Window-based example selection in learning vector quantization.
A variety of modifications have been employed to learning vector quantization (LVQ) algorithms using either crisp or soft windows for selection of data. Although these schemes have been shown in practice to improve performance, a theoretical study on the influence of windows has so far been limited. Here we rigorously analyze the influence of windows in a controlled environment of gaussian mixtures in high dimensions. Concepts from statistical physics and the theory of online learning allow an exact description of the training dynamics, yielding typical learning curves, convergence properties, and achievable generalization abilities. We compare the performance and demonstrate the advantages of various algorithms, including LVQ 2.1, generalized LVQ (GLVQ), Learning from Mistakes (LFM) and Robust Soft LVQ (RSLVQ). We find that the selection of the window parameter highly influences the learning curves but not, surprisingly, the asymptotic performances of LVQ 2.1 and RSLVQ. Although the prototypes of LVQ 2.1 exhibit divergent behavior, the resulting decision boundary coincides with the optimal decision boundary, thus yielding optimal generalization ability.


Anesthetic and Obstetric Management of Syringomyelia During Labor and Delivery: A Case Series and Systematic Review.
Syringomyelia is a rare, slowly progressive neurological condition characterized by the presence of a syrinx within the spinal cord. Consensus regarding the safest mode of delivery and anesthetic management in patients with syringomyelia remains controversial and presents management dilemmas. This study reviews the cases of syringomyelia at our institution and provides a systematic review of the literature to guide decisions regarding labor and delivery management. A retrospective review of cases at our hospital from 2002 to 2014 and a systematic review of the literature from 1946 to 2014 were undertaken. Hospital records and electronic databases were interrogated using International Classification of Diseases, 10th Revision codes and the keywords "syringomyelia," "syringobulbia," and "pregnancy." Data regarding demographics, diagnosis, radiology reports, neurological symptoms, mode of delivery, anesthetic management, and maternal-fetal outcomes were collected. We collected and analyzed data on a total of 43 pregnancies in 39 patients. The most common location for syrinx was in the cervicothoracic region (41.9%). The large majority of patients (n = 34; 87%) demonstrated signs and symptoms associated with syringomyelia before delivery. Syringomyelia associated with Arnold Chiari malformation was documented in 49% (n = 21) cases. General anesthesia was the most commonly used (n = 21/30, 70%) anesthetic technique for cesarean delivery. The majority (n = 9/13, 69%) of patients had an epidural sited for labor analgesia. There were no maternal or neonatal complications associated with neuraxial anesthesia; however, 3 cases (14%) raised concerns regarding general anesthesia including difficult intubation, transient worsening of neurological symptoms postpartum, and prolonged muscle paralysis after atracurium. Despite concerns regarding aggravation of the syrinx with vaginal delivery, this mode of delivery has never caused any documented long-term worsening of neurological condition. All techniques of anesthesia have been performed successfully without major lasting complications. All cases necessitate patient counseling and individualized multidisciplinary involvement to ensure maternal safety.


Identification of HLA-A*11:01-restricted Mycobacterium tuberculosis CD8(+) T cell epitopes.
New vaccines are needed to combat Mycobacterium tuberculosis (MTB) infections. The currently employed Bacillus Calmette-Guérin vaccine is becoming ineffective, due in part to the emergence of multidrug-resistant tuberculosis (MDR-TB) strains and the reduced immune capacity in cases of HIV coinfection. CD8(+) T cells play an important role in the protective immunity against MTB infections, and the identification of immunogenic CD8(+) T cell epitopes specific for MTB is essential for the design of peptide-based vaccines. To identify CD8(+) T cell epitopes of MTB proteins, we screened a set of 94 MTB antigens for HLA class I A*11:01-binding motifs. HLA-A*11:01 is one of the most prevalent HLA molecules in Southeast Asians, and definition of T cell epitopes it can restrict would provide significant coverage for the Asian population. Peptides that bound with high affinity to purified HLA molecules were subsequently evaluated in functional assays to detect interferon-γ release and CD8(+) T cell proliferation in active pulmonary TB patients. We identified six novel epitopes, each derived from a unique MTB antigen, which were recognized by CD8(+) T cells from active pulmonary TB patients. In addition, a significant level of epitope-specific T cells could be detected ex vivo in peripheral blood mononuclear cells from active TB patients by an HLA-A*11:01 dextramer carrying the peptide Rv3130c194-204 (from the MTB triacylglycerol synthase Tgs1), which was the most frequently recognized epitope in our peptide library. In conclusion, this study identified six dominant CD8(+) T cell epitopes that may be considered potential targets for subunit vaccines or diagnostic strategies against TB.


Imaging techniques and image interpretation for dental implant treatment.
This article reviews the literature on radiographic imaging techniques and image interpretation for dental implant treatment. MEDLINE was used to identify published peer-reviewed literature for this report. Radiographic images are indispensable in the evaluation of osseous structures when planning treatment for dental implants. Potential bone sites for implant placement can be assessed clinically by means of palpation or probing through the mucosa; however, diagnostic imaging provides the best means for indirectly measuring bone dimensions. After healing of the implant site, the application of radiology is useful to verify the amount of bone adjacent to the implant and that the transmucosal abutments fit the implant. Upon completion of the implant prosthesis, radiology may be used to monitor initial and long-term success of implant treatment. Recommendations for the application of radiology over the course of treatment are made for various implant cases ranging from the overdenture to the single-tooth implant.


Comparison of rRNA and polar-lipid-derived fatty acid biomarkers for assessment of 13C-substrate incorporation by microorganisms in marine sediments.
We determined whether a recently developed method to isolate specific small-subunit (SSU) rRNAs can be used in 13C-labeling studies to directly link community structure and function in natural ecosystems. Replicate North Sea sediment cores were incubated at the in situ temperature following addition of 13C-labeled acetate, propionate, amino acids, or glucose. Eukaryotic and bacterial SSU rRNAs were separated from total RNA by means of biotin-labeled oligonucleotide probes and streptavidin-coated paramagnetic beads, and the 13C content of the isolated rRNA was determined by elemental analysis-isotope ratio mass spectrometry. The SSU rRNA yield with the bead-capture protocol was improved by using helper probes. Incorporation of label into bacterial SSU rRNA was detectable after 2 h of incubation. The labeling was always much greater in bacterial SSU rRNA than in eukaryotic SSU rRNA, suggesting that bacteria were the main consumers of the 13C-labeled compounds. Similar results were obtained with the 13C-labeled polar-lipid-derived fatty acid (PLFA) approach, except that more label was detected in bacterial PLFA than in bacterial SSU rRNA. This may be attributable to the generally slow growth of sediment microbial populations, which results in low ribosome synthesis rates and relatively few ribosomes per cell. We discuss possible ways to improve the probe-capture protocol and the sensitivity of the 13C analysis of the captured SSU rRNA.


Relationships between structural and psychological empowerment, mediated by person-centred processes and thriving for nursing home staff.
Person-centred care has been shown to have positive outcomes for patients and for staff. However, the complexity of the link between structural conditions, work in a person-centred manner and outcomes for staff is insufficiently described. We tested the relationship between structural empowerment and psychological empowerment, as mediated by nursing home staff members' self-ratings of working in a person-centred manner, the person-centred climate and thriving. Questionnaires were distributed to staff working in 12 nursing homes in Sweden. A serial mediation model was tested. The results showed that higher access to structural empowerment was related to higher psychological empowerment mediated by staff working in a more person-centred manner, improved person-centred climate, and improved staff ratings of thriving. These results point to the importance of strengthening the preconditions for staff to work in a person-centred manner and nursing home managers play an important role in this.


Musculoskeletal and estrogen changes during the adolescent growth spurt in girls.
The adolescent growth spurt is associated with rapid growth and hormonal changes, thought to contribute to the increased anterior cruciate ligament injury risk in girls. However, relatively little is known about these musculoskeletal and estrogen changes during the growth spurt in girls. To investigate the longitudinal changes in estrogen as well as anterior knee laxity and lower limb strength and flexibility throughout the adolescent growth spurt in girls. Thirty-three healthy girls, age 10-13 yr, in Tanner stage II and 4-6 months from their peak height velocity were recruited. Participants were tested up to four times during the 12 months of their growth spurt, according to the timing of their maturity offset (test 1: maturity offset = -6 to -4 months; test 2: maturity offset = 0 months; test 3: maturity offset = +4 months; test 4: maturity offset = +8 months). During each testing session, anterior knee laxity, lower limb flexibility, and isokinetic strength as well as saliva measures of estradiol concentration were measured. A significant (P = 0.002) effect of time on anterior knee laxity was found from the time of peak height velocity, although no changes in estradiol concentration were displayed over time (P = 0.811). Participants displayed a significant increase (P < 0.05) in isokinetic quadriceps strength over time, with no apparent increase in isokinetic hamstring strength. We speculate that increased quadriceps strength, combined with increased knee laxity and no accompanying hamstring strength development during the adolescent growth spurt in girls, might contribute to a decrease in their knee joint stability during landing tasks. These musculoskeletal changes could potentially increase anterior cruciate ligament injury risk at a time of rapid height and lower limb growth.


Subcellular location and properties of bactericidal factors from human neutrophils.
We examined the subcellular location of bactericidal factors (BF) in human neutrophils, using an efficient fractionation scheme. Nitrogen bomb cavitates of DIFP-treated PMN were centrifuged through discontinuous Percoll gradients, each fraction extracted with 0.05 M glycine, pH 2.0, and tested for the killing of Escherichia coli. greater than 90% of BF coisolated with the azurophil granules. After lysis of azurophils, 98% of azurophil-derived BF (ADBF) sedimented with the membrane. ADBF activity was solubilized from azurophil membrane with either acid or nonionic detergent (Triton X-100, Triton X-114). Bactericidal activity was linear with respect to protein concentration over the range 0.3-30 micrograms/ml. 0.1-0.3 microgram/ml ADBF killed 10(5) E. coli within 30 min at 37 degrees C. At 1.4 micrograms/ml, 50% of 2 X 10(5) bacteria were killed within 5 min. ADBF was effective between pH 5-8, with peak activity at pH 5.5. Glucose (20 mM), EDTA (1-25 mM), and physiologic concentrations of NaCl or KCl had little or no inhibitory effect on ADBF. ADBF killed both Gram-positive and Gram-negative virulent clinical isolates, including listeria, staphylococci, beta-hemolytic streptococci, and Pseudomonas aeruginosa. Thus, under these conditions of cell disruption, fractionation, extraction, and assay, almost all BF in human PMN appeared to be localized to the membrane of azurophilic granules as a highly potent, broad-spectrum, rapidly acting protein(s) effective in physiologic medium. Some of these properties appear to distinguish ADBF from previously described PMN bactericidal proteins.


Bevacizumab specifically decreases elevated levels of circulating KIT+CD11b+ cells and IL-10 in metastatic breast cancer patients.
Whether bevacizumab exerts its anti-tumor properties through systemic effects beyond local inhibition of angiogenesis and how these effects can be monitored in patients, remain largely elusive. To address these questions, we investigated bone marrow-derived cells and cytokines in the peripheral blood of metastatic breast cancer patients undergoing therapy with bevacizumab. Circulating endothelial cells (CEC), circulating endothelial progenitor (CEP) and circulating CD11b+ cells in metastatic breast cancer patients before and during therapy with paclitaxel alone (n = 11) or in combination with bevacizumab (n = 10) were characterized using flow cytometry, real time PCR and RNASeq. Circulating factors were measured by ELISA. Aged-matched healthy donors were used as baseline controls (n = 12). Breast cancer patients had elevated frequencies of CEC, CEP, TIE2+CD11b+ and KIT+CD11b+ cell subsets. CEC decreased during therapy, irrespective of bevacizumab, while TIE2+CD11b+ remained unchanged. KIT+CD11b+ cells decreased in response to paclitaxel with bevacizumab, but not paclitaxel alone. Cancer patients expressed higher mRNA levels of the M2 polarization markers CD163, ARG1 and IL-10 in CD11b+ cells and increased levels of the M2 cytokines IL-10 and CCL20 in plasma. M1 activation markers and cytokines were low or equally expressed in cancer patients compared to healthy donors. Chemotherapy with paclitaxel and bevacizumab, but not with paclitaxel alone, significantly decreased IL-10 mRNA in CD11b+ cells and IL-10 protein in plasma. This pilot study provides evidence of systemic immunomodulatory effects of bevacizumab and identified circulating KIT+CD11b+ cells and IL-10 as candidate biomarkers of bevacizumab activity in metastatic breast cancer patients.


Virtual World Currency Value Fluctuation Prediction System Based on User Sentiment Analysis.
In this paper, we present a method for predicting the value of virtual currencies used in virtual gaming environments that support multiple users, such as massively multiplayer online role-playing games (MMORPGs). Predicting virtual currency values in a virtual gaming environment has rarely been explored; it is difficult to apply real-world methods for predicting fluctuating currency values or shares to the virtual gaming world on account of differences in domains between the two worlds. To address this issue, we herein predict virtual currency value fluctuations by collecting user opinion data from a virtual community and analyzing user sentiments or emotions from the opinion data. The proposed method is straightforward and applicable to predicting virtual currencies as well as to gaming environments, including MMORPGs. We test the proposed method using large-scale MMORPGs and demonstrate that virtual currencies can be effectively and efficiently predicted with it.


Anisotropic diffraction of light by volume holographic grating in birefringent photorefractive crystals with extended wavelength range.
The properties of anisotropic diffraction of light by volume holographic grating in birefringent photorefractive crystals are discussed. This diffraction takes place when the refractive index for diffracted light is different from the refractive index for incident light. It is found that in some special geometry of wavevector diagram the diffraction becomes less sensitive to the wavelength mismatch of Bragg condition. The wavelength range may extent in several times the range of ordinary isotropic diffraction on the grating of the same spacing and thickness. Theoretical explanation of this phenomena and experimental results of widerange diffraction in BaTiO3 photorefractive crystal are also presented.


Disorders of renal magnesium handling explain renal magnesium transport.
Magnesium is essential for bone stability, neuronal excitability, muscular relaxation and many other metabolic functions. Despite its fundamental biological importance, mechanisms controlling systemic magnesium homeostasis are only partially understood. The kidney plays a central role in maintaining magnesium balance as evident from several rare inherited disorders of renal magnesium transport. Recent studies shed new light on molecular mechanisms of renal magnesium handling and its control. Mutations in the claudin 16 (paracellin) paracellular protein in the thick ascending limb (TAL) of Henle's loop and in the transient receptor potential cation channel, subfamily 6, member 6 (TRPM6) magnesium channel expressed in distal tubules found in patients with renal magnesium wasting and hypomagnesemia underscore the importance of these transport proteins. A study by Hou et al (J Biol Chem 2007; 282: 17114-22) demonstrates a pathomechanism for claudin 16 mutations that gives interesting insights into the function of the TAL. Moreover, Groenestege and colleagues report (J Clin Invest 2007; 117: 2260-7) the identification of the epidermal growth factor (EGF) as a hormonal regulator of TRPM6 activity, and thereby explain how mutations in EGF can cause familial hypomagnesemia. Interestingly, cetuximab, a drug used in treatment of certain cancers, acts an inhibitor of the EGF receptor and causes hypomagnesemia which may be due to the inhibition of EGF signaling.


Preclinical and Clinical Studies on Antioxidative, Antihypertensive and Cardioprotective Effect of Marine Proteins and Peptides-A Review.
High seafood consumption has traditionally been linked to a reduced risk of cardiovascular diseases, mainly due to the lipid lowering effects of the long chained omega 3 fatty acids. However, fish and seafood are also excellent sources of good quality proteins and emerging documentation show that, upon digestion, these proteins are sources for bioactive peptides with documented favorable physiological effects such as antioxidative, antihypertensive and other cardioprotective effects. This documentation is mainly from in vitro studies, but also animal studies are arising. Evidence from human studies evaluating the positive health effects of marine proteins and peptides are scarce. In one study, a reduction in oxidative stress after intake of cod has been documented and a few human clinical trials have been performed evaluating the effect on blood pressure. The results are, however, inconclusive. The majority of the human clinical trials performed to investigate positive health effects of marine protein and lean fish intake, has focused on blood lipids. While some studies have documented a reduction in triglycerides after intake of lean fish, others have documented no effects.


Catalytic activation of histone acetyltransferase Rtt109 by a histone chaperone.
Most histone acetyltransferases (HATs) function as multisubunit complexes in which accessory proteins regulate substrate specificity and catalytic efficiency. Rtt109 is a particularly interesting example of a HAT whose specificity and catalytic activity require association with either of two histone chaperones, Vps75 or Asf1. Here, we utilize biochemical, structural, and genetic analyses to provide the detailed molecular mechanism for activation of a HAT (Rtt109) by its activating subunit Vps75. The rate-determining step of the activated complex is the transfer of the acetyl group from acetyl CoA to the acceptor lysine residue. Vps75 stimulates catalysis (> 250-fold), not by contributing a catalytic base, but by stabilizing the catalytically active conformation of Rtt109. To provide structural insight into the functional complex, we produced a molecular model of Rtt109-Vps75 based on X-ray diffraction of crystals of the complex. This model reveals distinct negative electrostatic surfaces on an Rtt109 molecule that interface with complementary electropositive ends of a symmetrical Vps75 dimer. Rtt109 variants with interface point substitutions lack the ability to be fully activated by Vps75, and one such variant displayed impaired Vps75-dependent histone acetylation functions in yeast, yet these variants showed no adverse effect on Asf1-dependent Rtt109 activities in vitro and in vivo. Finally, we provide evidence for a molecular model in which a 12 complex of Rtt109-Vps75 acetylates a heterodimer of H3-H4. The activation mechanism of Rtt109-Vps75 provides a valuable framework for understanding the molecular regulation of HATs within multisubunit complexes.


Dose-response trend tests for tumorigenesis adjusted for differences in survival and body weight across doses.
A relationship between rodent body weight and tumor incidence for some tissue/organ sites has been demonstrated in many studies. It is not uncommon for a chemical tested for carcinogenicity to also affect body weight due to toxicity and/or food consumption. In such cases, comparisons of tumor incidence may be biased by body weight differences across dose groups. A simple procedure was investigated for reducing this bias. This procedure divides the animals into a few groups on the basis of body weight. Body weight at 12 months was used, before the appearance of a tumor was likely to affect body weight. Statistics for dose-response trend tests are calculated within body weight strata and pooled to obtain an overall dose-response trend test. This procedure is analogous to stratifying animals on the basis of age at the time of removal from a study to account for differences in ages of animals across dose groups that can affect comparisons of tumor incidence. In this paper, differences in survival times of animals were adjusted by the Poly-3 technique used by the National Toxicology Program. This technique does not require the assignment of cause of death. Several examples from rodent chronic bioassays were investigated, where the high dose group had reduced body weights and associated reductions in tumor incidence. When we analyzed the data by body weight strata, some positive dose-response trends for tumor incidence were demonstrated. In one case, the body weight adjusted analysis indicated that a negative dose-response trend in tumor incidence was a real effect in addition to a body weight reduction. These examples indicate that it is important to consider the effects of body weight changes as low as 10%, and perhaps less, as possibly being caused by chemicals in 2-year bioassays for carcinogenesis. The simple procedure of analyzing tumor incidence within body weight strata can reduce the bias introduced by body weight differences across dose groups.


Impact of non-native terrestrial mammals on the structure of the terrestrial mammal food web of Newfoundland, Canada.
The island of Newfoundland is unique because it has as many non-native terrestrial mammals as native ones. The impacts of non-native species on native flora and fauna can be profound and invasive species have been identified as one of the primary drivers of species extinction. Few studies, however, have investigated the effects of a non-native species assemblage on community and ecosystem properties. We reviewed the literature to build the first terrestrial mammal food web for the island of Newfoundland and then used network analyses to investigate how the timing of introductions and trophic position of non-native species has affected the structure of the terrestrial mammal food web in Newfoundland. The first non-native mammals (house mouse and brown rat) became established in Newfoundland with human settlement in the late 15th and early 16th centuries. Coyotes and southern red-backed voles are the most recent mammals to establish themselves on the island in 1985 and 1998, respectively. The fraction of intermediate species increased with the addition of non-native mammals over time whereas the fraction of basal and top species declined over time. This increase in intermediate species mediated by non-native species arrivals led to an overall increase in the terrestrial mammal food web connectance and generality (i.e. mean number of prey per predator). This diverse prey base and sources of carrion may have facilitated the natural establishment of coyotes on the island. Also, there is some evidence that the introduction of non-native prey species such as the southern red-backed vole has contributed to the recovery of the threatened American marten. Long-term monitoring of the food web is required to understand and predict the impacts of the diverse novel interactions that are developing in the terrestrial mammal food web of Newfoundland.


Some biological actions of alkylglycerols from shark liver oil.
Shark liver oil has been used for over 40 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkylglycerols. Initial clinical use was for treating leukemias, and later to prevent radiation sickness from cancer x-ray therapy. Studies over the last 30 years have shown that alkylglycerols are multifunctional. The level of natural alkylglycerols rises within tumor cells, apparently in an effort to control cell growth. Recent studies indicate that the activation of protein kinase C, an essential step in cell proliferation, can be inhibited by alkylglycerols. This action suggests a competitive inhibition of 1.2-diacylglycerol by alkylglycerols. Further studies on the immunostimulatory action of alkylglycerols suggest a primary action on the macrophage. The process of macrophage activation has been demonstrated with both synthetic and natural alkylglycerols. While the exact mechanism has not been found, both an autocrine and paracrine system have been suggested. Shark liver is a major natural source of alkylglycerols, which have no known side effects in dosages of 100 mg three times a day. The information presented in this article suggests that alkylglycerols may be used both as an adjunct therapy in the treatment of neoplastic disorders and as an immune booster in infectious diseases.


Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis.
Recently, chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). This interaction led us to analyze the frequencies of sequence variants of the CHGB gene in ALS patients and matched controls from three different countries. Of particular interest was the finding of the P413L CHGB variant present in 10% of ALS patients (n = 705) as compared to 4.5% in controls (n = 751), conferring a 2.2-fold greater relative risk to develop the disease (P < 0.0001). This effect was mainly contributed by the samples of French origin that yielded a frequency of the P413L variation at 17% in ALS (n = 289) and 5% in controls (n = 448), conferring a 3.3-fold greater risk to develop ALS. Furthermore, the P413L CHGB variant is associated with an earlier age of onset by almost a decade in both sporadic ALS and familial ALS cases. Genetic variation influencing age of onset in ALS had not previously been reported. Expression of fusion CHGB-EGFP constructs in SHSY-5Y cells revealed that the P413L variation can cause defective sorting of CHGB into secretory granules. The finding that CHGB may act as a susceptibility gene and modifier of onset in ALS is consistent with the emerging view that dysfunction of the secretory pathway may contribute to increased vulnerability of motor neurons.


Break-induced loss of heterozygosity in fission yeast: dual roles for homologous recombination in promoting translocations and preventing de novo telomere addition.
Loss of heterozygosity (LOH), a causal event in tumorigenesis, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms leading to such extensive LOH are poorly understood. We investigated the mechanisms of DNA double-strand break (DSB)-induced extensive LOH by screening for auxotrophic marker loss approximately 25 kb distal to an HO endonuclease break site within a nonessential minichromosome in Schizosaccharomyces pombe. Extensive break-induced LOH was infrequent, resulting from large translocations through both allelic crossovers and break-induced replication. These events required the homologous recombination (HR) genes rad32(+), rad50(+), nbs1(+), rhp51(+), rad22(+), rhp55(+), rhp54(+), and mus81(+). Surprisingly, LOH was still observed in HR mutants, which resulted predominantly from de novo telomere addition at the break site. De novo telomere addition was most frequently observed in rad22Delta and rhp55Delta backgrounds, which disrupt HR following end resection. Further, levels of de novo telomere addition, while increased in ku70Delta rhp55Delta strains, were reduced in exo1Delta rhp55Delta and an rhp55Delta strain overexpressing rhp51. These findings support a model in which HR prevents de novo telomere addition at DSBs by competing for resected ends. Together, these results suggest that the mechanisms of break-induced LOH may be predicted from the functional status of the HR machinery.


Three-dimensional structural model analysis of the binding site of lithocholic acid, an inhibitor of DNA polymerase beta and DNA topoisomerase II.
The molecular action of lithocholic acid (LCA), a selective inhibitor of mammalian DNA polymerase beta (pol beta), was investigated. We found that LCA could also strongly inhibit the activity of human DNA topoisomerase II (topo II). No other DNA metabolic enzymes tested were affected by LCA. Therefore, LCA should be classified as an inhibitor of both pol beta and topo II. Here, we report the molecular interaction of LCA with pol beta and topo II. By three-dimensional structural model analysis and by comparison with the spatial positioning of specific amino acids binding to LCA on pol beta (Lys60, Leu77, and Thr79), we obtained supplementary information that allowed us to build a structural model of topo II. Modeling analysis revealed that the LCA-interaction interface in both enzymes has a pocket comprised of three amino acids in common, which binds to the LCA molecule. In topo II, the three amino acid residues were Lys720, Leu760, and Thr791. These results suggested that the LCA binding domains of pol beta and topo II are three-dimensionally very similar.


Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis.
Conceptual reasoning deficits are common in patients with multiple sclerosis (MS) and are typically associated with focal lesions involving the frontal lobes. In this study, we predicted that MS patients with frontal white matter lesions (MS-F) would be more impaired on a standard conceptual reasoning task (Wisconsin Card Sorting Test; WCST) than patients with minimal frontal lesions (MS-NF), even if the total cerebral lesion area (TLA), measured from MRI, was equivalent across groups. We subdivided 43 definite MS patients into three groups based on MRI findings: seven in the MS-F group (mean TLA = 41.4 cm2) and seven in the MS-NF group (mean TLA = 50.0 cm2); 29 MS patients served as a low lesion burden control group (MS-C; mean TLA = 6.4 cm2). The groups did not differ with regard to demographic and illness characteristics. Although the three subgroups obtained comparable scores on a measure of global cognitive functioning (verbal intelligence), the MS-F group achieved significantly fewer categories and made more total errors on the WCST than did the MS-NF and MS-C groups. The MS-F group made significantly more perseverative responses than the MS-C group and nonsignificantly more than the MS-NF group. These results suggest that the pattern of cognitive decline in MS is a function of the location of demyelinating lesions within the cerebral hemispheric white matter. Finally, we supplement the group study results with a case report of an MS patient who was studied serially with MRI and cognitive testing.


High energy density in PVDF nanocomposites using an optimized nanowire array.
TiO2 nanowire arrays are often utilized to prepare high performance polymer nanocomposites, however, the contribution to the energy density is limited due to their non-ferroelectric characteristics. A nanocomposite with an optimized nanowire array combining the ferroelectric properties of lead zirconate titanate (PZT) with TiO2, readily forming nanowires (denoted as a TiO2-P nanowire array), is prepared to enhance the permittivity. Poly(vinylidene fluoride) (PVDF) is used as the polymer matrix due to its high breakdown strength, e.g. 600-700 kV mm-1. As a result, the permittivity and breakdown electric field reach 53 at 1 kHz and 550 kV mm-1, respectively. Therefore, the nanocomposites achieve a higher discharge energy density of 12.4 J cm-3 with excellent cycle stability, which is the highest among nanocomposites based on a nanowire array as a filler in a PVDF matrix. This work provides not only a feasible approach to obtain high performance dielectric nanocomposites, but also a wide range of potential applications in the energy storage and energy harvesting fields.


Gender disparities in scientific production: A nationwide assessment among physicians in Peru.
To determine the presence of a gender gap in the scientific production among Peruvian physicians and analyze either gap is associated with the presence of observable factors or the presence of prejudices against female physicians. We analyzed data from the National Survey of User Satisfaction in Health 2016, a nationally representative survey that collected information about medical professionals working in health institutions in Peru. The outcome of interest was the number of publications in indexed journals. We estimated the gender gap in scientific production using the Oaxaca-Blinder (OB) decomposition method. From the 2216 physicians surveyed, 252 reported published at least one article in an indexed journal. From physicians with scientific production, 37.7% were women. The analysis of OB decomposition showed a gap of 2.11 indexed publications, disfavoring female physicians (p<0.01). Likewise, the explained component was 1.36 publications, representing 64.5% of the total gap (p<0.05). There is a gender gap in the number of publications in indexed journals among Peruvian physicians. This gap is mainly explained by observable factors, such as the years of medical practice, being an accredited researcher and being a professor.


Cortico-pontine theta synchronization phase shift following monoaminergic lesion in rat.
The experiments were performed in 14 adult, male Sprague Dawley rats chronically instrumented for sleep recording and recorded during baseline condition, following sham injection (saline i.p. 1 ml/kg), and every week for 5 weeks following injection of the systemic neurotoxins (DSP-4 or PCA; 1 ml/kg, i.p.) for chemical axotomy of the locus coeruleus (LC) and dorsal raphe (DR) axon terminals. In our former study we demonstrated that the systemically induced lesion of the noradrenergic or serotonergic axon terminals did not affect the sleep-wake distribution from control condition. In this study, by using spectral analysis and phase shift spectra of the cortical and pontine EEG we analyzed cortico-pontine theta oscillation synchronization phase shift on 6-hour recordings in control condition and 28 days following the monoaminergic lesions, as a time for permanently established DR or LC chemical axotomy. Our results demonstrated for the first time that chronically decreased brain monoamines in freely moving rats changed cortico-pontine theta synchronization phase shift. Pons became a leading theta oscillator. We assume that deficit of monoamines induced predominance of the NREM/REM transitions, characterized with phasic theta oscillations (the increased density of clustered P waves which intrinsic frequency corresponds to theta frequency oscillations), and may produced preceding phasic theta versus tonic theta oscillation drive.


Differential Valuation and Learning From Social and Nonsocial Cues in Borderline Personality Disorder.
Volatile interpersonal relationships are a core feature of borderline personality disorder (BPD) and lead to devastating disruption of patients' personal and professional lives. Quantitative models of social decision making and learning hold promise for defining the underlying mechanisms of this problem. In this study, we tested BPD and control subject weighting of social versus nonsocial information and their learning about choices under stable and volatile conditions. We compared behavior using quantitative models. Subjects (n = 20 BPD, n = 23 control subjects) played an extended reward learning task with a partner (confederate) that requires learning about nonsocial and social cue reward probability (the social valuation task). Task experience was measured using language metrics: explicit emotions/beliefs, talk about the confederate, and implicit distress (using the previously established marker self-referentiality). Subjects' weighting of social and nonsocial cues was tested in mixed-effect regression models. Subjects' learning rates under stable and volatile conditions were modeled (Rescorla-Wagner approach) and group × condition interactions tested. Compared to control subjects, BPD subject debriefings included more mentions of the confederate and less distress language. BPD subjects also weighted social cues more heavily but had blunted learning responses to (nonsocial and social) volatility. This is the first report of patient behavior in the social valuation task. The results suggest that BPD subjects expect higher volatility than control subjects. These findings lay the groundwork for a neurocomputational dissection of social and nonsocial belief updating in BPD, which holds promise for the development of novel clinical interventions that more directly target pathophysiology.


Observation of chemically protected polydimethylsiloxane: towards crack-free PDMS.
The current modification of polydimethylsiloxane (PDMS) substrates via oxygen plasma treatment causes surface cracks. Here, we demonstrate a method to prevent crack formation by chemical treatment. Chemical modification renders the surface hydrophilic for several days and is effective in preserving the elasticity of the PDMS surface at the nanoscale level.


New Roadmap for the Journey From Internist to Rheumatologist.
Measurement is necessary to gauge improvement. US training programs have not previously used shared standards to assess trainees' mastery of the knowledge, skills, and attitudes necessary to practice rheumatology competently. In 2014, the Accreditation Council for Graduate Medical Education (ACGME) Next Accreditation System began requiring semiannual evaluation of all medicine subspecialty fellows on 23 internal medicine subspecialty reporting milestones. Since these reporting milestones are not subspecialty specific, rheumatology curricular milestones were needed to guide rheumatology fellowship training programs and fellows on the training journey from internist to rheumatologist. Rheumatology curricular milestones were collaboratively composed by expanding the internal medicine reporting milestones to delineate the specific targets of rheumatology fellowship training within 6 ACGME core competencies. The 2006 American College of Rheumatology core curriculum for rheumatology training programs was updated. A total of 80 rheumatology curricular milestones were created, defining progressive learning through training; most focus on patient care and medical knowledge. The core curriculum update incorporates the new curricular milestones and rheumatology entrustable professional activities. Rheumatology curricular milestones are now available for implementation by rheumatology fellowship training programs, providing a clear roadmap for specific training goals and a guide to track each fellow's achievement over a 2-year training period. The comprehensive core curriculum delineates the essential breadth of knowledge, skills, and attitudes that define rheumatology, and provides a guide for educational activities during fellowship training. These guiding documents are now used to train and assess fellows as they prepare for independent rheumatology practice as the next generation of rheumatologists.


New systematic review methodology for visual impairment and blindness for the 2010 Global Burden of Disease study.
To describe a systematic review of population-based prevalence studies of visual impairment (VI) and blindness worldwide over the past 32 years that informs the Global Burden of Diseases, Injuries and Risk Factors Study. A systematic review (Stage 1) of medical literature from 1 January 1980 to 31 January 2012 identified indexed articles containing data on incidence, prevalence and causes of blindness and VI. Only cross-sectional population-based representative studies were selected from which to extract data for a database of age- and sex-specific data of prevalence of four distance and one near vision loss categories (presenting and best-corrected). Unpublished data and data from studies using rapid assessment methodology were later added (Stage 2). Stage 1 identified 14,908 references, of which 204 articles met the inclusion criteria. Stage 2 added unpublished data from 44 rapid assessment studies and four other surveys. This resulted in a final dataset of 252 articles of 243 studies, of which 238 (98%) reported distance vision loss categories. A total of 37 studies of the final dataset reported prevalence of mild VI and four reported near VI. We report a comprehensive systematic review of over 30 years of VI/blindness studies. While there has been an increase in population-based studies conducted in the 2000s compared to previous decades, there is limited information from certain regions (eg, Central Africa and Central and Eastern Europe, and the Caribbean and Latin America), and younger age groups, and minimal data regarding prevalence of near vision and mild distance VI.


Face recognition/detection by probabilistic decision-based neural network.
This paper proposes a face recognition system, based on probabilistic decision-based neural networks (PDBNN). With technological advance on microelectronic and vision system, high performance automatic techniques on biometric recognition are now becoming economically feasible. Among all the biometric identification methods, face recognition has attracted much attention in recent years because it has potential to be most nonintrusive and user-friendly. The PDBNN face recognition system consists of three modules: First, a face detector finds the location of a human face in an image. Then an eye localizer determines the positions of both eyes in order to generate meaningful feature vectors. The facial region proposed contains eyebrows, eyes, and nose, but excluding mouth (eye-glasses will be allowed). Lastly, the third module is a face recognizer. The PDBNN can be effectively applied to all the three modules. It adopts a hierarchical network structures with nonlinear basis functions and a competitive credit-assignment scheme. The paper demonstrates a successful application of PDBNN to face recognition applications on two public (FERET and ORL) and one in-house (SCR) databases. Regarding the performance, experimental results on three different databases such as recognition accuracies as well as false rejection and false acceptance rates are elaborated. As to the processing speed, the whole recognition process (including PDBNN processing for eye localization, feature extraction, and classification) consumes approximately one second on Sparc10, without using hardware accelerator or co-processor.


A double-blind placebo-controlled trial of paroxetine in the management of social phobia (social anxiety disorder) in South Africa.
Social phobia, also known as social anxiety disorder, is a highly prevalent disorder with significant morbidity. Patients with social phobia frequently develop co-morbid psychiatric disorders such as depression and substance abuse, and the disorder impacts significantly on social and occupational functioning. It has been suggested that the selective serotonin reuptake inhibitors (SSRIs) are useful in the management of this disorder, but few controlled trials have been undertaken in this regard. There are also few data on the pharmacotherapy of social phobia in South Africa. A double-blind randomised placebo-controlled multi-site flexible-dose trial of paroxetine was undertaken over 12 weeks among patients with a primary diagnosis of social phobia. Primary response measures were the Global Improvement item on the Clinical Global Impression scale (CGI) and mean change from baseline in the patient-rated Liebowitz Social Anxiety Scale (LSAS) total score. Ninety-three patients participated at 9 South African sites; their data are reported here. There was a significant drug effect on both the CGI Global Improvement score and the LSAS at 12 weeks. In addition, there was no significant difference in overall rate of adverse experiences between those on paroxetine and those on placebo. Paroxetine is both effective and safe in the acute treatment of social phobia. The findings here are consistent with those of previous controlled studies of the SSRIs as well as with previous work done in the USA on the use of paroxetine in the treatment of this disorder. Early diagnosis and treatment of social phobia should be encouraged. However, further research on long-term pharmacotherapy of social phobia is needed.


Investigation on the Collection and Economy of Medicinal Leeches from Wetlands Around Lake Eğirdir, Turkey.
This study aimed to investigate the collection and economy of medicinal leeches from wetlands around Lake Eğirdir, Turkey. Data used in this study were based on findings, observations, and face-to-face interviews obtained from a research performed between January 2013 - February 2016 on medicinal leech populations. The leech collecting is carried out without any permission, by both local peoples and others especially who are from Afyonkarahisar. This causes legal problems among leech collectors. Leech collecting is not done as main job. Using small leeches (<1.5 g) that have not reached a mature size for medicinal purposes impacts the collected leech size and their market price. Leeches are sold for 40-1000 TL/kg (1 TL=0.25 €) according to season, product abundance, demand intensity, and leech size. Because of leech collecting is carried out without under an economic organization, there is no effect of leech collectors at determining the sale price of leeches. According to the catchable stock size, the export potential of medicinal leeches is approximately 1,200,000 € from wetlands around Lake Eğirdir. The rational management of medicinal leech populations, socioeconomic benefits, sustainable products, and ecological balance will be provided by operating wetlands around Lake Eğirdir according to stock estimation studies at regular intervals and by evaluating effective marketing options under a cooperative.


Differences in clinical features between laparoscopy and open resection for primary tumor in patients with stage IV colorectal cancer.
To identify differences in clinical features between laparoscopy and open resection for primary tumor in patients with stage IV colorectal cancer. We also evaluated short-term and oncologic outcomes after laparoscopy and open surgery. A total of 100 consecutive stage IV patients undergoing open (n=61) or laparoscopic (n=39) major resection were analyzed. There were four cases (10%) of conversion to laparotomy in the laparoscopy group. Pathological T4 tumors (56% vs 26%), primary colon cancers (74% vs 51%), and larger tumor diameter (6 vs 5 cm) were more commonly managed with open surgery. Right colectomy was more common in the open surgery group (39%) and low anterior resection was more common in the laparoscopy group (39%, P=0.002). Hepatic metastases in segments II, III, IVb, V, and VI were more frequently resected with laparoscopy (100%) than with open surgery (56%), although the difference was not statistically significant. In colon and rectal cancers, mean operative time and 30-day complication rates of laparoscopy and open surgery did not differ. In both cancers, mean time to soft diet and length of hospital stay were shorter in the laparoscopy group. Mean time from surgery to chemotherapy commencement was significantly shorter with laparoscopy than with open surgery. In colon and rectal cancers, 2-year cancer-specific and progression-free survival rates were similar between the laparoscopy and open surgery groups. Based on our findings, laparoscopy can be selected as an initial approach in patients with a primary tumor without adjacent organ invasion and patients without primary tumor-related symptoms. In selected stage IV patients, tumor factors such as primary rectal tumor, peritoneal carcinomatosis, or liver metastasis may not be absolute contraindications for a laparoscopic approach.


Developmental origins of midlife grip strength: findings from a birth cohort study.
There is growing evidence that the prenatal environment has long-term effects on adult grip strength, but little is known about the effects of the postnatal environment. We tested whether prepubertal growth, pubertal growth, or the development of motor and cognitive capabilities was associated with midlife muscle strength independently of other determinants of grip strength. Handgrip strength and body size were measured in a representative British sample of 1406 men and 1444 women 53 years old with prospective childhood data. Normal regression models were used to examine the effects of birth weight, postnatal height and weight gain before 7 years and between 7 and 15 years, motor milestones and cognitive ability on grip strength at age 53, taking account of lifetime social class, current physical activity, and health status. Birth weight and prepubertal height gain were associated with midlife grip strength, independently of later weight and height gain and other determinants. Pubertal growth was also independently associated with midlife grip strength; for men weight gain during puberty was beneficial, whereas for women it was height gain. Those participants with earlier infant motor development had better midlife grip strength, which was partly confounded by the growth trajectory. This study showed that components of prenatal, prepubertal, and pubertal growth have long-term effects on midlife grip strength. To the extent that these associations are modifiable, interventions in childhood that help to build muscle mass and strength, such as increased physical exercise, may have long-term beneficial effects on adult muscle strength and may help to prevent sarcopenia, disability, and frailty in later life.


Combinatorial mapping of substrate step edge effects on diblock copolymer thin film morphology and orientation.
We have used a combinatorial gradient technique to map precisely how the terrace structure and microdomain lattice alignment in a thin film of a sphere-forming diblock copolymer are affected by both the thickness of the copolymer film and the height of a series of parallel step edges fabricated on the substrate. We find that for film thicknesses slightly incommensurate with integer numbers of sphere layers, the step edges act as nucleation sites for regions with one more or one fewer layers of spheres. We also find that for our system, the hexagonal lattice formed by a single layer of spheres on the low side of a step edge is aligned along the direction of the step edge only where the film on the high side is sufficiently thin to support only a wetting layer of copolymer material. This work will guide the tuning of film thickness and step height in future studies and applications of graphoepitaxy in block copolymer films.


Large and small fibre type sensory dysfunction in patients with cancer.
Quantitative sensory testing was used to assess the prevalence of sensory dysfunction in patients with cancer, carefully screened for other risk factors for neuropathy. Large fibre type sensory function was evaluated using vibration threshold (VT) determinations while small fibre type sensory function was assessed by thermal threshold (TT) determinations. Mean VT and TT were significantly elevated in the toes but not the fingers of cancer patients. VT elevations in the toes occurred in 31% of cancer patients and in 6% of control subjects. TT elevations in the toes occurred in 43% of cancer patients and 4% of control subjects. Based on these findings it is concluded that large and small fibre type sensory dysfunction is much more common in carefully screened cancer patients than in control subjects. This sensory dysfunction is most likely to represent a neuropathy related directly or indirectly associated with cancer.


Compressive SD-OCT: the application of compressed sensing in spectral domain optical coherence tomography.
We applied compressed sensing (CS) to spectral domain optical coherence tomography (SD OCT) and studied its effectiveness. We tested the CS reconstruction by randomly undersampling the k-space SD OCT signal. We achieved this by applying pseudo-random masks to sample 62.5%, 50%, and 37.5% of the CCD camera pixels. OCT images are reconstructed by solving an optimization problem that minimizes the l(1) norm of a transformed image to enforce sparsity, subject to data consistency constraints. CS could allow an array detector with fewer pixels to reconstruct high resolution OCT images while reducing the total amount of data required to process the images.


Direct, noncatalytic mechanism of IKK inhibition by A20.
A20 is a potent anti-inflammatory protein that inhibits NF-κB, and A20 dysfunction is associated with autoimmunity and B cell lymphoma. A20 harbors a deubiquitination enzyme domain and can employ multiple mechanisms to antagonize ubiquitination upstream of NEMO, a regulatory subunit of the IκB kinase complex (IKK). However, direct evidence of IKK inhibition by A20 is lacking, and the inhibitory mechanism remains poorly understood. Here we show that A20 can directly impair IKK activation without deubiquitination or impairment of ubiquitination enzymes. We find that polyubiquitin binding by A20, which is largely dependent on A20's seventh zinc-finger motif (ZnF7), induces specific binding to NEMO. Remarkably, this ubiquitin-induced recruitment of A20 to NEMO is sufficient to block IKK phosphorylation by its upstream kinase TAK1. Our results suggest a noncatalytic mechanism of IKK inhibition by A20 and a means by which polyubiquitin chains can specify a signaling outcome.


The Therapeutic Potential of Cannabinoids in Dermatology
Cannabinoids have demonstrated utility in the management of cancer, obesity, and neurologic disease. More recently, their immunosuppressive and anti-inflammatory properties have been identified for the treatment of several dermatologic conditions. This review thus assesses the therapeutic potential of phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids in the management of cutaneous disease. The PubMed® and Scopus® databases were subsequently reviewed in December 2017 using MeSH and keywords, such as cannabinoid, THC, dermatitis, pruritus, and skin cancer. The search yielded reports on the therapeutic role of cannabinoids in the management of skin cancer, acne vulgaris, pruritus, atopic and allergic contact dermatitis, and systemic sclerosis. While cannabinoids have exhibited efficacy in the treatment of inflammatory and neoplastic skin conditions, several reports suggest pro-inflammatory and pro-neoplastic properties. Further investigation is necessary to understand the complexities of cannabinoids and their therapeutic potential in dermatology.


The coordination of bimanual prehension movements in a centrally deafferented patient.
Many everyday tasks require that we use our hands co-operatively, for example, when unscrewing a jar. For tasks where both hands are required to perform the same action, a common motor programme can be used. However, where each hand needs to perform a different action, some degree of independent control of each hand is required. We examined the coordination of bimanual movement kinematics in a female patient recovering from a cerebrovascular accident involving anterior regions of the parietal lobe of the right hemisphere, which resulted in a dense hemianaesthesia of her left arm. Our results indicate that unimanual movements executed by our patient using her non-sensate hand are relatively unimpaired. In contrast, during bimanual movements, reaches executed by our patient using her non-sensate hand show gross directional errors and spatiotemporal irregularities, including the inappropriate coupling of movement velocities. These data are discussed with reference to the role played by limb proprioception in the planning and control of prehension movements.


IpgB1 and IpgB2, two homologous effectors secreted via the Mxi-Spa type III secretion apparatus, cooperate to mediate polarized cell invasion and inflammatory potential of Shigella flexenri.
Type III secretion systems (T3SS) are present in many pathogenic gram-negative bacteria and mediate the translocation of bacterial effector proteins into host cells. Here, we report the phenotypic characterization of S. flexneri ipgB1 and ipgB2 mutants, in which the genes encoding the IpgB1 and IpgB2 effectors have been inactivated, either independently or simultaneously. Like IpgB1, we found that IpgB2 is secreted by the T3SS and its secretion requires the Spa15 chaperone. Upon infection of semi-confluent HeLa cells, the ipgB2 mutant exhibited the same invasive capacity as the wild-type strain and the ipgB1 mutant was 50% less invasive. Upon infection of polarised Caco2-cells, the ipgB2 mutant did not show a significant defect in invasion and the ipgB1 mutant was slightly more invasive than the wild-type strain. Entry of the ipgB1 ipgB2 mutant in polarized cells was reduced by 70% compared to the wild-type strain. Upon infection of the cornea in Guinea pigs, the ipgB2 mutant exhibited a wild-type phenotype, the ipgB1 mutant was hypervirulent and elicited a more pronounced proinflammatory response, while the ipgB1 ipgB2 mutant was highly attenuated. The attenuated phenotype of the ipgB1 ipgB2 mutant was confirmed using a murine pulmonary model of infection and histopathology and immunochemistry studies.


Enantioselectivity of bunitrolol 4-hydroxylation is reversed by the change of an amino acid residue from valine to methionine at position 374 of cytochrome P450-2D6.
The enantioselectivity of 4-hydroxylation of bunitrolol (BTL), a beta-adrenoceptor blocking drug, was studied in microsomes from human liver, human hepatoma (Hep G2) cells expressing CYP2D6, and lymphoblastoid cells expressing CYP2D6. Kinetics in human liver microsomes showed that the Vmax value for (+)-BTL was 2.1-fold that of (-)-BTL, and that the Km value for (+)-BTL was lower than that for the (-)-antipode, resulting in the intrinsic clearance (Vmax/Km) of (+)-BTL being 2.1-fold over its (-)-antipode. CYP2D6 (CYP2D6-met) expressed in Hep G2 cells had a methionine residue at position 373 of the amino acid sequence and a rat-type N-terminal peptide (MELLNGTGLWSM) instead of the human-type (MGLEALVPLAVIV), and showed enantioselectivity of [(+)-BTL < (-)-BTL] for the rate of BTL 4-hydroxylation. In contrast, enantioselectivity [(+)-BTL > (-)-BTL] for Hep G2-CYP2D6 (CYP2D6-val) with a human-type N-terminal peptide that had a valine residue at 374, which corresponds to the methionine of the CYP2D6-met variant, was the same as that for human liver microsomes. We further confirmed that CYP2D6-met and CYP2D6-val expressed in human lymphoblastoid cells, both of which have methionine and valine, respectively, at position 374 and a human-type N-terminal peptide, exhibited the same enantioselectivities as those obtained from CYP2D6-met and CYP2D6-val expressed in the Hep G2 cell system. These results indicate that the amino acid at 374 of CYP2D6 is one of the key factors influencing the enantioselectivity of BTL 4-hydroxylation.


In vivo production, stabilization, and infectivity of baculovirus preoccluded virions.
Wild-type and polyhedrin-negative isolates of Autographa californica nuclear polyhedrosis virus were replicated in fifth-instar Trichoplusia ni larvae. Insect tissues infected with wild-type virus contained two types of virions that are highly infectious when ingested, those occluded in polyhedra and preoccluded virions. Tissue infected with the polyhedrin-negative virus contained only preoccluded virions. The relative potencies of the two types of infected tissue were determined by dose-mortality bioassays by using the neonate droplet feeding procedure. On a fresh weight basis, preparations of tissues infected with the polyhedrin-negative virus were approximately four times more potent than equivalent preparations of tissue infected with wild-type virus. Approximately half of the observed potency of the wild-type-virus preparations was due to polyhedra, and the remaining activity was due to preoccluded virions present in the tissue. The potency of the polyhedrin-negative preparations was not reduced significantly by lyophilization. The polyhedrin-negative isolate produced about 60% more infectious virus per unit of larval weight than did the wild-type isolate. The ability to produce large amounts of high-potency viral preparations in larvae and the convenience of being able to lyophilize the preparations for long-term storage shows promise for the use of preoccluded virus preparations as biopesticides.


Pandemic effects in the Solow growth model.
We show how diseases can affect economic growth in a Solow growth model, with population growth and no technical progress, but modified to include a saving rate that depends on the individual health status. We successively insert this model into the SIS (susceptible-infected-susceptible) and SIR (susceptible-infected-recovered) models of disease spreading. In these two models, the spread of the infection proceeds according to the so-called basic reproductive number. This number determines in which of the two possible equilibria, the disease-free or the pandemic equilibrium, the economy ends. We show that output per capita is always lower in the pandemic steady state, which implies a contraction in the economy's production possibilities frontier.


Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis.
Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).


Nonallergic rhinitis with eosinophilia syndrome.
Nonallergic rhinitis with eosinophilia syndrome (NARES) is a clinical syndrome comprising symptoms consistent with allergic rhinitis in which an absence of atopy has been demonstrated by allergen skin testing, and nasal cytology analysis demonstrates more than 20% eosinophils. Anosmia is a prominent feature not shared with allergic rhinitis. The pathophysiology of NARES is poorly understood, but a key component involves a self-perpetuating, chronic eosinophilic nasal inflammation with development of nasal micropolyposis and polyposis. Mast cells likely play an important role as well. NARES is a risk factor for the development of nasal polyposis and aspirin sensitivity, as well as obstructive sleep apnea. Treatment consists mainly of intranasal corticosteroids with or without the addition of second-generation antihistamines and/or leukotriene-receptor antagonists.


Conscious access in the near absence of attention: critical extensions on the dual-task paradigm.
Whether conscious perception requires attention remains a topic of intense debate. While certain complex stimuli such as faces and animals can be discriminated outside the focus of spatial attention, many simpler stimuli cannot. Because such evidence was obtained in dual-task paradigms involving no measure of subjective insight, it remains unclear whether accurate discrimination of unattended complex stimuli is the product of automatic, unconscious processing, as in blindsight, or is accessible to consciousness. Furthermore, these paradigms typically require extensive training over many hours, bringing into question whether this phenomenon can be achieved in naive subjects. We developed a novel dual-task paradigm incorporating confidence ratings to calculate metacognition and adaptive staircase procedures to reduce training. With minimal training, subjects were able to discriminate face-gender in the near absence of top-down attentional amplification, while also displaying above-chance metacognitive accuracy. By contrast, the discrimination of simple coloured discs was significantly impaired and metacognitive accuracy dropped to chance-level, even in a partial-report condition. In a final experiment, we used blended face/disc stimuli and confirmed that face-gender but not colour orientation can be discriminated in the dual task. Our results show direct evidence for metacognitive conscious access in the near absence of attention for complex, but not simple, stimuli.This article is part of the theme issue 'Perceptual consciousness and cognitive access'.


Chlorophyll and carotenoid radicals in photosystem II studied by pulsed ENDOR.
The stable carotenoid cation radical (Car(*+)) and chlorophyll cation radical (Chl(Z)(*+)) in photosystem II (PS II) have been studied by pulsed electron nuclear double resonance (ENDOR) spectroscopy. The spectra were essentially the same for oxygen-evolving PS II and Mn-depleted PS II. The radicals were generated by illumination given at low temperatures, and the ENDOR spectra were attributed to Car(*)(+) and Chl(Z)(*+) on the basis of their characteristic behavior with temperature as demonstrated earlier [Hanley et al. (1999) Biochemistry 38, 8189-8195]: i.e., (a) the Car(*)(+) alone was generated by illumination at < or =20 K, while Chl(Z)(*+) alone was generated at 200 K, and (b) warming of the sample containing the Car(*+) to 200 K resulted in the loss of the signal attributable to Car(*+) and its replacement by a spectrum attributable to the Chl(Z)(*+). A map of the hyperfine structure of Car(*+) in PS II and in organic solvent was obtained. The largest observed hyperfine splitting for Car(*+) in either environment was in the order of 8-9 MHz. Thus, the spin density on the cation is proposed to be delocalized over the carotenoid molecule. The pulsed ENDOR spectrum of Chl(Z)(*)(+) was compared to that obtained from a Chl a cation in frozen organic solvent. The hyperfine coupling constants attributed to the beta-protons at position 17 and 18 are well resolved from Chl(Z)(*+) in PS II (10. 8 and 14.9 MHz) but not in Chl a(*+) in organic solvent (12.5 MHz). This suggests a more defined conformation of ring IV with respect to the rest of the tetrapyrrole ring plane of Chl(Z)(*+) than Chl a(*+) probably induced by the protein matrix.


Transforming growth factor-beta 1 induces vascular endothelial growth factor expression in murine proximal tubular epithelial cells.
Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that promotes angiogenesis, vasculogenesis, and increases vascular permeability. VEGF is expressed in renal tubular epithelial cells and urinary VEGF excretion is increased in various glomerular disorders. However, the mechanisms underlying expression of VEGF in renal tubular epithelial cells have not been fully elucidated. In the present study, we attempted to define a predominant regulator of VEGF expression using a cultured murine renal proximal tubular epithelial cell line (mProx24). VEGF protein concentration in the culture supernatant was measured by sandwich enzyme-linked immunosorbent assay. mProx24 constitutively produced VEGF at low level. Major isoforms expressed in this cell line were VEGF164 and VEGF120 determined by reverse transcription-polymerase chain reaction method. Among various stimuli including angiotensin II, transforming growth factor-beta1 (TGF-beta1), lipopolysaccharides, interleukin-1beta, interleukin-10 and interferon-gamma, only TGF-beta1 significantly increased the level of VEGF protein at 24 h in a dose-dependent manner. The steady-state mRNA level of VEGF was dose dependently increased by TGF-beta1 detected by Northern blotting. Treatment with neutralizing anti-TGF-beta1 antibody abolished TGF-beta1-induced VEGF expression by 70%. Inhibitors of protein kinase C (PKC), Ro-31-8220 and staurosporin, significantly suppressed TGF-beta1-induced VEGF protein expression. These results demonstrate the role of TGF-beta1 on the expression of VEGF in proximal tubular epithelial cells mediated potentially via PKC pathway. This regulatory mechanism may be associated with the progression of tubulointerstitial lesions in renal disorders.


Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs.
Multiple sclerosis is considered to be initiated by a deregulated, myelin-specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow-derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin-specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease.


Systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions.
Melanoma is a cancer of the skin and is increasing in incidence in the UK and Europe. Melanoma is a condition that is often curable if detected at an early stage, which makes accurate diagnosis vital. Reflectance confocal microscopy (RCM) is a tool used to image the skin. It gives high magnification images of the skin, which may provide more accurate diagnosis of lesions that are equivocal on clinical examination and dermoscopy. To determine the diagnostic accuracy of reflectance confocal microscopy (RCM), for melanoma diagnosis, as an add-on test to clinical examination and dermoscopy in the diagnosis of equivocal pigmented skin lesions using histopathology as the reference standard. A search was conducted of MEDLINE, EMBASE and six other electronic databases from inception to present. Forward citation searching and hand searching of reference lists were also conducted. Diagnostic accuracy studies that assess RCM in the diagnosis of melanoma were included in the review. Two contributors conducted the search, data extraction and assessment of methodological quality using QUADAS-2. Statistical analysis was performed using hierarchical bivariate random effects meta-analysis. 951 titles and abstracts were screened. Five studies comprising 909 lesions were eligible for meta-analysis. Meta-analysis returned a per lesion sensitivity of 93% [95% CI 89-96] and a specificity of 76% [95% CI 68-83]. The utility of reflectance confocal microscopy (RCM) as an add-on test for the diagnosis of melanoma depends on the trade off between over-excising benign lesions and misdiagnosing melanoma as benign. This becomes important when considering lesions on surgically difficult or cosmetically important areas of the body.


Challenges of the information age: the impact of false discovery on pathway identification.
Pathways with members that have known relevance to a disease are used to support hypotheses generated from analyses of gene expression and proteomic studies. Using cancer as an example, the pitfalls of searching pathways databases as support for genes and proteins that could represent false discoveries are explored. The frequency with which networks could be generated from 100 instances each of randomly selected five and ten genes sets as input to MetaCore, a commercial pathways database, was measured. A PubMed search enumerated cancer-related literature published for any gene in the networks. Using three, two, and one maximum intervening step between input genes to populate the network, networks were generated with frequencies of 97%, 77%, and 7% using ten gene sets and 73%, 27%, and 1% using five gene sets. PubMed reported an average of 4225 cancer-related articles per network gene. This can be attributed to the richly populated pathways databases and the interest in the molecular basis of cancer. As information sources become enriched, they are more likely to generate plausible mechanisms for false discoveries.


3D-Reconstructions and Virtual 4D-Visualization to Study Metamorphic Brain Development in the Sphinx Moth Manduca Sexta.
DURING METAMORPHOSIS, THE TRANSITION FROM THE LARVA TO THE ADULT, THE INSECT BRAIN UNDERGOES CONSIDERABLE REMODELING: new neurons are integrated while larval neurons are remodeled or eliminated. One well acknowledged model to study metamorphic brain development is the sphinx moth Manduca sexta. To further understand mechanisms involved in the metamorphic transition of the brain we generated a 3D standard brain based on selected brain areas of adult females and 3D reconstructed the same areas during defined stages of pupal development. Selected brain areas include for example mushroom bodies, central complex, antennal- and optic lobes. With this approach we eventually want to quantify developmental changes in neuropilar architecture, but also quantify changes in the neuronal complement and monitor the development of selected neuronal populations. Furthermore, we used a modeling software (Cinema 4D) to create a virtual 4D brain, morphing through its developmental stages. Thus the didactical advantages of 3D visualization are expanded to better comprehend complex processes of neuropil formation and remodeling during development. To obtain datasets of the M. sexta brain areas, we stained whole brains with an antiserum against the synaptic vesicle protein synapsin. Such labeled brains were then scanned with a confocal laser scanning microscope and selected neuropils were reconstructed with the 3D software AMIRA 4.1.


Immunotherapy with biochemically dissociated fractions of Propionibacterium acnes in a murine ovarian cancer model.
The antitumor effect of two strains of Propionibacterium acnes (PAI and PAII) and chemically derived fractions from the whole bacterial cell were studied using a murine ovarian teratocarcinoma (MOT) model. When injected i.p. in high doses (700 to 1400 micrograms/mouse), both strains produce survival of a significant proportion of tumor-bearing mice (30 to 90%). On a weight to weight basis, however, PAI was significantly more effective than PAII. PAI and PAII were extracted using pyridine, which yielded four fractions, i.e., pyridine-extracted strains PAI and PAII (PA-PEI and PA-PEII, respectively) which are composed of the cell wall material extracted by pyridine, and the residues of PA-PEI and PA-PEII (PA-RI and PA-RII, respectively) which are composed of the residue material following the chemical extraction. The chemical composition of PA-PEI was different from that of PA-PEII (the latter had proportionately three times as many carbohydrates and one-third of the protein content of the former) and so were their antitumor properties in the MOT model. PA-PEI had markedly reduced antitumor effect when compared to the untreated cell on a per weight basis. Furthermore, curability was only seen when using a high dose (1400 micrograms/mouse). By contrast, the cell wall components extracted by pyridine from PAII (PA-PEII) had powerful antitumor effects, i.e., greater than 50% of mice given 1400-micrograms injections survived. The material contained in PA-PEII was further fractionated on the basis of its organic solubility in chloroform:methanol solvent. The water-soluble and solvent-insoluble fractions retained most of the antitumor effects of PA-PEII, while the water-insoluble and solvent-soluble fractions were only moderately effective, suggesting that the active moiety(ies) was associated with the nonlipid components of this fraction. Both residue fractions (PA-RI and PA-RII) were as effective on a per weight basis in controlling the growth of 10(5) tumor inoculum as were whole untreated cells. However, periodate oxidation of PA-RI resulted in complete loss of its antitumor effects. When surviving mice that had no evidence of tumor persistence following a tumor challenge (10(5) MOT cells) and i.p. treatment with PA were subsequently rechallenged with 10(4) tumor cells, survival was significantly prolonged, as compared to tumor-challenged (10(4) MOT) naive mice. In addition, 10 to 20% of these rechallenged mice had complete eradication of the tumor inoculum (no evidence of disease for greater than 120 days).(ABSTRACT TRUNCATED AT 400 WORDS)


Complication rate and pitfalls of temporary bridging external fixator in periarticular communited fractures.
A second staged operation using temporary bridging external fixation (TBEF) has been widely used in patients with periarticular complex fracture, yet few papers have been published on the related complications. The purpose of this study was to report the complication rate and pitfalls directly related to TBEF through a retrospective study and to suggest some solutions. Fifty-nine cases that were treated by using TBEF were studied among 195 periarticular complex fractures. We retrospectively collected the clinical and radiological data and then the study data was evaluated for 1) cases with unsatisfactory restoration of length, 2) cases with deep infection caused by half pins invading the zone of definitive fixation, and 3) neurovascular injuries related to half pins. Complications were observed in 7/59 cases (11%). Problems related to the achievement of length were observed in one case of distal tibia fracture and 2 cases of distal femur fracture. Half pin related infection was observed in 2 cases of distal femur fracture. Neurovascular injury (medial calcaneal nerve injury in a distal tibia fracture) was observed in 2 cases. Among 7 complications, four were related to using TBEF in distal femur fracture. This is because the abundant leg muscles have strong deforming force and infection might be increased due to frequent irritation by the half pins. TBEF is a simple procedure with several advantages. However, complications might be observed if certain principles are not followed. It is thought that many complications due to TBEF can be reduced if the half pins are not inserted in the zone of injury, restoration of length is fully achieved and the neurovascular characteristics are carefully considered. In particular, much more caution is needed in the distal femur, which has abundant muscles surrounding it.


Bioavailability of catechins from guaraná (Paullinia cupana) and its effect on antioxidant enzymes and other oxidative stress markers in healthy human subjects.
We assessed the effects of guaraná (Paullinia cupana) consumption on plasma catechins, erythrocyte antioxidant enzyme activity (superoxide dismutase, catalase and glutathione peroxidase) and biomarkers of oxidative stress (ex vivo LDL oxidation, plasma total antioxidant status and ORAC, and lymphocyte single cell gel electrophoresis) in healthy overweight subjects. Twelve participants completed a 15-day run-in period followed by a 15-day intervention with a daily intake of 3 g guaraná seed powder containing 90 mg (+)-catechin and 60 mg (-)-epicatechin. Blood samples were taken on the first and last day of the intervention period, fasting and 1 h post-dose. The administration of guaraná increased plasma ORAC, while reducing ex vivo LDL oxidation (only in the first study day) and hydrogen peroxide-induced DNA damage in lymphocytes, at 1 h post-dose. Plasma catechin (0.38 ± 0.12 and 0.44 ± 0.18 nmol mL(-1)), epicatechin (0.59 ± 0.18 and 0.64 ± 0.25 nmol mL(-1)) and their methylated metabolites were observed at 1 h post-dose but were almost negligible after overnight fasting. The activities of catalase (in both study days) and glutathione peroxidase (in the last intervention day) increased at 1 h post-dose. Furthermore, the activity of both enzymes remained higher than the basal levels in overnight-fasting individuals on the last intervention day, suggesting a prolonged effect of guaraná that continues even after plasma catechin clearance. In conclusion, guaraná catechins are bioavailable and contribute to reduce the oxidative stress of clinically healthy individuals, by direct antioxidant action of the absorbed phytochemicals and up-regulation of antioxidant/detoxifying enzymes.


A dynamic causal model of the coupling between pulse stimulation and neural activity.
We present a dynamic causal model that can explain context-dependent changes in neural responses, in the rat barrel cortex, to an electrical whisker stimulation at different frequencies. Neural responses were measured in terms of local field potentials. These were converted into current source density (CSD) data, and the time series of the CSD sink was extracted to provide a time series response train. The model structure consists of three layers (approximating the responses from the brain stem to the thalamus and then the barrel cortex), and the latter two layers contain nonlinearly coupled modules of linear second-order dynamic systems. The interaction of these modules forms a nonlinear regulatory system that determines the temporal structure of the neural response amplitude for the thalamic and cortical layers. The model is based on the measured population dynamics of neurons rather than the dynamics of a single neuron and was evaluated against CSD data from experiments with varying stimulation frequency (1-40 Hz), random pulse trains, and awake and anesthetized animals. The model parameters obtained by optimization for different physiological conditions (anesthetized or awake) were significantly different. Following Friston, Mechelli, Turner, and Price (2000), this work is part of a formal mathematical system currently being developed (Zheng et al., 2005) that links stimulation to the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal through neural activity and hemodynamic variables. The importance of the model described here is that it can be used to invert the hemodynamic measurements of changes in blood flow to estimate the underlying neural activity.


Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.
Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader-Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.


Enhanced structural connectivity within a brain sub-network supporting working memory and engagement processes after cognitive training.
The structural connectome provides relevant information about experience and training-related changes in the brain. Here, we used network-based statistics (NBS) and graph theoretical analyses to study structural changes in the brain as a function of cognitive training. Fifty-six young women were divided in two groups (experimental and control). We assessed their cognitive function before and after completing a working memory intervention using a comprehensive battery that included fluid and crystallized abilities, working memory and attention control, and we also obtained structural MRI images. We acquired and analyzed diffusion-weighted images to reconstruct the anatomical connectome and we computed standardized changes in connectivity as well as group differences across time using NBS. We also compared group differences relying on a variety of graph-theory indices (clustering, characteristic path length, global and local efficiency and strength) for the whole network as well as for the sub-network derived from NBS analyses. Finally, we calculated correlations between these graph indices and training performance as well as the behavioral changes in cognitive function. Our results revealed enhanced connectivity for the training group within one specific network comprised of nodes/regions supporting cognitive processes required by the training (working memory, interference resolution, inhibition, and task engagement). Significant group differences were also observed for strength and global efficiency indices in the sub-network detected by NBS. Therefore, the connectome approach is a valuable method for tracking the effects of cognitive training interventions across specific sub-networks. Moreover, this approach allowsfor the computation of graph theoretical network metricstoquantifythetopological architecture of the brain networkdetected. The observed structural brain changes support the behavioral results reported earlier (see Colom, Román, et al., 2013).


Yoga for Adults with Type 2 Diabetes: A Systematic Review of Controlled Trials.
A growing body of evidence suggests yogic practices may benefit adults with type 2 diabetes (DM2). In this systematic review, we evaluate available evidence from prospective controlled trials regarding the effects of yoga-based programs on specific health outcomes pertinent to DM2 management. To identify qualifying studies, we searched nine databases and scanned bibliographies of relevant review papers and all identified articles. Controlled trials that did not target adults with diabetes, included only adults with type 1 diabetes, were under two-week duration, or did not include quantitative outcome data were excluded. Study quality was evaluated using the PEDro scale. Thirty-three papers reporting findings from 25 controlled trials (13 nonrandomized, 12 randomized) met our inclusion criteria (N = 2170 participants). Collectively, findings suggest that yogic practices may promote significant improvements in several indices of importance in DM2 management, including glycemic control, lipid levels, and body composition. More limited data suggest that yoga may also lower oxidative stress and blood pressure; enhance pulmonary and autonomic function, mood, sleep, and quality of life; and reduce medication use in adults with DM2. However, given the methodological limitations of existing studies, additional high-quality investigations are required to confirm and further elucidate the potential benefits of yoga programs in populations with DM2.


Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects.
Studies in mice suggest that plasma apoM is lowered in hyperinsulinaemic diabetes and that apoM stimulates formation of pre-beta-HDL. Pre-beta-HDL is an acceptor of cellular cholesterol and may be critical for reverse cholesterol transport. Herein, we examined whether patients with type 2 diabetes have reduced plasma apoM and whether apoM is associated with pre-beta-HDL formation and cellular cholesterol efflux. In 78 patients with type 2 diabetes and 89 control subjects, we measured plasma apoM with ELISA, pre-beta-HDL and pre-beta-HDL formation, phospholipid transfer protein (PLTP) activity and the ability of plasma to promote cholesterol efflux from cultured fibroblasts. ApoM was approximately 9% lower in patients with type 2 diabetes compared to controls (0.025 +/- 0.006 vs. 0.027 +/- 0.007 g L(-1), P = 0.01). The difference in apoM was largely attributable to diabetes-associated obesity. ApoM was positively related to both HDL (r = 0.16; P = 0.04) and LDL cholesterol (r = 0.28; P = 0.0003). Pre-beta-HDL and pre-beta-HDL formation were not different between diabetic and control subjects. ApoM predicted pre-beta-HDL (r = 0.16; P = 0.04) and pre-beta-HDL formation (r = 0.19; P = 0.02), even independently of positive relationships with apoA-I, HDL-cholesterol and PLTP activity. Cellular cholesterol efflux to plasma was positively related to pre-beta-HDL and PLTP activity but not significantly to apoM. Plasma apoM is modestly reduced in type 2 diabetes. Pre-beta-HDL and pre-beta-HDL formation are positively associated with apoM, supporting the hypothesis that apoM plays a role in HDL remodelling in humans. Lower apoM may provide a mechanism to explain why pre-beta-HDL formation is not increased in type 2 diabetes despite elevated PLTP activity.


Full-field optical coherence tomography using immersion Mirau interference microscope.
In this study, an immersion Mirau interference microscope was developed for full-field optical coherence tomography (FFOCT). Both the reference and measuring arms of the Mirau interferometer were filled with water to prevent the problems associated with imaging a sample in air with conventional FFOCT systems. The almost-common path interferometer makes the tomographic system less sensitive to environmental disturbances. En face OCT images at various depths were obtained with phase-shifting interferometry and Hariharan algorithm. This immersion interferometric method improves depth and quality in three-dimensional OCT imaging of scattering tissue.


Phototoxicity and fluorotoxicity combine to alter the behavior of neutrophils in fluorescence microscopy based flow adhesion assays.
The use of fluorescent probes that allow visualization of leukocyte-endothelial cell (EC) interactions has greatly informed our understanding of leukocyte recruitment. However, effects of these agents on the biological functions of leukocytes are poorly described, leading to concerns about the interpretation of such data. Here we used two flow-based neutrophil adhesion assays to compare the effects of phase contrast illumination (PCI) with high intensity illumination (HII) used for fluorescent microscopy, in the presence or absence of five commonly used fluorochromes. Isolated neutrophils were either (1) perfused across P-selectin to establish a population of rolling cells, which were subsequently activated with fMLP; or (2) perfused across EC activated with TNF-alpha. In the absence of fluorescent dyes, HII did not affect levels of leukocyte adhesion; however, subsequent neutrophil behavior was dramatically altered when compared with cells under PCI, for example, dramatically reducing their migration velocities. In the presence of fluorescent dyes, the effects of HII were exacerbated, although the precise nature of the biological effects of these probes was agent specific. Thus, for the first time, our experiments describe the effects of fluorescent microscopy on the separate stages of the neutrophil recruitment process and reveal a previously unsuspected effect of HII on neutrophil migration.


A bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: uncovering the potential for adaptive walks in challenging environments.
The role of adaptation in the evolutionary process has been contentious for decades. At the heart of the century-old debate between neutralists and selectionists lies the distribution of fitness effects (DFE)--that is, the selective effect of all mutations. Attempts to describe the DFE have been varied, occupying theoreticians and experimentalists alike. New high-throughput techniques stand to make important contributions to empirical efforts to characterize the DFE, but the usefulness of such approaches depends on the availability of robust statistical methods for their interpretation. We here present and discuss a Bayesian MCMC approach to estimate fitness from deep sequencing data and use it to assess the DFE for the same 560 point mutations in a coding region of Hsp90 in Saccharomyces cerevisiae across six different environmental conditions. Using these estimates, we compare the differences in the DFEs resulting from mutations covering one-, two-, and three-nucleotide steps from the wild type--showing that multiple-step mutations harbor more potential for adaptation in challenging environments, but also tend to be more deleterious in the standard environment. All observations are discussed in the light of expectations arising from Fisher's geometric model.