)-sensitive and inwardly rectifying K(+) current. Immunohistochemistry using Kir3.1- and Kir3.2-specific antibodies demonstrated channel expression in circular and longitudinal smooth muscle cells. We conclude that an I(KACh) current is expressed in GI myocytes encoded by Kir3.1/3.2 heterotetramers.


Effects of en bloc esophagectomy on nutritional and immune status in patients with esophageal carcinoma.
En bloc esophagectomy has been established as the treatment of choice for patients with resectable esophageal carcinoma. However, an extensive surgical procedure may result in further impairment of the patient's nutritional status and immune system. Thus a prospective study was undertaken to evaluate the perioperative sequential changes in patients' nutritional and immune status and the timing to institute postoperative adjuvant therapy. Thirty-seven patients (34 male, 3 female) who had undergone en bloc esophagectomy with gastric institution for epidermoid carcinoma of the esophagus were studied. The mean age was 62.3 years. The nutritional and immune assessments were performed preoperatively, on the third postoperative day, in the first week, second week, third week, and at the end of the first and third month. The biochemical studies for nutritional evaluation included serum albumin, cholesterol, iron, transferrin, magnesium, zinc, total iron binding capacity (TIBC), and nitrogen balance. Evaluation of the immune status consisted of: (1) total lymphocyte count, (2) lymphocyte subpopulation, (3) immunoglobulins, (4) complements (C3 and C4), (5) lymphocyte blastogenic responses, (6) tumor necrosis factor-alpha and interleukin-2 secretion activity from mononuclear cells, and (7) C-reactive protein (CRP) level. All the parameters in nutritional assessment declined profoundly by the third postoperative day (P < 0.05). The most severe deterioration was in serum iron, followed by transferrin, TIBC, cholesterol, and zinc. Most of them returned to the preoperative levels within 2-3 weeks after surgery. However, the serum levels of iron, transferrin, and TIBC required a longer period of time (> 1 month) to return to normal. A remarkable increase of serum CRP was detected in the first postoperative week (P < 0.05), but immunoglobulins and complements decreased significantly yet variably (P < 0.05) in the second or third postoperative week before gradually returning to preoperative levels. Moreover, during the first week after surgery, CD3 and CD8 diminished following esophageal surgery, whereas CD20, CD4/CD8 ratio, and lymphocyte blastogenic responses increased significantly (P < 0.05). Except for iron-related parameters, all the other nutritional parameters returned to the preoperative level by the third postoperative week. An adequate supplementation of iron and protein for 1-3 months after surgery is needed. En bloc esophagectomy might have only a mild and temporarily adverse effect on the host immune defense. Regarding the postoperative recovery of a patient's nutritional and immune status, postoperative chemo-radiotherapy is optimally instituted after the third postoperative week, instead of within 2 weeks of surgery.


Medicaid Expansion For Adults Had Measurable 'Welcome Mat' Effects On Their Children.
Before the implementation of the Affordable Care Act (ACA), most children in low-income families were already eligible for public insurance through Medicaid or the Children's Health Insurance Program. Increased coverage observed for these children since the ACA's implementation suggest that the legislation potentially had important spillover or "welcome mat" effects on the number of eligible children enrolled. This study used data from the 2013-15 American Community Survey to provide the first national-level (analytical) estimates of welcome-mat effects on children's coverage post ACA. We estimated that 710,000 low-income children gained coverage through these effects. The study was also the first to show a link between parents' eligibility for Medicaid and welcome-mat effects for their children under the ACA. Welcome-mat effects were largest among children whose parents gained Medicaid eligibility under the ACA expansion to adults. Public coverage for these children increased by 5.7 percentage points-more than double the 2.7-percentage-point increase observed among children whose parents were ineligible for Medicaid both pre and post ACA. Finally, we estimated that if all states had adopted the Medicaid expansion, an additional 200,000 low-income children would have gained coverage.


Staphylococcus aureus Small Colony Variants (SCVs): News From a Chronic Prosthetic Joint Infection.
Small colony variants (SCV) of Staphylococcus aureus have been reported as implicated in chronic infections. Here, we investigated the genomic and transcriptomic changes involved in the evolution from a wild-type to a SCV from in a patient with prosthetic joint infection relapse. The SCV presented a stable phenotype with no classical auxotrophy and the emergence of rifampicin resistance. Whole Genome Sequencing (WGS) analysis showed only the loss of a 42.5 kb phage and 3 deletions, among which one targeting the rpoB gene, known to be the target of rifampicin and to be associated to SCV formation in the context of a constitutively active stringent response. Transcriptomic analysis highlighted a specific signature in the SCV strain including a complex, multi-level strategy of survival and adaptation to chronicity within the host including a protection from the inflammatory response, an evasion of the immune response, a constitutively activated stringent response and a scavenging of iron sources.


Liver transplantation: the last measure in the treatment of bile duct injuries.
Bile duct injury (BDI) is a severe complication that may arise during the surgical treatment of a benign disease. A significant proportion of cases develop end-stage liver disease and a liver transplant is required. The aim of this study was to analyze the indications and results of liver transplantation as treatment for BDI. Between January 1988 and May 2007, 20 patients with end-stage liver disease secondary to BDI were included on the liver transplant waiting list. Retrospective charts were analyzed and survival was estimated by the Kaplan-Meier test. Four patients died while on the waiting list and 16 received a transplant. Injury to the bile duct occurred during a cholecystectomy in 13 of 16 patients, with the main cause of the lesion being duct division in six patients and resection in four. All patients had received some surgical treatment (median = 2 procedures) before being considered for a transplant. The liver transplant came from a cadaveric donor for all patients and the median time between BDI and liver transplant was 60 months. Two patients died in the postoperative period and nine had complications. Three patients died in the late postoperative period. Median follow-up was 62 (range = 24-152) months. One-, three-, and five-year survival rates were 81, 75, and 75%, respectively. Complex bile duct injuries and bile duct injuries with previous repair attempts can result in end-stage liver disease. In these cases, liver transplantation provides long-term survival.


TNF signaling via the ligand-receptor pair ectodysplasin and edar controls the function of epithelial signaling centers and is regulated by Wnt and activin during tooth organogenesis.
Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, edar. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and edar (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. Edar was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFbeta, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of edar was induced by activinbetaA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial-mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor edar in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.


Electrical Tuning of Nonlinearities in Exciton-Polariton Condensates.
A primary limitation of the intensively researched polaritonic systems compared to their atomic counterparts for the study of strongly correlated phenomena and many-body physics is their relatively weak two-particle interactions compared to disorder. Here, we show how new opportunities to enhance such on-site interactions and nonlinearities arise by tuning the exciton-polariton dipole moment in electrically biased semiconductor microcavities incorporating wide quantum wells. The applied field results in a twofold enhancement of exciton-exciton interactions as well as more efficiently driving relaxation towards low energy polariton states, thus, reducing condensation threshold.


The subthalamic nucleus, oscillations, and conflict.
The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation (DBS) for Parkinson's disease (PD), has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article, we highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential among this evidence has been the reported effect of STN DBS in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patients' everyday lives remains uncertain.


Long-term outcomes among older patients with non-ST-segment elevation myocardial infarction complicated by cardiogenic shock.
Cardiogenic shock complicating acute myocardial infarction (MI) in older patients is associated with a high risk of inhospital mortality; however, the long-term prognosis among these patients who survive the index hospitalization is uncertain. We evaluated 42,656 patients 65 years or older with non-ST-segment elevation MI from the CRUSADE Registry treated at 448 hospitals in the United States from 2003 to 2006 and linked to Medicare longitudinal claims data. Among patients who survived to hospital discharge, Cox proportional hazards modeling was used to compare survival between patients with and without inhospital shock. The secondary outcome of "percent days alive and out of hospital" (%DAOH) was also compared between the 2 groups. Overall, 2,001 (4.7%) patients had shock on presentation and/or developed shock during the index hospitalization. Inhospital mortality rates among those with and without shock were 39.1% versus 4.5% (P < .001). Among the 40,036 index hospital survivors, postdischarge survival curves diverged early with lower survival (48.1% [95% CI 45.0-51.2] vs 56.5% [95% CI 56.0-57.1], P < .001) and lower %DAOH (65.5% ± 40.6% and 73.4% ± 36.8 %, P < .001) among patients with shock through 4 years. Based on the observation of parallel survival curves starting 6 months postdischarge, we performed landmark analyses and found no difference in mortality (hazard ratio 1.02, 95% CI 0.91-1.14) or %DAOH (79.7% ± 32.0% vs 81.3% ± 31.0%, P = .17) beyond 6 months between those with and without shock. Our results highlight the time-dependent hazard of risk during the early postdischarge period for older patients with non-ST-segment elevation MI and cardiogenic shock that appears to be mitigated after 6 months, thereby lending support for the examination of new therapies designed to ameliorate this early risk.


High performance PbS quantum dot sensitized solar cells via electric field assisted in situ chemical deposition on modulated TiO2 nanotube arrays.
Quantum dot sensitized solar cells (QDSSCs) are attractive photovoltaic devices due to their simplicity and low material requirements. However, efforts to realize high efficiencies in QDSSCs have often been offset by complicated processes and expensive or toxic materials, significantly limiting their useful application. In this work, we have realized for the first time, high performance PbS QDSSCs based on TiO2 nanotube arrays (NTAs) via an in situ chemical deposition method controlled by a low electric field. An efficiency, η, of ~3.41% under full sun illumination has been achieved, which is 133.6% higher than the best result previously reported for a simple system without doping or co-sensitizing, and comparable to systems with additional chemicals. Furthermore, a high open-circuit voltage (0.64 V), short-circuit current (8.48 mA cm(-2)) and fill factor (0.63) have been achieved. A great increase in the quantity of the loaded quantum dots (QDs) in the NTAs was obtained from the in situ electric field assisted chemical bath deposition (EACBD) process, which was the most significant contributing factor with respect to the high JSC. The high VOC and FF have been attributed to a much shorter electron path, less structural and electronic defects, and lower recombination in the ordered TiO2 NTAs produced by oscillating anodic voltage. Besides, the optimal film thickness (~4 μm) based on the NTAs was much thinner than that of the control cell based on nanoporous film (~30.0 μm). This investigation can hopefully offer an effective way of realizing high performance QDSSCs and QD growth/installation in other nanostructures as well.


Effect of nesiritide infusion duration on renal function in acutely decompensated heart failure patients.
Nesiritide, a synthetic B-type natriuretic peptide, is used for the treatment of patients with acutely decompensated heart failure. Although nesiritide has been reported to worsen renal function, as reflected by significant elevations in serum creatinine (SCr), the impact of infusion duration on renal function has not been evaluated. To investigate the effect of nesiritide infusion duration (< 24 h vs > or = 24 h) on worsening renal function in patients with acutely decompensated heart failure. Medical records of hospitalized patients receiving nesiritide were retrospectively reviewed, and 84 consecutive charts of patients with acute decompensated heart failure and available renal function tests were identified for the study. SCr and blood urea nitrogen (BUN) were documented at baseline and during infusion. Worsening renal function was defined as an increase in SCr of 0.5 mg/dL or more or BUN 10 mg/dL or more from baseline. Univariate analysis showed a significant association between nesiritide infusion duration of 24 hours or more (26.1% vs 2.6%; p = 0.003), high diuretic doses (61.5% vs 32.4%; p = 0.045), and baseline SCr (2.0 +/- 0.8 vs 1.5 +/- 0.7 mg/dL; p = 0.04) with increases in SCr of 0.5 mg/dL or more. However, only infusion duration of 24 hours or more was statistically significant on multivariate analysis, after adjusting for baseline SCr (OR 10.46; 95% CI 1.26 to 86.72; p = 0.03). Longer duration of infusion was also a consistent variable in both univariate and multivariate analysis when elevated BUN was evaluated (34.8 vs 2.6%; p < 0.001 and OR 19.73; 95% CI 2.47 to 157.46; p = 0.005, respectively). Nesiritide infusion of 24 hours or more appears to be significantly associated with elevated markers of worsening renal function in patients with acutely decompensated heart failure compared with infusion of less than 24 hours; however, prospective studies are needed to corroborate this finding.


Alpha v beta 5 integrin-dependent programmed cell death triggered by a peptide mimic of annexin V.
The diverse cytoplasmic domain sequences within the various integrin subunits are critical for integrin-mediated signaling into the cell (outside-in signaling) and for activation of ligand binding affinity (inside-out signaling). Here we introduce an approach based on phage display technology to identify molecules that specifically interact with the cytoplasmic domain of the beta 5 integrin subunit. We show that a peptide selected for binding specifically to the beta 5 cytoplasmic domain (VVISYSMPD) induces apoptosis upon internalization. The cell death process induced by VVISYSMPD is sensitive to modulation by growth factors and by protein kinase C (PKC), and it cannot be triggered in beta 5 null cells. Finally, we show that the VVISYSMPD peptide is a mimic of annexin V. Our results suggest a functional link between the alpha v beta 5 integrin, annexin V, and programmed cell death. We propose the term "endothanatos" to designate this phenomenon.


Sub-micron and nanoscale feature depth modulates alignment of stromal fibroblasts and corneal epithelial cells in serum-rich and serum-free media.
Topographic features are generally accepted as being capable of modulating cell alignment. Of particular interest is the potential that topographic feature geometry induces cell alignment indirectly through impacting adsorbed proteins from the cell culture medium on the surface of the substrate. However, it has also been reported that micron-scale feature depth significantly impacts the level of alignment of cellular populations on topography, despite being orders of magnitude larger than the average adsorbed protein layer (nm). In order to better determine the impact of biomimetic length scale topography and adsorbed protein interaction on cellular morphology we have systematically investigated the effect of combinations of sub-micron to nanoscale feature depth and lateral pitch on corneal epithelial cell alignment. In addition we have used the unique properties of a serum-free media alternative in direct comparison to serum-rich medium to investigate the role of culture medium protein composition on cellular alignment to topographically patterned surfaces. Our observation that increasing groove depth elicited larger populations of corneal epithelial cells to align regardless of culture medium composition and of cell orientation with respect to the topography, suggests that these cells can sense changes in topographic feature depths independent of adsorbed proteins localized along ridge edges and tops. However, our data also suggests a strong combinatory effect of topography with culture medium composition, and also a cell type dependency in determining the level of cell elongation and alignment to nanoscale topographic features.


Beginning and duration of pregnancy in automated health care databases: review of estimation methods and validation results.
To describe methods reported in the literature to estimate the beginning or duration of pregnancy in automated health care data, and to present results of validation exercises where available. Papers reporting methods for determining the beginning or duration of pregnancy were identified based on Pubmed searches, by consulting investigators with expertise in the field and by reviewing conference abstracts and reference lists of relevant papers. From each paper or abstract, we extracted information to characterize the study population, data sources, and estimation algorithm. We then grouped these studies into categories reflecting their general methodological approach. Methods were classified into 5 categories: (i) methods that assign a uniform duration for all pregnancies, (ii) methods that assign pregnancy duration based on preterm-delivery or health care related codes, or codes for other pregnancy outcomes, (iii) methods based on the timing of prenatal care, (iv) methods based on birth weight, and (v) methods that combine elements from 2 and 3. Validation studies evaluating these methods used varied approaches, with results generally reporting on the mistiming of the start of pregnancy, incorrect estimation of the duration of pregnancy, or misclassification of drug exposure during pregnancy or early pregnancy. In the absence of accurate information on the beginning or duration of pregnancy, several methods of varying complexity are available to estimate them. Validation studies have been performed for many of them and can serve as a guide for method selection for a particular study.


A 37-year-old woman presenting with impaired visual function during antituberculosis drug therapy: a case report.
Combination antituberculosis drug therapy remains the mainstay of treating tuberculosis. Unfortunately, antituberculosis drugs produce side effects including (toxic) impaired visual function, which may be irreversible. We report a case of antituberculosis-drug-induced impaired visual function that was reversed following early detection and attention. A 37-year-old Yoruba woman, weighing 48 kg, presented to our facility with impaired visual functions and mild sensory polyneuropathy in about the fourth month of antituberculosis treatment. Her therapy comprised ethambutol 825 mg, isoniazid 225 mg, rifampicin 450 mg, and pyrazinamide 1200 mg. Her visual acuity was 6/60 in her right eye and 1/60 in her left eye. She had sluggish pupils, red-green dyschromatopsia, hyperemic optic discs and central visual field defects. Her intraocular pressure was 14 mmHg. Her liver and kidney functions were essentially normal. Screening for human immunodeficiency virus was not reactive. Her impaired visual function improved following prompt diagnosis and attention, including the discontinuation of medication. The ethambutol and isoniazid in antituberculosis medication are notorious for causing impaired visual function. The diagnosis of ocular toxicity from antituberculosis drugs should never be delayed, and should be possible with the patient's history and simple but basic eye examinations and tests. Tight weight-based antituberculosis therapy, routine peri-therapy visual function monitoring towards early detection of impaired function, and prompt attention will reduce avoidable ocular morbidity.


Occurrence of Belonolaimus in Sinaloa, Northwestern Mexico: A New Report on Distribution and Host Range.
The present study reports the occurrence of the genus Belonolaimus in the state of Sinaloa, Mexico, associated with native plants (i.e., Ziziphus amole and Stenocereus alamosensis) in a natural coastal ecosystem. Both morphological and molecular approaches were employed to characterize the Sinaloa population. Notwithstanding of some morphological and morphometric variation between Belonolaimus from Sinaloa and other valid species, the characterization indicates that this population might belong to the Belonolaimus longicaudatus species complex. Molecular analyses based on the 28S gene and ITS1-5.8S-ITS2 regions of the ribosomal RNA (rRNA) identified four major clades within Belonolaimus; however, none of the species including B. longicaudatus, B. gracilis, and B. euthychilus were supported as monophyletic; yet monophyly is argued to be a basic requirement of species status. Sequence divergence among different Belonolaimus populations and species varied according to the rRNA dataset (i.e., ITS1-5.8S-ITS2 > 28S > 18S) used, thus showing the importance of using genes with different rates of evolution to estimate species relationships. The fact that Belonolaimus has not been found in other cultivated (including on suitable hosts) areas in Sinaloa and that this population is relatively distant from the common B. longicaudatus groups (i.e., clades A and B) suggests that its appearance was not due to a recent introduction associated with the local agriculture.


Linear response functions for a vibrational configuration interaction state.
Linear response functions are implemented for a vibrational configuration interaction state allowing accurate analytical calculations of pure vibrational contributions to dynamical polarizabilities. Sample calculations are presented for the pure vibrational contributions to the polarizabilities of water and formaldehyde. We discuss the convergence of the results with respect to various details of the vibrational wave function description as well as the potential and property surfaces. We also analyze the frequency dependence of the linear response function and the effect of accounting phenomenologically for the finite lifetime of the excited vibrational states. Finally, we compare the analytical response approach to a sum-over-states approach.


Platelet-rich plasma for the spinal fusion.
There has been a wide interest in using platelet-rich plasma (PRP) as a therapeutic agent to enhance spinal fusion. There are two review articles based only on clinical studies regarding the effect of PRP on spinal fusion. However, with regard to both animal model studies and clinical studies, there is no review studies regarding its effect on spinal fusion and no review studies focusing on the platelet count and the concentration of the growth factor in the PRP. The purpose is to review the literatures about the effect of PRP on spinal fusion according to the animal model studies and clinical studies, focusing on the effect of the platelet count and the concentration of the growth factor in the PRP. A PubMed search was performed for English-language articles. We identified 20 articles regarding the effect of PRP on fusion in animal model studies and clinical studies, of which 16 articles met the study criteria of case-control studies or prospective randomized studies for the spinal fusion. The articles were categorized into small-sized animal model, middle-sized animal model, and clinical studies. Studies have shown both beneficial and inhibitory effects. The conclusion that PRP has the stimulating effect on spinal fusion was not reached. However, PRP might promote the human spinal fusion if the platelet count or the concentration of growth factors in the PRP increases.


Oscillatory activity in the basal ganglia and deep brain stimulation.
Over the past 10 years, research into the neurophysiology of the basal ganglia has provided new insights into the pathophysiology of movement disorders. The presence of pathological oscillations at specific frequencies has been linked to different signs and symptoms in PD and dystonia, suggesting a new model to explain basal ganglia dysfunction. These advances occurred in parallel with improvements in imaging and neurosurgical techniques, both of which having facilitated the more widespread use of DBS to modulate dysfunctional circuits. High-frequency stimulation is thought to disrupt pathological activity in the motor cortex/basal ganglia network; however, it is not easy to explain all of its effects based only on changes in network oscillations. In this viewpoint, we suggest that a return to classic anatomical concepts might help to understand some apparently paradoxical findings. © 2016 International Parkinson and Movement Disorder Society.


Swapping of transmembrane domains in the epithelial calcium channel TRPV6.
Tetrameric ion channels have either swapped or non-swapped arrangements of the S1-S4 and pore domains. Here we show that mutations in the transmembrane domain of TRPV6 can result in conversion from a domain-swapped to non-swapped fold. These results reveal structural determinants of domain swapping and raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states.


Kinetics of rouleaux formation using TV image analyzer. I. Human erythrocytes.
An apparatus for determining the velocity of erythrocyte rouleaux formation was constructed, combining an inverted microscope, a transparent cone-plate viscometer, a TV image analyzer, and a computer. At lower shear rates, the overall process is the sedimentation and the rouleaux formation followed by the development of three-dimensional aggregates. The individual erythrocyte could be observed and the process was expressed by the time courses of the changes in the count and area of particles; taking the computed increment in the area/count, the rate of rouleaux formation could be estimated. The effects of shear rates, hematocrits, plasma proteins, and pH were quantified. The rate of rouleaux formation in autologous plasma increased by (1) lowering the shear rates (1.9 less than or equal to gamma less than or equal to 15 s-1),2) increasing the hematocrit (up to 0.6%), 3) adding human fibrinogen (up to 600 mg/dl) or gamma-globulin, and 4) increasing pH. The transformation to echinocytes or to stomatocytes decreased the rate of rouleaux formation. The pH effect was explained by the increase in mean corpuscular volume at lower pH rather than by the changes in the electrostatic repulsion or in the protein binding.


Evolution of Dip-Pen Nanolithography (DPN): From Molecular Patterning to Materials Discovery.
Dip-pen nanolithography (DPN) is a nanofabrication technique that can be used to directly write molecular patterns on substrates with high resolution and registration. Over the past two decades, DPN has evolved in its ability to transport molecular and material "inks" (e.g., alkanethiols, biological molecules like DNA, viruses, and proteins, polymers, and nanoparticles) to many surfaces in a high-throughput fashion, enabling the synthesis and study of complex chemical and biological structures. In addition, DPN has laid the foundation for a series of related scanning probe methodologies, for example, polymer pen lithography (PPL), scanning probe block copolymer lithography (SPBCL), and beam-pen lithography (BPL), which do not rely on cantilever tips. Structures prepared with these methodologies have been used to understand the consequences of miniaturization and open a door to new capabilities in catalysis, optics, biomedicine, and chemical synthesis, where, in sum, a process originally intended to compete with tools used by the semiconductor industry for rapid prototyping has transcended that application to advanced materials discovery. This review outlines the major DPN advances, the subsequent methods based on the technique, and the opportunities for future fundamental and technological exploration. Most importantly, it commemorates the 20th anniversary of the discovery of DPN.


Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo.
Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte β3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of β3-adrenoceptors and adiponectin. In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using β3-adrenoceptor inhibition, and activation of β3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The β3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon β3-adrenoceptor activation. These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte β3-adrenoceptors, which may trigger release of the vasodilator adiponectin.


Analysis of morbidity and mortality in 227 cases of esophageal atresia and/or tracheoesophageal fistula over two decades.
This report analyzes the morbidity and mortality in 227 infants (127 boys and 100 girls) with variants of esophageal atresia and/or tracheoesophageal fistula who were treated from 1971 to 1993. Data were collected retrospectively from hospital and office records. Mean follow-up was 76 months, ranging from 1 month to 22 years. Patients were treated at a tertiary care children's hospital. The mean birth weight was 2557 g (range, 1100 to 4460 g), and the mean gestational age was 38 weeks (range, 28 to 42 weeks). Classification included 29 cases of type A esophageal atresia (13%); two cases of type B (1%), 178 cases of type C (78%), five cases of type D (2%), and 13 cases of type E (6%). Associated anomalies occurred in 146 infants (64%), including cardiac defects in 86 (38%), skeletal defects in 44 (19%), neurological defects in 34 (15%), renal defects in 35 (15%), anorectal defects in 18 (8%), and other abnormalities in 30 (13%). A single-layer anastomosis was performed in 81%, and a two-layer repair, in 17%. Esophagomyotomy was necessary in 9% of the patients. Anastomotic complications included leakage (16%), symptomatic stricture (35%), and recurrent tracheoesophageal fistula (3%). Gastroesophageal reflux was present in 127 cases (58%), with 56 (44%) requiring an antireflux procedure. Tracheomalacia occurred in 32 cases (15%), and 13 required operative treatment. Postoperative esophageal dysmotility was documented in 56 children (30%). The overall survival rate was 95%. The cause of death in 12 patients included severe cardiac anomalies (n = 3), fatal sleep apnea (n = 1), renal failure (n = 1), trisomy 18 (n = 2), accidental decannulation of tracheostomy (n = 1), pulmonary failure (n = 1), and unknown causes (n = 3). Early diagnosis, improved surgical technique, neonatal anesthesia, sophisticated ventilatory support, advanced intensive care management, early treatment of associated anomalies, responsiveness of anastomotic strictures to dilatation, and aggressive treatment of gastroesophageal reflux have influenced survival positively. Improved survival rates were noted irrespective of the traditional Waterston criteria, which now seem outdated. With few exceptions, most infants with esophageal atresia and/or tracheoesophageal fistula should survive in the current era.


A smart hydrogel-based time bomb triggers drug release mediated by pH-jump reaction.
We demonstrate a timed explosive drug release from smart pH-responsive hydrogels by utilizing a phototriggered spatial pH-jump reaction. A photoinitiated proton-releasing reaction of o-nitrobenzaldehyde (o-NBA) was integrated into poly(N-isopropylacrylamide-co-2-carboxyisopropylacrylamide) (P(NIPAAm-co-CIPAAm)) hydrogels. o-NBA-hydrogels demonstrated the rapid release of protons upon UV irradiation, allowing the pH inside the gel to decrease to below the pKa value of P(NIPAAm-co-CIPAAm). The generated protons diffused gradually toward the non-illuminated area, and the diffusion kinetics could be controlled by adjusting the UV irradiation time and intensity. After irradiation, we observed the enhanced release of entrapped L-3,4-dihydroxyphenylalanine (DOPA) from the gels, which was driven by the dissociation of DOPA from CIPAAm. Local UV irradiation also triggered the release of DOPA from the non-illuminated area in the gel via the diffusion of protons. Conventional systems can activate only the illuminated region, and their response is discontinuous when the light is turned off. The ability of the proposed pH-jump system to permit gradual activation via proton diffusion may be beneficial for the design of predictive and programmable devices for drug delivery.


Dietary intake of working women with children does not appear to be influenced by hours of employment: A secondary analysis of the Australian Health Survey (2011-2013).
Women with children often fulfil multiple roles of running a household, raising a family and working outside the home. Good nutrition during this time is important to optimise their performance and prevent lifestyle diseases. Women also act as nutritional gatekeepers for their family. The dual burden of paid employment and unpaid family work may be associated with time scarcity in mothers which can impact food preparation and therefore nutritional adequacy. The aim of this study was to examine the diet of women who lived with children by comparison of hours worked. This was a secondary analysis of the Australian National Nutrition and Physical Activity Survey 2011-12. Subjects were women aged 18-65 years who resided with ≥1 child (<18 years). Women were grouped according to hours of employment: not working; working <25 h a week; and working ≥25 hours a week. Data from two 24-h dietary recalls were used to compare differences between groups in nutrient intake and proportion of energy from discretionary foods. Covariates included were age, education, smoker status, Socio-Economic Indexes for Areas (SEIFA), number of persons in household, week or weekend day of the survey and the sequence of recalls. Analyses included 1869 women. Dietary intakes varied minimally between groups with intakes of fibre, vitamin C, and calcium lowest in the group not working. Overall diet quality was poor with >30% of energy coming from discretionary foods in all groups. Usual hours of employment per week have a minimal effect on diet quality in women with children. It is likely that different factors specific to each group contribute to the poor dietary intakes and should be further investigated.


Recent Progress in Nucleic Acid Aptamer-Based Biosensors and Bioassays.
As the key constituents of the genetic code, the importance of nucleic acids to life has long been appreciated. Despite being composed of only four structurally similar nucleotides, single-stranded nucleic acids, as in single-stranded DNAs and RNAs, can fold into distinct three-dimensional shapes due to specific intramolecular interactions and carry out functions beyond serving as templates for protein synthesis. These functional nucleic acids (FNAs) can catalyze chemical reactions, regulate gene expression, and recognize target molecules. Aptamers, whose name is derived from the Latin word aptus meaning "to fit", are oligonucleotides that can bind their target ligands with high affinity and specificity. Since aptamers exist in nature but can also be artificially isolated from pools of random nucleic acids through a process called in vitro selection, they can potentially bind a diverse array of compounds. In this review, we will discuss the research that is being done to develop aptamers against various biomolecules, the progress in engineering biosensors by coupling aptamers to signal transducers, and the prospect of employing these sensors for a range of chemical and biological applications. Advances in aptamer technology emphasizes that nucleic acids are not only the fundamental molecules of life, they can also serve as research tools to enhance our understanding of life. The possibility of using aptamer-based tools in drug discovery and the identification of infectious agents can ultimately augment our quality of life.


Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone.
To evaluate the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML) in the network of Italian multiple sclerosis (MS) clinics. We performed a multicenter retrospective cohort study of patients treated with MTX in MS centers under the Italian national health care system between 1998 and 2008. Demographic, disease, treatment, and follow-up information were collected using hospital records. Data were available for 3,220 patients (63% women) from 40 Italian centers. Follow-up (mean ± SD) was 49 ± 29 months (range 12-140 months). We observed 30 cases of AML (incidence 0.93% [95% confidence interval 0.60%-1.26%]). The mean cumulative dose was higher in patients with AML (78 vs 65 mg/m(2), p = 0.028). The median interval from the start of therapy to AML diagnosis was longer than expected at 33 months (range 13-84 months); 8 patients (27%) developed AML 4 years or more after the first MTX infusion. The rate of mortality associated with AML was 37%. This higher than expected risk of AML and related mortality requires that treatment decisions must be made jointly between clinicians and patients who understand their prognosis, treatment options, and treatment-related risks. The now large exposed MS population must be monitored for hematologic abnormalities for at least 6 years from the end of therapy, to ensure the rapid actions needed for early diagnosis and treatment of AML.


Expanding Pharmacotherapy Data Collection, Analysis, and Implementation in ERAS® Programs-The Methodology of an Exploratory Feasibility Study.
Surgical organizations dedicated to the improvement of patient outcomes have led to a worldwide paradigm shift in perioperative patient care. Since 2012, the Enhanced Recovery After Surgery (ERAS®) Society has published guidelines pertaining to perioperative care in numerous disciplines including elective colorectal and gynecologic/oncology surgery patients. The ERAS® and ERAS-USA® Societies use standardized methodology for collecting and assessing various surgical parameters in real-time during the operative process. These multi-disciplinary groups have constructed a bundled framework of perioperative care that entails 22 specific components of clinical interventions, which are logged in a central database, allowing a system of audit and feedback. Of these 22 recommendations, nine of them specifically involve the use of medications or pharmacotherapy. This retrospective comparative pharmacotherapy project will address the potential need to (1) collect more specific pharmacotherapy data within the existing ERAS Interactive Audit System® (EIAS) program, (2) understand the relationship between medication regimen and patient outcomes, and (3) minimize variability in pharmacotherapy use in the elective colorectal and gynecologic/oncology surgical cohort. Primary outcomes measures include data related to surgical site infections, venous thromboembolism, and post-operative nausea and vomiting as well as patient satisfaction, the frequency and severity of post-operative complications, length of stay, and hospital re-admission at 7 and 30 days, respectively. The methodology of this collaborative research project is described.


Decreased hemoglobin levels, cerebral small-vessel disease, and cortical atrophy: among cognitively normal elderly women and men.
Decreased hemoglobin levels increase the risk of developing dementia among the elderly. However, the underlying mechanisms that link decreased hemoglobin levels to incident dementia still remain unclear, possibly due to the fact that few studies have reported on the relationship between low hemoglobin levels and neuroimaging markers. We, therefore, investigated the relationships between decreased hemoglobin levels, cerebral small-vessel disease (CSVD), and cortical atrophy in cognitively healthy women and men. Cognitively normal women (n = 1,022) and men (n = 1,018) who underwent medical check-ups and magnetic resonance imaging (MRI) were enrolled at a health promotion center. We measured hemoglobin levels, white matter hyperintensities (WMH) scales, lacunes, and microbleeds. Cortical thickness was automatically measured using surface based methods. Multivariate regression analyses were performed after controlling for possible confounders. Decreased hemoglobin levels were not associated with the presence of WMH, lacunes, or microbleeds in women and men. Among women, decreased hemoglobin levels were associated with decreased cortical thickness in the frontal (Estimates, 95% confidence interval, -0.007, (-0.013, -0.001)), temporal (-0.010, (-0.018, -0.002)), parietal (-0.009, (-0.015, -0.003)), and occipital regions (-0.011, (-0.019, -0.003)). Among men, however, no associations were observed between hemoglobin levels and cortical thickness. Our findings suggested that decreased hemoglobin levels affected cortical atrophy, but not increased CSVD, among women, although the association is modest. Given the paucity of modifiable risk factors for age-related cognitive decline, our results have important public health implications.


Modeling carbon allocation in trees: a search for principles.
We review approaches to predicting carbon and nitrogen allocation in forest models in terms of their underlying assumptions and their resulting strengths and limitations. Empirical and allometric methods are easily developed and computationally efficient, but lack the power of evolution-based approaches to explain and predict multifaceted effects of environmental variability and climate change. In evolution-based methods, allocation is usually determined by maximization of a fitness proxy, either in a fixed environment, which we call optimal response (OR) models, or including the feedback of an individual's strategy on its environment (game-theoretical optimization, GTO). Optimal response models can predict allocation in single trees and stands when there is significant competition only for one resource. Game-theoretical optimization can be used to account for additional dimensions of competition, e.g., when strong root competition boosts root allocation at the expense of wood production. However, we demonstrate that an OR model predicts similar allocation to a GTO model under the root-competitive conditions reported in free-air carbon dioxide enrichment (FACE) experiments. The most evolutionarily realistic approach is adaptive dynamics (AD) where the allocation strategy arises from eco-evolutionary dynamics of populations instead of a fitness proxy. We also discuss emerging entropy-based approaches that offer an alternative thermodynamic perspective on allocation, in which fitness proxies are replaced by entropy or entropy production. To help develop allocation models further, the value of wide-ranging datasets, such as FLUXNET, could be greatly enhanced by ancillary measurements of driving variables, such as water and soil nitrogen availability.


Communication during prosthodontic treatment--dentist, patient, and dental nurse.
This study described and explored verbal communication during prosthodontic treatment. Sixty-one patients and 15 dentists participated. Sixty-one prosthetic treatment periods, during which fixed tooth- or implant-supported prostheses were placed, were followed. One visit during each treatment period was audio recorded. The recorded verbal communication was analyzed with the Roter Interaction Analysis System-dental. The inter-rater reliability was 95% to 97% for utterance classification and kappa = 0.71 to 0.78 for categorization definition. There were 43,663 utterances available for analysis. Of those, 59% was dentist communication, 28% was patient communication, and 10% was dental nurse communication. Other persons, e.g., dental technicians, contributed with 3%. The dentist-patient communication contained more task-focused than socioemotional behaviors. Female patients used socioemotional talk to a greater extent than did the male patients. Dentists and patients of different genders communicated more overall, especially male dentists with female patients. The age difference between dentist and patient had no effect on the amount or type of communication. The dental nurse talked slightly more with male patients. When different genders met there was more communication, and the talk was more socioemotional when the patient was female.


Oxytocin and neuroadaptation to cocaine.
Oxytocin (OT) has been implicated in neuroadaptive processes such as learning, memory, and social-affiliative behavior as well as in the regulation of physiological responses leading to adaptation to the changing external and internal environment. Drugs of abuse constitute a major challenge to the homeostasis of the body and behavior. Drug tolerance, dependence and addiction may involve neuroadaptive mechanisms related to learning and memory at cellular and systems levels. Considerable effort has been made toward the understanding the neurobiological mechanisms of addictive behavior. Neuropeptides OT and vasopressin (VP) might be involved in these processes based on their effects on neuroadaptation and on their neuroanatomical localization and pharmacological actions. It has been demonstrated that both OT and VP have modulatory effects on opiate and alcohol tolerance and dependence. This chapter summarize the effects of OT, and in lesser extent VP, on neuroadaptation to cocaine, a psychostimulant drug of abuse. We have shown that OT inhibits acute cocaine-induced locomotor hyperactivity, exploratory activity and stereotyped behavior in rodents. Furthermore, OT facilitated, whereas VP inhibited the development of behavioral sensitization to cocaine. In a different model, OT inhibited the development of tolerance to the stereotyped behavior-inducing effects of cocaine as well as cocaine intravenous self-administration in rats. We demonstrated that OT acts through its specific receptors in the basal forebrain and in the hippocampus. OT and VP contents in the hypothalamus and limbic structures were altered by acute and chronic cocaine administration in a dose-dependent and region-selective manner. The differential plasticity of the brain OT-ergic and VP-ergic neurotransmissions in response to cocaine may underlie the differences in the involvement of these neuropeptides in cocaine addiction. Interaction of OT with dopaminergic neurotransmission in the nucleus accumbens, a key brain structure in drug addiction, as well as OT-ergic regulation of hippocampal processes may be among the mechanisms of action through which OT modulates neuroadaptation to cocaine. A better understanding of the role of OT in neuroadaptation to cocaine may provide an insight into both the mechanisms of neuropeptide actions in the brain as well as into the neurobiology of drug addiction.


Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk.
Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes. A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here, we assess the ability of 18 confirmed type 2 diabetes variants to differentiate between type 2 diabetic case and control subjects. We assessed index single nucleotide polymorphisms (SNPs) for the 18 independent loci in 2,598 control subjects and 2,309 case subjects from the Genetics of Diabetes Audit and Research Tayside Study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of type 2 diabetes and by calculating the area under the receiver-operator characteristic curve (AUC). Individuals carrying more risk alleles had a higher risk of type 2 diabetes. For example, 1.2% of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI 2.11-8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI, and sex was 0.78, and adding the genetic risk variants only marginally increased this to 0.80. Currently, common risk variants for type 2 diabetes do not provide strong predictive value at a population level. However, the joint effect of risk variants identified subgroups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing.


Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies.
The facilitative glucose transporter Glut-1 is overexpressed and confers poor prognosis in a wide range of solid tumours. The peri-necrotic pattern of expression often seen in human tumour samples is linked with its transcriptional control in hypoxic conditions by hypoxia-inducible factor HIF-1 or through a reduced rate of oxidative phosphorylation. Hypoxia-regulated genes offer promise as novel therapeutic targets as a means of preventing the proliferation and eventual metastatic spread of tissue originating from residual chemically and radio resistant hypoxic cells that have survived treatment. Inhibiting the expression or functionality of Glut-1 may be a way of specifically targeting hypoxic cells within the tumour that depend upon a high rate of glucose uptake for anaerobic glycolysis. We used an array of formalin-fixed, paraffin-embedded samples of the NCI-60 panel of cell lines to carry out immunohistochemical detection of Glut-1 and to select possible candidate lead compounds by COMPARE analysis with agents from the NCI diversity screen, which may work via inhibition of Glut-1 or Glut-1-dependent processes. "Positive" COMPARE hits were mostly conjugated Pseudomonas toxins binding the epidermal growth factor receptor (EGFR). However, correlations with standard anticancer agents were virtually all negative, indicating a link between Glut-1 and chemoresistance. MTT proliferation assays carried out using stable, Glut-1 overexpressing cell lines generated from the bladder EJ138, human fibrosarcoma HT 1080 and the hepatoma wild type Hepa and HIF-1B-deficient c4 tumour cell lines revealed a cell line-dependent increase in chemoresistance to dacarbazine, vincristine and the bioreductive agent EO9 in Glut-1 overexpressing EJ138 relative to WT and empty vector controls. Metabolomic analysis ((31)P-MRS and (1)H MRS) carried out using cell lysates and xenografts generated from Glut-1 overexpressing Hepa and c4 cell lines showed higher glucose levels in Glut-1 overxpressing c4 relative to parental tumour extracts occurred in the absence of an increase in lactate levels, which were in turn significantly higher in the Glut-1 overexpressing Hepa xenografts. This implies that Glut-1 over-expression without a co-ordinate increase in HIF-1-regulated glycolytic enzymes increases glucose uptake but not the rate of glycolysis. Glut-1 overexpressing xenografts also showed higher levels of phosphodiester (PDE), which relates to the metabolite turnover of phospholipids and is involved in membrane lipid degradation, indicating a mechanism by which Glut-1 may increase cell turnover.


What is an effective portable air cleaning device? A review.
The use of portable air cleaning devices in residential settings has been steadily growing over the last 10 years. Three out of every 10 households now contain a portable air cleaning device. This increased use of air cleaners is accompanied by, if not influenced by, a fundamental belief by consumers that the air cleaners are providing an improved indoor air environment. However, there is a wide variation in the performance of air cleaners that is dependent on the specific air cleaner design and various indoor factors. The most widely used method in the United States to assess the performance of new air cleaners is the procedure described in the American National Standards Institute (ANSI)/Association of Home Appliance Manufacturers (AHAM) AC-1-2002. This method describes both the test conditions and the testing protocol. The protocol yields a performance metric that is based on the measured decay rate of contaminant concentrations with the air cleaner operating compared with the measured decay rate with the air cleaner turned off. The resulting metric, the clean air delivery rate (CADR), permits both an intercomparison of performance among various air cleaners and a comparison of air cleaner operation to other contaminant removal processes. In this article, we comment on the testing process, discuss its applicability to various contaminants, and evaluate the resulting performance metrics for effective air cleaning.


Allogeneic Platelet-Rich Plasma Versus Corticosteroid Injection for the Treatment of Rotator Cuff Disease: A Randomized Controlled Trial.
The use of platelet-rich plasma (PRP) for the treatment of rotator cuff disease is still controversial. The purpose of the present study was to investigate the safety and efficacy of a fully characterized allogeneic pure PRP injection into the subacromial space of patients with rotator cuff disease in comparison with corticosteroid injection. A 2-group, parallel, assessor-blinded, randomized controlled trial was conducted. A total of 60 patients with clinically and structurally diagnosed rotator cuff disease were randomly assigned to receive a subacromial injection of either 4 mL of allogeneic pure PRP or a 4-mL mixture of 1 mL of 40-mg/mL triamcinolone acetonide and 3 mL of 2% lidocaine under ultrasonographic guidance. The primary outcomes were safety and the Constant score at 1 month. The secondary outcomes were pain, range of motion, muscle strength, functional scores, and overall satisfaction and function. There were no treatment-related adverse events. The Constant score at 1 month did not significantly differ between the PRP and corticosteroid groups. At 6 months, the DASH (Disabilities of the Arm, Shoulder and Hand) score, overall function, and external rotation were significantly better in the PRP group than in the corticosteroid group, and the other clinical outcomes did not show significant differences. All pain measurements, the strength of the supraspinatus and infraspinatus, and 5 functional scores also improved slowly and steadily after injection, becoming significantly better at 6 months compared with those before the injection, whereas those in the corticosteroid group responded promptly but did not further improve. Allogeneic PRP injections for the treatment of rotator cuff disease are safe but are not definitely superior to corticosteroid injections with respect to pain relief and functional improvement during 6 months. The DASH score, overall function, and external rotation were significantly better in the PRP group than in the steroid group at 6 months. Generally, PRP slowly but steadily reduced pain and improved function of the shoulder until 6 months, whereas corticosteroid did not. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


Genetic contributions to attentional response time slopes across repeated trials.
Attention provides vital contribution to everyday functioning, and deficits in attention feature in many psychological disorders. Improved understanding of attention may eventually be critical to early identification and treatment of attentional deficits. One step in that direction is to acquire a better understanding of genetic associations with performance on a task measuring reflexive (exogenous) visual attention. Reflexive attention is an important component of overall attention because (along with voluntary selective attention) it participates in determining where attention is allocated and how susceptible to distractors the subject might be. The task that we used involves the presentation of a target that is preceded by one of several different types of cues (none, double, or single, either ipsilateral or contralateral to where the target subsequently appears). We used several different outcome measures depending on the cue presented. We have previously studied the relationship between selected genes and mean response time (RT). Here we report on the contributions of genetic markers to RT increases or decreases over the course of the task (linear trend in RT slope). Specifically, we find that RT slope for a variety of reflexive attention outcome measures is dependent on DAT1 genotype. DRD4 was near significant for one outcome measure in the final (best) model. APOE, COMT, and DBH were not significant in any models. It is especially interesting that genotype predicts linear changes in RT across trials (and not just mean differences or moment-to-moment variability). DAT1 is a gene that produces a protein involved in the transport of dopamine from the synapse. To our knowledge, this is the first study that has associated neurotransmitter genotypes with RT slope on a reflexive attention experiment. The direction of these effects is consistent with genetic risk for attention deficit hyperactivity disorder (ADHD). That is, those with two risk alleles for ADHD (6R/6R on the DAT1 intron 8 VNTR) either got slower as the task progressed or had the least improvement. Those with no risk alleles (5R/5R) had the most improvement in RT as the task progressed.


Frequency and characteristics of myocardial ischemia recorded during stress echocardiography in patients with high coronary risk.
Ischemic heart disease is the major cause of morbidity and mortality in the world as well as in our country. Ischemic heart disease has the multifactorial origin and the presence of several risk factors increases the risk of myocardial ischemia. The aim of the study was to evaluate the frequency and characteristics of myocardial ischemia in asymptomatic subjects with two or more risk factors for coronary artery disease during stress echocardiography. In 240 high risk asymptomatic subjects (an absolute risk of fatal cardiovascular disease of more than 5%, according to the Systemic Coronary Risk Evaluation Chart), the exercise stress echocardiography test was performed. The criterion for myocardial ischemia was the appearance of transient segmental wall motion abnormality (WMA). The wall motion score index was calculated before and after the exercise stress echocardiography. During exercise stress echocardiography, in 36 (15%) subjects WMA occurred. Out of 36 subjects with myocardial ischemia, in 10 (27.8%) subjects WMA and ST segment depression were accompanied with the first occurrence of chest pain (the subgroup with symptomatic myocardial ischemia), in 20 (55.6%) subjects WMA and ST segment depression were detected and in 6 (16.6%) subjects only WMA occurred (the subgroup with silent myocardial ischemia). There were no significant differences between the subgroups with symptomatic and silent myocardial ischemia with regard to exercise tolerance, heart rate at the onset of WMA, and time to the onset of WMA, but the wall motion score index was significantly higher in the subjects with symptomatic myocardial ischemia (p < 0.01). In all the individuals with symptomatic myocardial ischemia, significant stenosis of the coronary arteries was found by coronary angiography. Out of 26 subjects with asymptomatic myocardial ischemia, coronary angiography was performed in 18 and significant stenosis of the coronary arteries was diagnosed in all of them. The number and grade of coronary stenosis in subjects with symptomatic and silent myocardial ischemia were similar. The obtained results presented the incidence of myocardial ischemia in 15% of asymptomatic subjects with high coronary risk during stress echocardiography. Silent myocardial ischemia was markedly more frequent than symptomatic one, but in the subjects with symptomatic ischemia, the wall motion score index was significantly higher.


Quaternary structure of hemoglobin in solution.
Many important proteins perform their physiological functions under allosteric control, whereby the binding of a ligand at a specific site influences the binding affinity at a different site. Allosteric regulation usually involves a switch in protein conformation upon ligand binding. The energies of the corresponding structures are comparable, and, therefore, the possibility that a structure determined by x-ray diffraction in the crystalline state is influenced by its intermolecular contacts, and thus differs from the solution structure, cannot be excluded. Here, we demonstrate that the quaternary structure of tetrameric human normal adult carbonmonoxy-hemoglobin can readily be determined in solution at near-physiological conditions of pH, ionic strength, and temperature by NMR measurement of (15)N-(1)H residual dipolar couplings in weakly oriented samples. The structure is found to be a dynamic intermediate between two previously solved crystal structures, known as the R and R2 states. Exchange broadening at the subunit interface points to a rapid equilibrium between different structures that presumably include the crystallographically observed states.


Physical disruption of intervertebral disc promotes cell clustering and a degenerative phenotype.
To test the hypothesis that physical disruption of an intervertebral disc disturbs cell-matrix binding, leading to cell clustering and increased expression of matrix degrading enzymes that contribute towards degenerative disc cell phenotype. Lumbar disc tissue was removed at surgery from 21 patients with disc herniation, 11 with disc degeneration, and 8 with adolescent scoliosis. 5 μm sections were examined with histology, and 30-µm sections by confocal microscopy. Antibodies were used against integrin α5beta1, matrix metalloproteinases (MMP) 1, MMP-3, caspase 3, and denatured collagen types I and II. Spatial associations were sought between cell clustering and various degenerative features. An additional, 11 non-herniated human discs were used to examine causality: half of each specimen was cultured in a manner that allowed free 'unconstrained' swelling (similar to a herniated disc in vivo), while the other half was cultured within a perspex ring that allowed 'constrained' swelling. Changes were monitored over 36 h using live-cell imaging. 1,9-Di-methyl methylene blue (DMMB) assay for glycosaminoglycan loss was carried out from tissue medium. Partially constrained specimens showed little swelling or cell movement in vitro. In contrast, unconstrained swelling significantly increased matrix distortion, glycosaminoglycan loss, exposure of integrin binding sites, expression of MMPs 1 and 3, and collagen denaturation. In the association studies, herniated disc specimens showed changes that resembled unconstrained swelling in vitro. In addition, they exhibited increased cell clustering, apoptosis, MMP expression, and collagen denaturation compared to 'control' discs. Results support our hypothesis. Further confirmation will require longitudinal animal experiments.


Certolizumab Pegol: A Review in Moderate to Severe Plaque Psoriasis.
Certolizumab pegol (Cimzia®) is a PEGylated, Fab'-only, recombinant humanized antibody against TNF-α. Subcutaneous certolizumab pegol is indicated for the treatment of various immune-mediated inflammatory diseases (IMIDs), including moderate to severe plaque psoriasis. In pivotal phase III trials in adults with moderate to severe plaque psoriasis, significantly more patients receiving certolizumab pegol 200 mg or 400 mg once every 2 weeks than placebo recipients achieved a ≥ 75% reduction in PASI score (PASI75 responder) and a PGA score of clear/mostly clear with a ≥ 2 point improvement from baseline (PGA0/1 responder) at week 12 (CIMPACT) or 16 (CIMPASI-1 and -2). In CIMPACT, certolizumab pegol 400 mg once every 2 weeks was superior to etanercept (highest recommended dosage) at 12 weeks, with certolizumab pegol 200 mg once every 2 weeks demonstrating non-inferiority, but not superiority, to etanercept. The clinical benefits of certolizumab pegol were maintained during the maintenance phase (to week 48) and the open-label extension phase of these trials. Certolizumab pegol is unique among the biologics, with the absence of an Fc fragment conferring pharmacokinetic advantages; most notably, its minimal transfer across the placenta, and low relative infant dose during breastfeeding in conjunction with its low oral bioavailability. Certolizumab pegol was generally well tolerated and no new safety signals were identified in these phase III trials, which complements its established safety profile in other IMIDs. Certolizumab pegol is a useful option for the treatment of moderate to severe plaque psoriasis and provides an important treatment option for women of childbearing age, for whom there are limited options available.


CodY is a global regulator of virulence-associated properties for Clostridium perfringens type D strain CN3718.
CodY is known to regulate various virulence properties in several Gram-positive bacteria but has not yet been studied in the important histotoxic and intestinal pathogen Clostridium perfringens. The present study prepared an isogenic codY-null mutant in C. perfringens type D strain CN3718 by insertional mutagenesis using the Targetron system. Western blot analysis indicated that, relative to wild-type CN3718 or a complementing strain, this isogenic codY mutant produces reduced levels of epsilon toxin (ETX). Using supernatants from cultures of the wild-type, codY-null mutant, and complementing strains, CodY regulation of ETX production was shown to have cytotoxic consequences for MDCK cells. The CodY regulatory effect on ETX production was specific, since the codY-null mutant still made wild-type levels of alpha-toxin and perfringolysin O. Sialidase activity measurements and sialidase Western blot analysis of supernatants from CN3718 and its isogenic derivatives showed that CodY represses overall exosialidase activity due to a reduced presence of NanH in culture supernatants. Inactivation of the codY gene significantly decreased the adherence of CN3718 vegetative cells or spores to host Caco-2 cells. Finally, the codY mutant showed increased spore formation under vegetative growth conditions, although germination of these spores was impaired. Overall, these results identify CodY as a global regulator of many C. perfringens virulence-associated properties. Furthermore, they establish that, via CodY, CN3718 coordinately regulates many virulence-associated properties likely needed for intestinal infection. Clostridium perfringens is a major human and livestock pathogen because it produces many potent toxins. C. perfringens type D strains cause intestinal infections by producing toxins, especially epsilon toxin (ETX). Previous studies identified CodY as a regulator of certain virulence properties in other Gram-positive bacteria. Our study now demonstrates that CodY is a global regulator of virulence-associated properties for type D strain CN3718. It promotes production of ETX, attachment of CN3718 vegetative cells or spores to host enterocyte-like Caco-2 cells, and spore germination; the last two effects may assist intestinal colonization. In contrast, CodY represses sporulation. These results provide the first evidence that CodY can function as a global regulator of C. perfringens virulence-associated properties and that this strain coordinately regulates its virulence-associated properties using CodY to increase ETX production, host cell attachment, and spore germination but to repress sporulation, as would be optimal during type D intestinal infection.


The use of full-setting non-invasive ventilation in the home care of people with amyotrophic lateral sclerosis-motor neuron disease with end-stage respiratory muscle failure: a case series.
Little has been written about the use of non-invasive ventilation in the home care of amyotrophic lateral sclerosis-motor neuron disease patients with end-stage respiratory muscle failure. Nocturnal use of non-invasive ventilation has been reported to improve daytime blood gases but continuous non-invasive ventilation dependence has not been studied in this regard. There continues to be great variation by country, economics, physician interest and experience, local concepts of palliation, hospice requirements, and resources available for home care. We report a case series of home-based amyotrophic lateral sclerosis-motor neuron disease patients who refused tracheostomy and advanced non-invasive ventilation to full-setting, while maintaining normal alveolar ventilation and oxygenation in the course of the disease. Since this topic has been presented in only one center in the United States and nowhere else, it is appropriate to demonstrate that this can be done in other countries as well. We present here the cases of three Caucasian patients (a 51-year-old Caucasian man, a 45-year-old Caucasian woman and a 57-year-old Caucasian woman) with amyotrophic lateral sclerosis who developed continuous non-invasive ventilation dependence for 15 to 27 months without major complications and were able to maintain normal CO2 and pulse oxyhemoglobin saturation despite a non-measurable vital capacity. All patients were wheelchair-dependent and receiving riluzole 50 mg twice a day. Patient one developed mild-to-moderate bulbar-innervated muscle weakness. He refused tracheostomy but accepted percutaneous gastrostomy. Patient two had two lung infections, acute bronchitis and pneumonia, which were treated with antibiotics and cough assistance at home. Patient three had three chest infections (bronchitis and pneumonias) and asthmatic episodes treated with antibiotics, bronchodilators and cough assistance at home. All patients had normal speech while receiving positive pressure; they died suddenly and with normal oxygen saturation. Although warned that prognosis was poor as vital capacity diminished, our patients survived without invasive airway tubes and despite non-measurable vital capacity. No patient opted for tracheostomy. Our patients demonstrate the feasibility of resorting to full-setting non-invasive management to prolong survival, optimizing wellness and management at home, and the chance to die peacefully.