A novel kernel method for clustering.
Kernel Methods are algorithms that, by replacing the inner product with an appropriate positive definite function, implicitly perform a nonlinear mapping of the input data into a high-dimensional feature space. In this paper, we present a kernel method for clustering inspired by the classical K-Means algorithm in which each cluster is iteratively refined using a one-class Support Vector Machine. Our method, which can be easily implemented, compares favorably with respect to popular clustering algorithms, like K-Means, Neural Gas, and Self-Organizing Maps, on a synthetic data set and three UCI real data benchmarks (IRIS data, Wisconsin breast cancer database, Spam database).


Isolation of two genes that encode subunits of the yeast transcription factor IIA.
The yeast transcription factor IIA (TFIIA), a component of the basal transcription machinery of RNA polymerase II and implicated in vitro in regulation of basal transcription, is composed of two subunits of 32 and 13.5 kilodaltons. The genes that encode these subunits, termed TOA1 and TOA2, respectively, were cloned. Neither gene shares obvious sequence similarity with the other or with any other previously identified genes. The recombinant factor bound to a TATA binding protein-DNA complex and complemented yeast and mammalian in vitro transcription systems depleted of TFIIA. Both the TOA1 and TOA2 genes are essential for growth of yeast.


Genetic evolution of low pathogenecity H9N2 avian influenza viruses in Tunisia: acquisition of new mutations.
Since the end of 2009, H9N2 has emerged in Tunisia causing several epidemics in poultry industry resulting in major economic losses. To monitor variations of Influenza viruses during the outbreaks, Tunisian H9N2 virus isolates were identified and genetically characterized. The genomic RNA segments of Tunisian H9N2 strains were subjected to RT-PCR amplifications followed by sequencing analysis. Phylogenetic analysis demonstrated that A/Ck/TUN/12/10 and A/Migratory Bird/TUN/51/10 viruses represent multiple reassortant lineages, with genes coming from Middle East strains, and share the common ancestor Qa/HK/G1/97 isolate which has contributed internal genes of H5N1 virus circulating in Asia. Some of the internal genes seemed to have undergone broad reassortments with other influenza subtypes. Deduced amino acid sequences of the hemagglutinin (HA) gene showed the presence of additional glycosylation site and Leu at position 234 indicating to binding preference to α (2, 6) sialic acid receptors, indicating their potential to directly infect humans. The Hemagglutinin cleavage site motif sequence is 333 PARSSR*GLF341 which indicates the low pathogenicity nature of the Tunisian H9N2 strains and the potential to acquire the basic amino acids required for the highly pathogenic strains. Their neuraminidase protein (NA) carried substitutions in the hemadsorption (HB) site, similar to those of other avian H9N2 viruses from Asia, Middle Eastern and human pandemic H2N2 and H3N2 that bind to α -2, 6 -linked receptors. Two avian virus-like aa at positions 661 (A) and 702 (K), similar to H5N1 strains, were identified in the polymerase (PB2) protein. Likewise, matrix (M) protein carried some substitutions which are linked with increasing replication in mammals. In addition, H9N2 strain recently circulating carried new polymorphism, "GSEV" PDZ ligand (PL) C-terminal motif in its non structural (NS) protein.Two new aa substitutions (I) and (V), that haven't been previously reported, were identified in the polymerase and matrix proteins, respectively. Nucleoprotein and non-structural protein carried some substitutions similar to H5N1 strains. Considering these new mutations, the molecular basis of tropism, host responses and enhanced virulence will be defined and studied. Otherwise, Continuous monitoring of viral genetic changes throughout the year is warranted to monitor variations of Influenza viruses in the field.


The expression and roles of Nde1 and Ndel1 in the adult mammalian central nervous system.
Mental and neurological illnesses affect one in four people. While genetic linkage analyses have shown an association of nuclear distribution factor E (NDE1, or NudE) and its ohnolog NDE-like 1 (NDEL1, or Nudel) with mental disorders, the cellular mechanisms remain unclear. In the present study, we have demonstrated that Nde1 and Ndel1 are differentially localised in the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the hippocampus, two regions where neurogenesis actively occurs in the adult brain. Nde1, but not Ndel1, is localized to putative SVZ stem cells, and to actively dividing progenitors of the SGZ. The influence of these proteins on neural stem cell differentiation was investigated by overexpression in a hippocampal neural stem cell line, HCN-A94. Increasing Nde1 expression in this neural stem cell line led to increased neuronal differentiation while decreasing levels of astroglial differentiation. In primary cultured neurons and astrocytes, Nde1 and Ndel1 were found to have different but comparable subcellular localizations. In addition, we have shown for the first time that Nde1 is heterogeneously distributed in cortical astrocytes of human brains. Our data indicate that Nde1 and Ndel1 have distinct but overlapping distribution patterns in mouse brain and cultured nerve cells. They may function differently and therefore their dosage changes may contribute to some aspects of mental disorders.


Cation-exchanged SAPO-34 for adsorption-based hydrocarbon separations: predictions from dispersion-corrected DFT calculations.
The influence of the nature of the cation on the interaction of the silicoaluminophosphate SAPO-34 with small hydrocarbons (ethane, ethylene, acetylene, propane, propylene) is investigated using periodic density-functional theory calculations including a semi-empirical dispersion correction (DFT-D). Initial calculations are used to evaluate which of the guest-accessible cation sites in the chabazite-type structure is energetically preferred for a set of ten cations, which comprises four alkali metals (Li(+), Na(+), K(+), Rb(+)), three alkaline earth metals (Mg(2+), Ca(2+), Sr(2+)), and three transition metals (Cu(+), Ag(+), Fe(2+)). All eight cations that are likely to be found at the SII site (centre of a six-ring) are then included in the following investigation, which studies the interaction with the hydrocarbon guest molecules. In addition to the interaction energies, some trends and peculiarities regarding the adsorption geometries are analysed, and electron density difference plots obtained from the calculations are used to gain insights into the dominant interaction types. In addition to dispersion interactions, electrostatic and polarisation effects dominate for the main group cations, whereas significant orbital interactions are observed for unsaturated hydrocarbons interacting with transition metal (TM) cations. The differences between the interaction energies obtained for pairs of hydrocarbons of interest (such as ethylene-ethane and propylene-propane) deliver some qualitative insights: if this energy difference is large, it can be expected that the material will exhibit a high selectivity in the adsorption-based separation of alkene-alkane mixtures, which constitutes a problem of considerable industrial relevance. While the calculations show that TM-exchanged SAPO-34 materials are likely to exhibit a very high preference for alkenes over alkanes, the strong interaction may render an application in industrial processes impractical due to the large amount of energy required for regeneration. In this respect, SAPOs exchanged with alkaline earth cations could provide a better balance between selectivity and energy cost of regeneration.


The contribution of transforming growth factor-beta and epidermal growth factor signalling to airway remodelling in chronic asthma.
Asthma is increasing in prevalence in the developing world, affecting approximately 10% of the world's population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time. Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity. Transforming growth factor-beta is a potent profibrogenic factor whose expression is increased in the asthmatic airways and is a prime candidate for the initiation and persistence of airway remodelling in asthma. This review highlights the role of transforming growth factor-beta in the asthmatic lung, incorporating biosynthesis, signalling pathways and functional outcome. In vivo, however, it is the balance between transforming growth factor-beta and other growth factors, such as epidermal growth factor, which will determine the extent of fibrosis in the airways. A fuller comprehension of the actions of transforming growth factor-beta, and its interaction with other signalling pathways, such as the epidermal growth factor receptor signalling cascade, may enable development of therapies that control airway remodelling where there is an unmet clinical need.


PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes.
The disease association of the common 1858C>T Arg620Trp (rs2476601) nonsynonymous single nucleotide polymorphism (SNP) of protein tyrosine phosphatase; nonreceptor type 22 (PTPN22) on chromosome 1p13 has been confirmed in type 1 diabetes and also in other autoimmune diseases, including rheumatoid arthritis and Graves' disease. Some studies have reported additional associated SNPs independent of rs2476601/Trp(620), suggesting that it may not be the sole causal variant in the region and that the relative risk of rs2476601/Trp(620) is greater in lower risk by HLA class II genotypes than in the highest risk class II risk category. We resequenced PTPN22 and used these and other data to provide >150 SNPs to evaluate the association of the PTPN22 gene and its flanking chromosome region with type 1 diabetes in a minimum of 2,000 case subjects and 2,400 control subjects. Due to linkage disequilibrium, we were unable to distinguish between rs2476601/Trp(620) (P = 2.11 x10(-87)) and rs6679677 (P = 3.21 x10(-87)), an intergenic SNP between the genes putative homeodomain transcription factor 1 and round spermatid basic protein 1. None of the previously reported disease-associated SNPs proved to be independent of rs2476601/Trp(620). We did not detect any interaction with age at diagnosis or sex. However, we found that rs2476601/Trp(620) has a higher relative risk in type 1 diabetic case subjects carrying lower risk HLA class II genotypes than in those carrying higher risk ones (P = 1.36 x 10(-4) in a test of interaction). In our datasets, there was no evidence for allelic heterogeneity at the PTPN22 locus in type 1 diabetes, indicating that the SNP rs2476601/Trp(620) remains the best candidate in this chromosome region in European populations. The heterogeneity of rs2476601/Trp(620) disease risk by HLA class II genotype is consistent with previous studies, and the joint effect of the two loci is still greater in the high-risk group.


Fabry Disease Prevalence in Renal Replacement Therapy in Turkey.
Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from lack of alpha-galactosidase A (AGALA) activity in lysosomes. In this multicenter study, we aimed to evaluate the prevalence of FD in renal transplant (Tx) recipients in Turkey. We also screened dialysis patients as a control group. All Tx and dialysis patients were screened regardless of the presence of a primary disease. We measured the AGALA activity in all male patients as initial analysis. Mutation analysis was performed in male patients with decreased AGALA activity and in female patients as the initial diagnostic assay. We screened 5,657 patients. A total of 17 mutations were identified. No significant difference was observed between the groups regarding the prevalence of patients with mutation. We found FD even in patients with presumed primary kidney diseases. Seventy-one relatives were analyzed and mutation was detected in 43 of them. We detected a patient with a new, unknown mutation (p.Cys223) in the GLA gene. There are important implications of the screening. First, detection of the undiagnosed patients leads to starting appropriate therapies for these patients. Second, the transmission of the disease to future generations may be prevented by prenatal screening after appropriate genetic counseling. In conclusion, we suggest screening of kidney Tx candidates for FD, regardless of etiologies of chronic kidney disease.


Medicaid expansion: chronically homeless adults will need targeted enrollment and access to a broad range of services.
Homeless adults may gain access to health services under the Affordable Care Act's Medicaid expansion, which takes effect in 2014. This study analyzed the health coverage, health status, and health services use of 725 chronically homeless adults with disabilities in eleven cities in the United States. Nearly three-quarters of the chronically homeless adults in this study with incomes below the threshold for the Medicaid expansion were not enrolled in Medicaid. Fifty-three percent were uninsured or relied solely on state or local assistance, and 21 percent had other coverage that included Department of Veterans Affairs health care. The findings on differences in health status and service use across groups suggest that the Medicaid expansion offers important opportunities to increase coverage and access to care for chronically homeless adults. There may be potential savings for states that expand Medicaid, as people transition from state and local assistance to more comprehensive services under Medicaid. Targeted outreach and assistance to enroll eligible homeless people will be necessary. A broad range of physical and mental health services will be required, including case management to coordinate services.


Probing the active sites and mechanisms of rat metalloproteases meprin A and B.
Meprin A and B are highly regulated, secreted and cell-surface homo- and hetero-oligomeric enzymes. Meprins are abundantly expressed in kidney and intestine. The multidomain alpha and beta subunits have high sequence identity, however they have very different substrate specificities, oligomerization potentials and are differentially regulated. Here we describe that meprin subunit activities are modulated differently by physico-chemical factors. Homo-oligomeric meprin B had an acidic pH optimum. The low pH protonation indicated the existence of at least two ionizable groups. An additional ionizable group generated a shoulder in the basic pH range. Homo-oligomeric meprin A had a neutral pH optimum and the activity curve revealed that two ionizable groups might be protonated at acidic pH similar to meprin B. Increasing the concentration of salt generally inhibited meprin B activity. Meprin A was inhibited at low salt concentrations but activated as salt was increased. This work has important implications in the elucidation of the catalytic mechanisms of meprins and other metalloproteases. In addition, the activity of meprin oligomers that arise in tissues will be affected by variations in pH and NaCl. This could have profound implications because meprins are exposed to a range of conditions in the extracellular milieu of renal and intestinal tissues and in inflammation and cancer.


Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development.
We investigated the function of Lhx2, a LIM homeobox gene expressed in developing B-cells, forebrain and neural retina, by analyzing embryos deficient in functional Lhx2 protein. Lhx2 mutant embryos are anophthalmic, have malformations of the cerebral cortex, and die in utero due to severe anemia. In Lhx2-/- embryos specification of the optic vesicle occurs; however, development of the eye arrests prior to formation of an optic cup. Deficient cellular proliferation in the forebrain results in hypoplasia of the neocortex and aplasia of the hippocampal anlagen. In addition to the central nervous system malformations, a cell non-autonomous defect of definitive erythropoiesis causes severe anemia in Lhx2-/- embryos. Thus Lhx2 is necessary for normal development of the eye, cerebral cortex, and efficient definitive erythropoiesis.


Transposon mutagenesis as a tool to study the role of hemolysin in the virulence of Listeria monocytogenes.
The role of hemolysin in the virulence of Listeria monocytogenes was studied by using transposon mutagenesis. The 26-kilobase conjugative transposon Tn1545, originally found in Streptococcus pneumoniae, was transferred to a hemolytic virulent strain of L. monocytogenes. The frequency of transfer was estimated to be about 10(-8) per recipient. This allowed us to isolate a nonhemolytic mutant which most likely harbors a single copy of Tn1545. Loss of hemolysin production was associated with loss of virulence. The 50% lethal dose of the mutant was assessed to about 10(9.6) bacteria per mouse after intravenous challenge. Nonhemolytic bacteria were unable to grow in host tissues and were rapidly eliminated from the spleen and liver of infected mice. Virulence was restored in hemolysin-producing revertant obtained by spontaneous loss of transposon Tn1545. These results strongly suggest that hemolysin is a major virulence factor implicated in the intracellular growth of L. monocytogenes.


Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines.
To determine to which extent inflammatory cytokines affect chemokine secretion by primary human choroidal melanocytes (HCMs), their capacity to attract monocytes, and whether HCMs are able to influence the proliferation of activated T cells. Primary cultures of HCMs were established from eyes of 13 donors. Human choroidal melanocytes were stimulated with IFN-γ and TNF-α or with supernatant from activated T cells (T-cell-conditioned media [TCM]). Gene expression analysis was performed by using microarrays. Protein levels were quantified with ELISA or cytometric bead array. Supernatants of HCMs were assessed for the capability to attract monocytes in a transwell plate. Proliferation of activated T cells was assessed in a direct coculture with HCMs by a [3H]-thymidine incorporation assay. Stimulation of HCMs with TCM or IFN-γ and TNF-α resulted in increased expression and secretion of CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5 and intercellular adhesion molecule 1. Vascular endothelial growth factor and monocyte migration inhibitory factor were constitutively expressed without changes in response to proinflammatory cytokines. Supernatants derived from unstimulated cultures of 10 HCM donors induced a high initial level of monocyte migration, which decreased upon stimulation with either TCM or IFN-γ and TNF-α. The supernatants from three HCM donors initially showed a low level of monocyte attraction, which increased after exposure to proinflammatory cytokines. Direct coculture of HCMs with T cells resulted in inhibition of T-cell proliferation. These results showed that normal and activated HCMs are immunologically active by secreting chemokines, and that HCMs are able to attract monocytes in addition to inhibiting T-cell proliferation.


2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential.
2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ), a metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. However, the mechanisms by which TGHQ induces apoptosis are unclear, and they were the focus of the present investigation. TGHQ stimulated the rapid formation (30 min) of reactive oxygen species (ROS) in HL-60 cells, and co-treatment with catalase or the antioxidant N-acetylcysteine (NAC) completely blocked TGHQ-induced apoptosis, implicating a causative role for ROS in HL-60 cell death. Western blot analysis revealed the complete disappearance of pro-caspase 9 between 1 and 2 hours after exposure of HL-60 cells to TGHQ, concomitant with the appearance of cleaved caspase 9 and increases in caspase 9 activity. The appearance of two cleaved forms of caspase 3 occurred subsequent to increases in caspase 9 activity. Levels of the anti-apoptotic Bcl-2 protein remained constant during TGHQ-induced apoptosis of HL-60 cells, but Bcl-2 S70 phosphorylation decreased. In contrast, changes in the subcellular localization of the pro-apoptotic molecule Bax were observed, with a rapid (15-60 min) increase in the ratio of cytosolic to mitochondrial Bax. Cytochrome c release from mitochondria to the cytosol occurred after Bax translocation and the dephosphorylation of pS70 Bcl-2. However the mitochondrial inner transmembrane potential (deltapsi(m)) was maintained, even after cytochrome c was released from the mitochondria. Cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition pore (PTP), did not completely rescue HL-60 cells from apoptosis. Taken together, we conclude that TGHQ facilitates ROS production, alters the post-translational modification of Bcl-2 and subcellular localization of Bax, culminating in the release of cytochrome c and caspase activation.


Dyadic Effects of Individual and Friend on Physical Activity in College Students.
Physical activity (PA) tends to decline throughout the college years, and close friends' influence is known to be an important factor in maintaining PA. This study examined the actor effect and partner effect between an individual and his/her friend regarding the influence of self-efficacy and social support on PA among Korean college students. Cross-sectional survey data from 108 pairs of individual students and friends were analyzed. The survey questionnaire measured PA, self-efficacy toward exercise, social support for PA, anxiety and depression, community environments, and perceived health status. Structural equation modeling with path analysis was conducted to test Actor-Partner Interdependence Model (APIM) explaining close relationships on PA. One-sided partner effect that friends' perceived friend support was directly related to individual's PA (β = 0.20, p < .05) was revealed. Regarding actor effects, self-efficacy was directly related to higher levels of PA for individual and friend. Perceived health status was related to higher level of individuals' PA. These results suggest a role for public health nurses in developing interventions for college-aged young adults that promotes friend support for PA as well as individual self-efficacy toward PA, to engage young adults in establishing lifelong health-promoting PA.


Presbyopic LASIK using hybrid bi-aspheric micro-monovision ablation profile for presbyopic corneal treatments.
To evaluate distance and near image quality after hybrid bi-aspheric multifocal central presbyLASIK treatments. Consecutive case series. Sixty-four eyes of 32 patients consecutively treated with central presbyLASIK were assessed. The mean age of the patients was 51 ± 3 years with a mean spherical equivalent refraction of -1.08 ± 2.62 diopters (D) and mean astigmatism of 0.52 ± 0.42 D. Monocular corrected distance visual acuity (CDVA), corrected near visual acuity (CNVA), and distance corrected near visual acuity (DCNVA) of nondominant eyes; binocular uncorrected distance visual acuity (UDVA); uncorrected intermediate visual acuity (UIVA); distance corrected intermediate visual acuity (DCIVA); and uncorrected near visual acuity (UNVA) were assessed pre- and postoperatively. Subjective quality of vision and near vision was assessed using the 10-item Rasch-scaled Quality of Vision and Near Activity Visual Questionnaire, respectively. At 1 year postoperatively, 93% of patients achieved 20/20 or better binocular UDVA; 90% and 97% of patients had J2 or better UNVA and UIVA, respectively; 7% lost 2 Snellen lines of CDVA; Strehl ratio reduced by ∼-4% ± 14%. Defocus curves revealed a loss of half a Snellen line at best focus, with no change for intermediate vergence (-1.25 D) and a mean gain of 2 lines for near vergence (-3 D). Presbyopic treatment using a hybrid bi-aspheric micro-monovision ablation profile is safe and efficacious. The postoperative outcomes indicate improvements in binocular vision at far, intermediate, and near distances with improved contrast sensitivity. A 19% retreatment rate should be considered to increase satisfaction levels, besides a 3% reversal rate.


Haematological indices as predictors of atrial fibrillation following isolated coronary artery bypass grafting, valvular surgery, or combined procedures: a systematic review with meta-analysis.
New postoperative atrial fibrillation (POAF) is one of the most critical and common complications after cardiovascular surgery precipitating early and late morbidities. Complete blood count (CBC) is an imperative blood test in clinical practice, routinely used in the examination of cardiovascular diseases. This systematic review with meta-analysis aimed to determine the strength of evidence for evaluating the association of haematological indices in CBC tests with atrial fibrillation following isolated coronary artery bypass graft (CABG), isolated valvular surgery, or a combination of these treatments. We conducted a meta-analysis of studies evaluating pre- and postoperative haematological indices in patients with POAF. A comprehensive subgroup analysis was performed to explore potential sources of heterogeneity. A literature search of all major databases retrieved 732 studies. After screening, 22 studies were analysed including a total of 6098 patients. Pooled analysis showed preoperative platelet count (PC) (weighted mean difference [WMD] = -7.07 × 10^9/L and p < 0.001), preoperative mean platelet volume (MPV) (WMD = 0.53 FL and p < 0.001), preoperative white blood cell count (WBC) (WMD = 0.130 × 10^9/L and p < 0.001), preoperative neutrophil-to-lymphocyte ratio (NLR) (WMD = 0.33 and p < 0.001), preoperative red blood cell distribution width (RDW) (WMD = 0.36% and p < 0.001), postoperative WBC (WMD = 1.36 × 10^9/L and p < 0.001), and postoperative NLR (WMD = 0.74 and p < 0.001) as associated factors with POAF. Haematological indices may predict the risk of POAF before surgery. These easily-performed tests should definitely be taken into account in patients undergoing isolated CABG, valvular surgery, or combined procedures.


The Clinical Global Impression Scale and the influence of patient or staff perspective on outcome.
Since its first publication, the Clinical Global Impression Scale (CGI) has become one of the most widely used assessment instruments in psychiatry. Although some conflicting data has been presented, studies investigating the CGI's validity have only rarely been conducted so far. It is unclear whether the improvement index CGI-I or a difference score of the severity index CGI-S (dif) is more valid in depicting clinical change. The current study examined the validity of these two measures and investigated whether therapists' CGI ratings correspond to the view the patients themselves have on their condition. Thirty-one inpatients of a German psychotherapeutic hospital suffering from a major depressive disorder (age M = 45.3, SD = 17.2; 58.1% women) participated. Patients filled in the Beck Depression Inventory (BDI). CGI-S and CGI-I were rated from three perspectives: the treating therapist (THER), the team of therapists involved in the patient's treatment (TEAM), and the patient (PAT). BDI and CGI-S were filled in at admission and discharge, CGI-I at discharge only. Data was analysed using effect sizes, Spearman's ρ and intra-class correlations (ICC). Effect sizes between CGI-I and CGI-S (dif) ratings were large for all three perspectives with substantially higher change scores on CGI-I than on CGI-S (dif). BDI (dif) correlated moderately with PAT ratings, but did not correlate significantly with TEAM or THER ratings. Congruence between CGI-ratings from the three perspectives was low for CGI-S (dif) (ICC = .37; Confidence Interval [CI] .15 to .59; F(30,60) = 2.77, p < .001; mean ρ = 0.36) and moderate for CGI-I (ICC = .65 (CI .47 to .80; F(30,60) = 6.61, p < .001; mean ρ = 0.59). Results do not suggest a definite recommendation for whether CGI-I or CGI-S (dif) should be used since no strong evidence for the validity of neither of them could be found. As congruence between CGI ratings from patients' and staff's perspective was not convincing it cannot be assumed that CGI THER or TEAM ratings fully represent the view of the patient on the severity of his impairment. Thus, we advocate for the incorporation of multiple self- and clinician-reported scales into the design of clinical trials in addition to CGI in order to gain further insight into CGI's relation to the patients' perspective.


Synthesis of multifunctionalized 1,2,3,4-tetrahydropyridines, 2,3-dihydropyridin-4(1H)-ones, and pyridines from tandem reactions initiated by [5+1] cycloaddition of N-formylmethyl-substituted enamides to isocyanides: mechanistic insight and synthetic application.
Tandem reactions for the efficient synthesis of multifunctionalized 1,2,3,4-tetrahydropyridines, 2,3-dihydropyridin-4(1H)-ones, and pyridine derivatives have been developed and reaction mechanisms have been investigated. Synthetic cascades are initiated by the Zn(OTf)2-mediated [5+1] cycloaddition of N-formylmethyl-substituted tertiary enamides to isocyanides, thus leading to the versatile heterocyclic enamino imine intermediates. Interception of the intermediates by diastereoselective reduction of imine functionality with Me4NBH(OAc)3 afforded 1,6-disubstituted trans-3-hydroxy-4-arylamino- or -alkylamino-1,2,3,4-tetrahydropyridines, whereas acylation of the imino group followed by acidic hydrolysis produced 1,6-disubstituted 3-acyloxy-2,3-dihydropyridin-4(1H)-ones. Aerobic oxidation led to the aromatization followed by intermolecular acyl-group transfer from the pyridinium nitrogen to the 3-hydroxy moiety, thereby yielding substituted 3-acyloxy-4-aminopyridines. Synthetic potentials of the resulting products have been demonstrated by expedient and highly stereoselective synthesis of cis,cis-4,5-dihydroxy-2-phenylpiperidine and trans,trans-4-amino-5-hydroxy-2-phenylpiperidine compounds, which are important in medicinal chemistry, through simple and practical reduction reactions.


Development and validation of high definition phenotype-based mortality prediction in critical care units.
The objectives of this study are to construct the high definition phenotype (HDP), a novel time-series data structure composed of both primary and derived parameters, using heterogeneous clinical sources and to determine whether different predictive models can utilize the HDP in the neonatal intensive care unit (NICU) to improve neonatal mortality prediction in clinical settings. A total of 49 primary data parameters were collected from July 2018 to May 2020 from eight level-III NICUs. From a total of 1546 patients, 757 patients were found to contain sufficient fixed, intermittent, and continuous data to create HDPs. Two different predictive models utilizing the HDP, one a logistic regression model (LRM) and the other a deep learning long-short-term memory (LSTM) model, were constructed to predict neonatal mortality at multiple time points during the patient hospitalization. The results were compared with previous illness severity scores, including SNAPPE, SNAPPE-II, CRIB, and CRIB-II. A HDP matrix, including 12 221 536 minutes of patient stay in NICU, was constructed. The LRM model and the LSTM model performed better than existing neonatal illness severity scores in predicting mortality using the area under the receiver operating characteristic curve (AUC) metric. An ablation study showed that utilizing continuous parameters alone results in an AUC score of >80% for both LRM and LSTM, but combining fixed, intermittent, and continuous parameters in the HDP results in scores >85%. The probability of mortality predictive score has recall and precision of 0.88 and 0.77 for the LRM and 0.97 and 0.85 for the LSTM. The HDP data structure supports multiple analytic techniques, including the statistical LRM approach and the machine learning LSTM approach used in this study. LRM and LSTM predictive models of neonatal mortality utilizing the HDP performed better than existing neonatal illness severity scores. Further research is necessary to create HDP-based clinical decision tools to detect the early onset of neonatal morbidities.


PET-MR and SPECT-MR multimodality probes: Development and challenges.
Positron emission tomography (PET)-magnetic resonance (MR) or single photon emission computed tomography (SPECT)-MR hybrid imaging is being used in daily clinical practice. Due to its advantages over stand-alone PET, SPECT or MR imaging, in many areas such as oncology, the demand for hybrid imaging techniques is increasing dramatically. The use of multimodal imaging probes or biomarkers in a single molecule or particle to characterize the imaging subjects such as disease tissues certainly provides us with more accurate diagnosis and promotes therapeutic accuracy. A limited number of multimodal imaging probes are being used in preclinical and potential clinical investigations. The further development of multimodal PET-MR and SPECT-MR imaging probes includes several key elements: novel synthetic strategies, high sensitivity for accurate quantification and high anatomic resolution, favourable pharmacokinetic profile and target-specific binding of a new probe. This review thoroughly summarizes all recently available and noteworthy PET-MR and SPECT-MR multimodal imaging probes including small molecule bimodal probes, nano-sized bimodal probes, small molecular trimodal probes and nano-sized trimodal probes. To the best of our knowledge, this is the first comprehensive overview of all PET-MR and SPECT-MR multimodal probes. Since the development of multimodal PET-MR and SPECT-MR imaging probes is an emerging research field, a selection of 139 papers were recognized following the literature review. The challenges for designing multimodal probes have also been addressed in order to offer some future research directions for this novel interdisciplinary research field.


Ecological Momentary Assessment and Intervention in the Treatment of Psychotic Disorders: A Systematic Review.
Ecological momentary assessment (EMA) and ecological momentary intervention (EMI) are technologies used to track fluctuations in experiences and prompt behavioral responses within the context of a person's daily life. Most commonly delivered via smartphone, EMA and EMI have potential to provide simple, cost-effective, and user-led treatment for psychotic disorders. This systematic review aimed to synthesize current research exploring the feasibility, acceptability, and clinical outcomes of EMA and EMI in the treatment of psychotic disorders. A systematic search was conducted identifying studies published between 1980 and July 7, 2016, by searching PubMed, PsycINFO, PsycARTICLES, and the Cochrane Central Register of Controlled Trials with combinations of search terms related to mobile devices, EMA and EMI, and psychotic disorders. Of 1,623 studies identified, nine met inclusion criteria for the review. These studies found satisfactory feasibility and acceptability and preliminary evidence of improved clinical outcomes. The interventions, which had a broad array of features, targeted remote monitoring of illness and symptoms, and they also targeted illness self-management by using momentary reminders or instructions for behaviors, including medication adherence, management of symptoms and psychosocial impairments, daily living skills, and goal achievement. The findings of this review provide preliminary support for the clinical utility of EMA and EMI in the treatment of psychotic disorders. Future research should explore further applications of these technologies with larger sample sizes and controlled designs.


Starling resistor versus compliance. Which explains the zero-flow pressure of a dynamic arterial pressure-flow relation?
Arterial pressure at zero flow (Pz = 0) that is higher than venous pressure (Pv) in dynamic pressure-flow relations has been explained by the presence of an arteriolar Starling resistor (SR) mechanism (i.e., vascular waterfall) or the discharge of vascular capacitance. To determine which was predominant, I studied in vivo hind limbs of 18 anesthetized dogs in which femoral arteries were cannulated with in-line electromagnetic flow probes to measure inflow (Qin), Pv was controlled, and collateral flow was eliminated with a tourniquet. Pz = 0 was obtained by turning flow to zero. Three tests were applied: 1) Pv was raised in steps with either constant Qin or constant arterial pressure (Pa) to determine the pressure at which upstream vascular characteristics were affected by a change in Pv, 2) the time to reach Pz = 0 was varied to determine compliance effects, and 3) an equation was developed to determine if experimentally derived parameters could explain Pz = 0 without invoking an SR. With constant Qin and a Pz = 0 of 56.9 +/- 11.7 mm Hg (time to Pz = 0, 3 seconds), Pv could be raised by 9.6 +/- 6.2 to 16.3 +/- 6.0 mm Hg before Pa increased, and with constant Pa, Pv could be raised by 6.8 +/- 7.3 to 14.0 +/- 8.0 mm Hg before Qin decreased. With increasing times to reach Pz = 0, Pz = 0 initially dropped precipitously, but then decreased by only a small amount over the next 5-10 seconds even though arterial pressure was much above Pv. This could be explained by an SR mechanism with a critical pressure of 42.3 +/- 11.4 mm Hg and an arterial compliance of 0.0104 +/- 0.0023 ml.mm Hg-1 (n = 6). There was no value for the compliance that described the results when the arterial outflow pressure was Pv. Thus, this study supports the hypothesis that an SR mechanism is present in the vascular system. It is most likely precapillary, and in the resting limb, it has a value of 40-50 mm Hg. However, Pz = 0 in dynamic pressure-flow studies of less than 4 seconds is also greatly influenced by capacitance effects and the initial Pa.


Effect of chronic ingestion of tarbush (Flourensia cernua) on ewe lambs.
Efforts to increase livestock utilization of tarbush are being coupled with studies to examine tarbush toxicity. Thirty-eight (19/treatment) ewe lambs were assigned at birth to receive either tarbush or alfalfa (15%, dry matter basis) in a sorghum-based growing ration. Lambs were pen-fed this diet 60 d pre-weaning and 60 d post-weaning. No differences existed between treatments in feed consumption. In the tarbush group, 1 lamb died of unknown causes at 90 d of age, while 3 lambs died between 115 and 120 d of age. There were no deaths in the alfalfa group. Shortly before death, lambs fed tarbush appeared lethargic, disoriented and anorectic. At 122 d of age, 5 lambs were randomly selected from each group. Feces and jugular blood samples were obtained from each lamb before being euthanized and necropsied the following day. All fecal samples were negative for occult blood. Serum gamma glutamyl-transpeptidase (P < 0.001) and aspartate aminotransferase (P < 0.001) activities and platelet counts (P < 0.05) were elevated in lambs fed tarbush, while serum calcium concentrations tended (P < 0.10) to be greater. Histologic examination revealed diffuse liver apoptosis in lambs fed tarbush. These data indicate tarbush leaves cause liver damage when fed for extended periods of time.


Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line.
CWR22 has been a valuable xenograft model for the study of prostate cancer progression from an androgen-dependent tumor to one that grows in castrated animals. Herein, we report the identification and characterization of a novel androgen receptor (AR) mutation occurring in a relapsed tumor (CWR22R-2152) and in the CWR22Rv1 cell line established from it. The mutation was not detected in the original, hormone-dependent CWR22 xenograft, indicating that this change occurred during the progression to androgen independence. It is characterized by an in-frame tandem duplication of exon 3 that encodes the second zinc finger of the AR DNA-binding domain. Accordingly, immunoblot analyses demonstrated the expression of an AR species having an approximately 5-kDa increase in size relative to the LNCaP AR. This was accompanied by a COOH-terminally truncated AR species migrating with a relative mass of 75-80 kDa, referred to as ARDeltaLBD because it lacks the ligand-binding domain. By recreating the exon 3 duplication mutation in a wild-type AR expression construct, the generation of ARDeltaLBD could be recapitulated. Whereas ARDeltaLBD exhibited constitutive nuclear localization and DNA binding, these functions in the full-length AR remained androgen dependent. The CWR22Rv1 AR repertoire displayed dose-dependent, androgen-responsive transcriptional transactivation in reporter assays, albeit to a lesser extent in comparison with LNCaP. This cell line also expressed low levels of prostate-specific antigen mRNA and did not express or secrete detectable levels of prostate-specific antigen protein in androgen-depleted medium or in response to physiological androgenic stimulation. In summary, the CWR22Rv1 cell line displays both androgen-responsive and androgen-insensitive features due, at least in part, to a novel insertional mutation of the AR.


Human stefin B role in cell's response to misfolded proteins and autophagy.
Alternative functions, apart from cathepsins inhibition, are being discovered for stefin B. Here, we investigate its role in vesicular trafficking and autophagy. Astrocytes isolated from stefin B knock-out (KO) mice exhibited an increased level of protein aggregates scattered throughout the cytoplasm. Addition of stefin B monomers or small oligomers to the cell medium reverted this phenotype, as imaged by confocal microscopy. To monitor the identity of proteins embedded within aggregates in wild type (wt) and KO cells, the insoluble cell lysate fractions were isolated and analyzed by mass spectrometry. Chaperones, tubulins, dyneins, and proteosomal components were detected in the insoluble fraction of wt cells but not in KO aggregates. In contrast, the insoluble fraction of KO cells exhibited increased levels of apolipoprotein E, fibronectin, clusterin, major prion protein, and serpins H1 and I2 and some proteins of lysosomal origin, such as cathepsin D and CD63, relative to wt astrocytes. Analysis of autophagy activity demonstrated that this pathway was less functional in KO astrocytes. In addition, synthetic dosage lethality (SDL) gene interactions analysis in Saccharomyces cerevisiae expressing human stefin B suggests a role in transport of vesicles and vacuoles These activities would contribute, directly or indirectly to completion of autophagy in wt astrocytes and would account for the accumulation of protein aggregates in KO cells, since autophagy is a key pathway for the clearance of intracellular protein aggregates.


L-tryptophan and correlates of self-injurious behavior in small-eared bushbabies (Otolemur garnettii).
Self-injurious behavior (SIB) among captive primates is a recurring problem for those who manage such facilities. Its prevalence highlights the need for research evaluating the effectiveness of potential treatment approaches. In the present study, 4 wk of dietary supplementation with L-tryptophan (100 mg daily) was evaluated for the treatment of self-inflicted wounds in 22 small-eared bushbabies, a prosimian primate, with a history of SIB. The treatment significantly reduced stereotypy and was associated with a reduction in wound area and severity. In terms of physiologic measures, preexisting high levels of cortisol were reduced in bushbabies with SIB, whereas serotonin concentrations were increased after 4 wk of treatment. Results indicate that L-tryptophan as a dietary supplement may be a viable adjunct to standard husbandry procedures for animals exhibiting maladaptive behaviors such as stereotypy and SIB.


How does a millimeter-sized cell find its center?
Microtubules play a central role in centering the nucleus or mitotic spindle in eukaryotic cells. However, despite common use of microtubules for centering, physical mechanisms can vary greatly, and depend on cell size and cell type. In the small fission yeast cells, the nucleus can be centered by pushing forces that are generated when growing microtubules hit the cell boundary. This mechanism may not be possible in larger cells, because the compressive force that microtubules can sustain are limited by buckling, so maximal force decreases with microtubule length. In a well-studied intermediate sized cell, the C. elegans fertilized egg, centrosomes are centered by cortex-attached motors that pull on microtubules. This mechanism is widely assumed to be general for larger cells. However, re-evaluation of classic experiments in a very large cell, the fertilized amphibian egg, argues against such generality. In these large eggs, movement of asters away from a part of the cell boundary that they are touching cannot be mediated by cortical pulling, because the astral microtubules are too short to reach the opposite cell boundary. Additionally, Herlant and Brachet discovered a century ago that multiple asters within a single egg center relative to the cell boundary, but also relative to each other. Here, we summarize current understanding of microtubule organization during the first cell cycle in a fertilized Xenopus egg, discuss how microtubule asters move towards the center of this very large cell, and how multiple asters shape and position themselves relative to each other.


Stent assisted coiling of the ruptured wide necked intracranial aneurysm.
Stent assisted coiling of unruptured wide necked intracranial aneurysms require antiplatelets to prevent stent thrombosis. The effect of the loading dose of antiplatelets prior to the stent coiling procedure in an unsecured wide necked ruptured intracranial aneurysm is not known. To report any potential complication associated with the use of both aspirin and clopidogrel in stent assisted coiling of ruptured wide necked intracranial aneurysms. Consecutive patients who underwent stent assisted coiling for ruptured wide necked intracranial aneurysm were enrolled from 2005 to 2009. Patients' demographics, including Hunt and Hess grade, Fisher scale, and location and size of aneurysms, were collected. Complications such as rupture of aneurysm, thromboembolic events, ventriculostomy associated or systemic hemorrhages were recorded. Additionally, a 90 day outcome measurement was obtained using the Glasgow Outcome Scale. 22 patients with a mean age of 50±13 years underwent stent assisted coiling. A loading dose of clopidogrel 300 mg and aspirin 325 mg orally were given prior to stent placement. There was no intraoperative rupture of aneurysm, ventriculostomy associated hemorrhage or systemic hemorrhagic event. There were two episodes of stent thrombosis; one was an asymptomatic event which developed during the stent assisted coiling procedure and resolved spontaneously; the other was symptomatic which required intra-arterial administration of glycoprotein IIbIIIa receptor antagonist. There was no mortality and good outcome was observed in 82% of patients. In our series of carefully selected patients, therapeutic dual antiplatelet loading prior to stent assisted coiling of ruptured wide necked intracranial aneurysm was not associated with increased bleeding complications. However, thromboembolic events remain the main challenge. Further study is required to confirm the safety of antiplatelet loading in stent assisted ruptured intracranial aneurysm coiling.


Berberine Inhibits Uterine Leiomyoma Cell Proliferation via Downregulation of Cyclooxygenase 2 and Pituitary Tumor-Transforming Gene 1.
We previously demonstrated that berberine (BBR) inhibits cell proliferation and induces apoptosis in a human uterine leiomyoma (UtLM) cell line but does not demonstrate a significant cytotoxic effect in a normal human uterine smooth muscle (UtSM) cell line. However, the mechanisms of this inhibition are unclear. Of note, cyclooxygenase 2 (COX2) and pituitary tumor-transforming gene 1 (PTTG1) are overexpressed in human uterine leiomyomata and are involved in the pathogenesis of uterine fibroids (UFs). We found that COX2 and PTTG1 were overexpressed in UtLM and that BBR decreased COX2 and PTTG1 expression in UtLM cells. Our data support that UtLM and UtSM are immortalized cell lines without phenotypic alterations from parental cell types and suggest that COX2 and PTTG1 are molecular targets for BBR. However, studies in these cell lines may not reveal all activities of BBR in vivo, and we therefore proceeded to test in this report the antitumor effects of BBR in an UF nude mouse xenograft model. When UF nude mice were killed at 7 weeks, tumor weight in controls was 45 ± 7 mg versus 20 ± 3 mg ( P < .05) in the low-dose (5 mg/kg) and 7 ± 3 mg ( P < .01) in the high-dose (10 mg/kg) BBR groups, respectively. Expression of proliferation markers, cell cycle-related genes, and UF-related genes was downregulated in tumors. No unusual behavioral changes and no signs of kidney or liver damage were observed in the animals with BBR treatment. In conclusion, our data suggests that (a) COX2 and PTTG1 are molecular targets for BBR and (b) BBR is potentially an effective and safe anti-UF agent.


The impact of growth history and flagellation on the adhesion of various Listeria monocytogenes strains to polystyrene.
The contribution of growth history and flagella to adhesion of Listeria monocytogenes was analysed. An in-frame deletion on the flagellin encoding gene (flaA) was performed in L. monocytogenes EGD-e to compare its adhesion ability with the parental strain, after cultivation at various pH values and temperatures. The pH, as well as the temperature, affected the adhesion of L. monocytogenes EGD-e. In addition, the adhesion of L. monocytogenes EGD-e was reduced in energy-depressed cells. Conversely, the physicochemical bacterial surface characteristics affected by growth history did not influence the adhesion. Adhesion variations observed among environmental and clinical strains was attributed to the flagella. The naturally aflagellated strains resulted in an adhesion capacity similar to that observed for mutants and parental strains cultivated under flagellum expression repressing conditions. However, L. monocytogenes is able to adhere to inert surfaces through a residual adhesion process without flagella. All these observations emphasize the importance to consider the food environmental factors in the risk assessment of L. monocytogenes in food industry.


Fast and accurate haplotype frequency estimation for large haplotype vectors from pooled DNA data.
Typically, the first phase of a genome wide association study (GWAS) includes genotyping across hundreds of individuals and validation of the most significant SNPs. Allelotyping of pooled genomic DNA is a common approach to reduce the overall cost of the study. Knowledge of haplotype structure can provide additional information to single locus analyses. Several methods have been proposed for estimating haplotype frequencies in a population from pooled DNA data. We introduce a technique for haplotype frequency estimation in a population from pooled DNA samples focusing on datasets containing a small number of individuals per pool (2 or 3 individuals) and a large number of markers. We compare our method with the publicly available state-of-the-art algorithms HIPPO and HAPLOPOOL on datasets of varying number of pools and marker sizes. We demonstrate that our algorithm provides improvements in terms of accuracy and computational time over competing methods for large number of markers while demonstrating comparable performance for smaller marker sizes. Our method is implemented in the "Tree-Based Deterministic Sampling Pool" (TDSPool) package which is available for download at http://www.ee.columbia.edu/~anastas/tdspool. Using a tree-based determinstic sampling technique we present an algorithm for haplotype frequency estimation from pooled data. Our method demonstrates superior performance in datasets with large number of markers and could be the method of choice for haplotype frequency estimation in such datasets.


Vacuum ultraviolet absolute radiometry utilizing total blackbody radiation.
A new calibration technique is described which allows a monochromatic source and detectors to be obtained as secondary standards in the vacuum ultraviolet spectral range. The method of operation is based on the comparison, against a thermopile, between an ultraviolet flux from a monochromator and the total flux from a blackbody simulator. The over-all uncertainty does not exceed 20%.


Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB).
Sanfilippo syndrome type B or mucopolysaccharidosis type IIIB (MPS IIIB) is one of a group of lysosomal storage disorders that are characterised by the inability to breakdown heparan sulphate. In MPS IIIB, there is a deficiency in the enzyme alpha-N-acetylglucosaminidase (NAGLU) and early clinical symptoms include aggressive behaviour and hyperactivity followed by progressive mental retardation. The disease is autosomal recessive and the gene for NAGLU, which is situated on chromosome 17q21, is approximately 8.5 kb in length and contains six exons. Primers were designed to amplify the entire coding region and intron/exon boundaries of the NAGLU gene in 10 fragments. The PCR products were analysed for sequence changes using SSCP analysis and fluorescent DNA sequencing technology. Sixteen different putative mutations were detected in DNA from 14 MPS IIIB patients, 12 of which have not been found previously. The mutations include four deletions (219-237del19, 334-358del25, 1335delC, 2099delA), two insertions (1447-1448insT, 1932-1933insGCTAC), two nonsense mutations (R297X, R626X), and eight missense mutations (F48C, Y140C, R234C, W268R, P521L, R565W, L591P, E705K). In this study, the Y140C, R297X, and R626X mutations were all found in more than one patient and together accounted for 25% of mutant alleles.


Length variations in the NA stalk of an H7N1 influenza virus have opposite effects on viral excretion in chickens and ducks.
A deletion of ∼20 amino acids in the stalk of neuraminidase is frequently observed upon transmission of influenza A viruses from waterfowl to domestic poultry. A pair of recombinant H7N1 viruses bearing either a short- or long-stalk neuraminidase was genetically engineered. Inoculation of the long-stalk-neuraminidase virus resulted in a higher cloacal excretion in ducks and led conversely to lower-level oropharyngeal excretion in chickens, associated with a higher-level local immune response and better survival. Therefore, a short-stalk neuraminidase is a determinant of viral adaptation and virulence in chickens but is detrimental to virus replication and shedding in ducks.


Patients' long-term experiences following obesity surgery with a focus on eating behaviour: A qualitative study.
This study explored long-term consequences of obesity surgery. Interpretative phenomenological analysis was used to analyse transcripts of 10 interviews with patients who underwent surgery 8 or more years ago. Experiences were described under three broad themes: eating behaviours, relationship with food and quality of life. Although patients described variability within these themes, describing different patterns of change, analysis revealed associations between themes and outcomes. In particular, those who reported successful weight loss also described the functionalization of food, the development of new coping strategies and a process of positive reinvention creating a new sense of self.


Unusual anti-leukemia activity of nanoformulated naproxen and other non-steroidal anti-inflammatory drugs.
The non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used pharmaceuticals worldwide. Interestingly, many of them have significant anticancer properties too. However, the poor water solubility of certain NSAIDs limits their application for cancer treatment. Nanosizing of such drugs can help to improve the solubility and this may result in enhanced anticancer activities too. Moreover, over dosages and the accompanying side effects of NSAIDs can be minimized by improving their solubility and bioavailability. Successful nanoformulation of three NSAIDs: ibuprofen (IBP), ketoprufen (KP) and naproxen (NAP) using a novel evaporation assisted solvent-antisolvent interaction (EASAI) method is reported here. Three water soluble and biocompatible polymers: polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC) were used to stabilize the drug nanoparticles. Particles having spherical morphology with average size below 30nm were thoroughly characterized using dynamic light scattering and field emission scanning electron microscopy (FESEM) imaging. The nanoformulation resulted in ten to fifteen fold improvements in the solubility and significant enhancement in the in-vitro drug release profiles of the NSAIDs. Anticancer screening of the nanoformulated NSAIDs against five different cancer cell lines such as MCF-7 (Human breast cancer cell line), (Human pancreatic cancer cell line) MIA-PA-CA-2, (Human colon cancer cell line) HT-29, (Human leukemia cell line) Jurkat and (human ovarian carcinoma cell line) A2780 was performed. All the nanoformulated samples showed improved anticancer activity against the Leukemia cancer cell line, out of which NAP-PVP showed the highest anti-cancer activity. The anti-Leukemia activity of NAP-PVP was more than twice that of doxorubicin which is a standard anticancer drug.


The role and impact of research positions within health care settings in allied health: a systematic review.
Embedding dedicated research positions within healthcare settings is a potential strategy to build allied health research capacity, with different health care organisations investing in such positions. The aim of this review was to gather evidence regarding the nature of the role of the research position in allied health professional (AHP) healthcare settings and the impact that these positions have on building research capacity. A systematic review was undertaken searching eight databases (Medline CINAHL, Cochrane, OTSeeker, Speechbite, PEDro, Web of Science, and Proquest) using English language restrictions. Both authors independently screened abstracts, reviewed full-text articles, extracted data and performed quality assessments using the Mixed Methods Appraisal Tool. Studies were included that reported the evaluation and/or components of the role of a dedicated research position with AHPs in any healthcare setting. A thematic analysis approach was used to synthesise findings. A total of 360 abstracts were initially screened, with 58 full text articles being reviewed. Eight unique studies were included in the thematic analysis clarifying either the nature of role of the research position (n = 7) or impact of the position (n = 4). Studies included mixed methods (n = 3), descriptive case study (n = 4), and observational (n = 1) designs. The majority of studies reported the research positions to provide academic support to individual clinicians and their teams, while developing their own research projects. Other studies reported support for research capacity building at a service and organisational level. Positive changes from these research positions was reported via increased individual research skills and participation and research outputs, improvements in research culture, attitudes and team and organisational level skills. Emerging evidence suggests that research positions embedded within healthcare settings can influence individual and team based research skills and research participation of AHPs. Future research is needed to further investigate the sustainability of changes arisen from research positions and what mechanisms of the positions have the greatest impact. Healthcare managers should consider how to support potential components of the research position roles identified in the literature, as well consider evaluating their impact on research capacity, cultural and attitudinal changes of AHP staff in addition to traditional research metrics.


The insular cortex and the neuroanatomy of major depression.
The neuroanatomical substrate underlying Major Depressive Disorder (MDD) is incompletely understood. Recent reports have implicated the insular cortex. Two cohorts of participants with MDD were tested. In the first MDD cohort, we used standardised facial expression recognition tasks. In the second cohort, we focused on facial disgust recognition, a function associated with the insular cortex. T1 weighted MR imaging was used in the second cohort to test the hypothesis of abnormal insular volume being associated with impaired disgust recognition. Disgust recognition was particularly impaired in both cohorts. In the second cohort, the magnitude of the disgust recognition deficit correlated with reduced insula grey matter volume. Exploring the idea of insula involvement in MDD further, we identified the insular cortex and the anterior cingulate cortex as key neural correlates of core symptoms, in that scores of 3 clinical scales (the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Snaith-Hamilton Pleasure Scale) correlated with grey matter volume in these structures. MDD participants were clinically representative of specialist and academic psychiatric practice in the UK and presented with robust primary diagnoses; we did not exclude common co-morbidities such as anxiety and personality disorders. We propose that cognitive and emotional functions assumed to be associated with the insula are adversely affected in patients with MDD and that this may, therefore, represent the substrate for some core clinical features of MDD. Further exploration of the involvement of the insular cortex in MDD is warranted.


SNPchiMp v.3: integrating and standardizing single nucleotide polymorphism data for livestock species.
In recent years, the use of genomic information in livestock species for genetic improvement, association studies and many other fields has become routine. In order to accommodate different market requirements in terms of genotyping cost, manufacturers of single nucleotide polymorphism (SNP) arrays, private companies and international consortia have developed a large number of arrays with different content and different SNP density. The number of currently available SNP arrays differs among species: ranging from one for goats to more than ten for cattle, and the number of arrays available is increasing rapidly. However, there is limited or no effort to standardize and integrate array- specific (e.g. SNP IDs, allele coding) and species-specific (i.e. past and current assemblies) SNP information. Here we present SNPchiMp v.3, a solution to these issues for the six major livestock species (cow, pig, horse, sheep, goat and chicken). Original data was collected directly from SNP array producers and specific international genome consortia, and stored in a MySQL database. The database was then linked to an open-access web tool and to public databases. SNPchiMp v.3 ensures fast access to the database (retrieving within/across SNP array data) and the possibility of annotating SNP array data in a user-friendly fashion. This platform allows easy integration and standardization, and it is aimed at both industry and research. It also enables users to easily link the information available from the array producer with data in public databases, without the need of additional bioinformatics tools or pipelines. In recognition of the open-access use of Ensembl resources, SNPchiMp v.3 was officially credited as an Ensembl E!mpowered tool. Availability at http://bioinformatics.tecnoparco.org/SNPchimp.


Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice.
The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-γ-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3β. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-γ-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice.


The Modifying Effects of Galactomannan from Canadian-Grown Fenugreek (Trigonella foenum-graecum L.) on the Glycemic and Lipidemic Status in Rats.
Using high sucrose-fed male Sprague-Dawley rats, a study was conducted to determine the effects of feeding Galactomannan (GAL), a soluble dietary fiber extracted from Canadian-grown fenugreek seeds, on blood lipid and glucose responses. Rats (n = 8, 175-200 g) were randomly assigned to one of three high sucrose diets containing 10% cellulose (control), 7.5% cellulose + 2.5% GAL, and 5% cellulose + 5% GAL, respectively for 4 weeks. After 3 weeks, an oral glucose tolerance test (OGTT) was performed on each rat. A week later blood samples were collected to determine the effect on blood lipids. A significant reduction in glycemic response was observed only in 5% GAL group at 120 min following OGTT, when compared with that of control and 2.5% GAL groups. The plasma level of insulin was also significantly reduced (p<0.001) in 5% GAL-fed rats but at all times during OGTT. These animals also showed a reduction in body weight gain (p<0.05) in parallel with less food intake (p<0.05). All GAL-fed (2.5% and 5.0%) rats had significantly reduced plasma levels of triglycerides and total cholesterol in association with a reduction in epididymal adipose weight. Overall, this study demonstrated that feeding GAL from Canadian-grown fenugreek seeds has the potential to alter glycemic and lipidemic status and reduce abdominal fat in normal rats.


Is sperm FISH analysis still useful for Robertsonian translocations? Meiotic analysis for 23 patients and review of the literature.
Robertsonian translocations (RobT) are common structural chromosome rearrangements where carriers display a majority of chromosomally balanced spermatozoa from alternate segregation mode. According to some monotony observed in the rates of balanced segregation, is sperm FISH analysis obsolete for RobT carriers? Retrospective cohort research study on 23 patients analyzed in our center from 2003 to 2017 and compared to the data of 187 patients in literature from 1983 to 2017.Robertsonian translocation carriers were divided in six groups according to the chromosomes involved in the translocation: 9 patients from our center and 107 from literature carrying 45,XY,der(13;14) karyotype, 3 and 35 patients respectively with 45,XY,der(14;21), 5 and 11 patients respectively with 45,XY,der(13;15), 4 and 7 patients respectively with 45,XY,der(14;15), 1 and 4 patients respectively with 45,XY,der(13;22),and 1 and 10 patients respectively with 45,XY,der(14;22). Alternate segregation mode is predominant in our group of Robertsonian translocation carriers with 73.45% ±8.05 of balanced spermatozoa (min 50.92%; max 89.99%). These results are compliant with the data from literature for all translocations types (p > 0.05) and are consistent among the different types of Robertsonian translocations (p > 0.05) except for der(13;15) that exhibit lower balanced spermatozoa rates (p < 0.05 versus der(13;14), der(14;21), (13;21) and der(15;22)). Normozoospermic patients also display a significantly (p < 0.01) higher rate of balanced sperm cells than patients with abnormal seminograms whatever the defect implied. According to the discrepancies observed between der(13;15) and all the other Rob T carriers, the differences observed among patients presenting normal and abnormal sperm parameters and the input in genetical counselling, sperm FISH does not seem obsolete for these patients. Moreover, it seems important to collect more data for rare RobT.


Stochastic simulations of a synthetic bacteria-yeast ecosystem.
The field of synthetic biology has greatly evolved and numerous functions can now be implemented by artificially engineered cells carrying the appropriate genetic information. However, in order for the cells to robustly perform complex or multiple tasks, co-operation between them may be necessary. Therefore, various synthetic biological systems whose functionality requires cell-cell communication are being designed. These systems, microbial consortia, are composed of engineered cells and exhibit a wide range of behaviors. These include yeast cells whose growth is dependent on one another, or bacteria that kill or rescue each other, synchronize, behave as predator-prey ecosystems or invade cancer cells. In this paper, we study a synthetic ecosystem comprising of bacteria and yeast that communicate with and benefit from each other using small diffusible molecules. We explore the behavior of this heterogeneous microbial consortium, composed of Saccharomyces cerevisiae and Escherichia coli cells, using stochastic modeling. The stochastic model captures the relevant intra-cellular and inter-cellular interactions taking place in and between the eukaryotic and prokaryotic cells. Integration of well-characterized molecular regulatory elements into these two microbes allows for communication through quorum sensing. A gene controlling growth in yeast is induced by bacteria via chemical signals and vice versa. Interesting dynamics that are common in natural ecosystems, such as obligatory and facultative mutualism, extinction, commensalism and predator-prey like dynamics are observed. We investigate and report on the conditions under which the two species can successfully communicate and rescue each other. This study explores the various behaviors exhibited by the cohabitation of engineered yeast and bacterial cells. The way that the model is built allows for studying the dynamics of any system consisting of two species communicating with one another via chemical signals. Therefore, key information acquired by our model may potentially drive the experimental design of various synthetic heterogeneous ecosystems.


A Hypersensitivity-Like Response to Meloidogyne graminicola in Rice (Oryza sativa).
Meloidogyne graminicola is a major plant-parasitic nematode affecting rice cultivation in Asia. Resistance to this nematode was found in the African rice genotypes Oryza glaberrima and O. longistaminata; however, due to interspecific hybrid sterility, the introgression of resistance genes in the widely consumed O. sativa varieties remains challenging. Recently, resistance was found in O. sativa and, here, we report for the first time the histological and genetic characterization of the resistance to M. graminicola in Zhonghua 11, an O. sativa variety. Bright-light microscopy and fluorescence observations of the root tissue of this variety revealed that the root cells surrounding the nematode displayed a hypersensitivity-like reaction with necrotic cells at early stages of infection when nematodes are migrating in the root's mesoderm. An accumulation of presumably phenolic compounds in the nematodes' neighboring root cells was also observed. In addition, at a later stage of infection, not only were few feeding sites observed but also the giant cells were underdeveloped, underlining an incompatible interaction. Furthermore, we generated a hybrid O. sativa population by crossing Zhonghua 11 with the susceptible O. sativa variety IR64 in order to describe the genetic background of this resistance. Our data suggested that the resistance to M. graminicola infection was qualitative rather than quantitative and, therefore, major resistance genes must be involved in this infection process. The full characterization of the defense mechanism and the preliminary study of the genetic inheritance of novel sources of resistance to Meloidogyne spp. in rice constitute a major step toward their use in crop breeding.


Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase.
Natural killer (NK) cell cytotoxicity toward target cells depends on synergistic coactivation by NK cell receptors such as NKG2D and 2B4. How synergy occurs is not known. Synergistic phosphorylation of phospholipase PLC-gamma2, Ca(2+) mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 siRNA knockdown, but enhanced by knockdown of c-Cbl. c-Cbl inhibited Vav1-dependent signals, given that c-Cbl knockdown did not rescue the Vav1 defect. Moreover, c-Cbl knockdown and Vav1 overexpression each circumvented the necessity for synergy because NKG2D or 2B4 alone became sufficient for activation. Thus, synergy requires not strict complementation but, rather, strong Vav1 signals to overcome inhibition by c-Cbl. Inhibition of NK cell cytotoxicity by CD94-NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-Cbl knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms.


Disparate survival outcomes after front-line chemoimmunotherapy in older patients with follicular, nodal marginal zone and small lymphocytic lymphoma.
Using Surveillance, Epidemiology and End Results (SEER)-Medicare data (1996-2010), we compared survival and toxicity outcomes in 6993 patients older than 65 years with follicular (FL), nodal marginal zone (NMZL) and small lymphocytic lymphoma (SLL) receiving front-line therapy with rituximab (R), RCHOP (R, cyclophosphamide, doxorubicin, vincristine, prednisone), RCVP (R, cyclophosphamide, vincristine, prednisone) or R-fludarabine-containing regimens within 3 years from diagnosis. We demonstrated significant heterogeneity by histology after various regimens in multivariable survival models. Compared with RCHOP, overall survival was inferior with fludarabine-based regimens in FL (hazard ratio [HR] 1.53, p = 0.0001) and NMZL (HR 1.88, p = 0.0018). Conversely, in SLL outcomes were similar with any regimen. In NMZL and SLL, survival was not significantly different after single-agent R compared with multi-agent combinations. Choice of front-line chemotherapy may thus impact survival in older patients with indolent lymphomas, and heterogeneity by histology should be accounted for in clinical trials.


Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide Y neurons.
Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.


Expression profile of tyrosine kinases in breast cancer.
The tyrosine kinase (TK) family includes many growth factor receptors, cell cycle regulators, and oncoproteins. Moreover, the receptor TKs HER2/neu and epidermal growth factor receptor are overexpressed in a subgroup of breast tumors and correlate with more aggressive behavior. Thus, TKs are being actively pursued as therapeutic targets. The purpose of this study was to determine the expression pattern of TKs in breast cancer. Reverse transcription-PCR was performed with degenerate primers based on conserved motifs of the catalytic domains of TKs, and the identities of the reverse transcription-PCR products were determined by digestion with a panel of restriction enzymes. Using a TK display assay, we studied the TK profiles of 13 breast cancer cell lines and two normal immortalized breast epithelial cell lines. The TK display assay reproducibly demonstrated known differences in HER-2/neu expression between cell lines. Several TKs, including receptor TKs Axl, Cak, fibroblast growth factor receptor 4, HEK8, HER2/neu, c-MET, RET, and nonreceptor TKs ARG, BRK, Janus kinase 1, Rak, and YES were detected in breast cancer cells. Several kinases were differentially expressed among the cell lines. Similar TK profiles were found using RNA from human breast tumors. We conclude that there is significant variability in the TK expression pattern of breast cancers. This variability should be considered when selecting TK inhibitors to treat patients.


Perceptions of Acute Malnutrition and Its Management in Infants Under 6 Months of Age: A Qualitative Study in Rural Bangladesh.
World Health Organization guidelines advise community-based care (CBC) for "uncomplicated" severe acute malnutrition (SAM) infants <6 months old (u6m), whereas current national protocols refer to inpatient care. Our aim was to inform and shape future management strategies by understanding caregivers' and different stakeholders' perceptions on malnutrition among infants u6m on barriers/facilitators to future CBC. The methods used in this study are as follows: in-depth interviews and focus group discussions (FGDs) in southern Bangladesh, thematic analysis of transcripts, and sample size by data saturation. We conducted 5 FGDs with 29 caregivers, 4 with 29 health care workers, 4 key informant interviews each with community leaders and health supervisors. Five themes emerged. 1) Identification of SAM infants and care-seeking behavior: malnutrition was not noticed until severe, caregivers focused on clinical symptoms. Both allopathic and traditional healers were consulted. (2) Perceived causes of infant malnutrition: underlying illness, poor feeding practices, poverty, and local superstitions. (3) Views and preferences on treatment: hospitals and doctors were perceived as offering the best treatment, health care workers were also important, and respondents highlighted the need care of the caregiver/mother along with the infant. (4) Perceived benefits and risks of CBC: lower cost and greater accessibility were appreciated but worried about quality. (5) Community networks: wider family and social support networks were considered important aspects of care. There is considerable potential for CBC but needs to be better and earlier identification of at-risk infants, strengthening of health systems to avoid community options being perceived as "second best," engagement with families and communities to tackle "upstream" determinants of SAM, and care for mother-infant pairs.


Cost-effectiveness of malaria diagnostic methods in sub-Saharan Africa in an era of combination therapy.
To evaluate the relative cost-effectiveness in different sub-Saharan African settings of presumptive treatment, field-standard microscopy and rapid diagnostic tests (RDTs) to diagnose malaria. We used a decision tree model and probabilistic sensitivity analysis applied to outpatients presenting at rural health facilities with suspected malaria. Costs and effects encompassed those for both patients positive on RDT (assuming artemisinin-based combination therapy) and febrile patients negative on RDT (assuming antibiotic treatment). Interventions were defined as cost-effective if they were less costly and more effective or had an incremental cost per disability-adjusted life year averted of less than US$ 150. Data were drawn from published and unpublished sources, supplemented with expert opinion. RDTs were cost-effective compared with presumptive treatment up to high prevalences of Plasmodium falciparum parasitaemia. Decision-makers can be at least 50% confident of this result below 81% malaria prevalence, and 95% confident below 62% prevalence, a level seldom exceeded in practice. RDTs were more than 50% likely to be cost-saving below 58% prevalence. Relative to microscopy, RDTs were more than 85% likely to be cost-effective across all prevalence levels, reflecting their expected better accuracy under real-life conditions. Results were robust to extensive sensitivity analysis. The cost-effectiveness of RDTs mainly reflected improved treatment and health outcomes for non-malarial febrile illness, plus savings in antimalarial drug costs. Results were dependent on the assumption that prescribers used test results to guide treatment decisions. RDTs have the potential to be cost-effective in most parts of sub-Saharan Africa. Appropriate management of malaria and non-malarial febrile illnesses is required to reap the full benefits of these tests.


Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation.
Lymphadenopathy is a hallmark of acute infection with Borrelia burgdorferi, a tick-borne spirochete and causative agent of Lyme borreliosis, but the underlying causes and the functional consequences of this lymph node enlargement have not been revealed. The present study demonstrates that extracellular, live spirochetes accumulate in the cortical areas of lymph nodes following infection of mice with either host-adapted, or tick-borne B. burgdorferi and that they, but not inactivated spirochetes, drive the lymphadenopathy. The ensuing lymph node response is characterized by strong, rapid extrafollicular B cell proliferation and differentiation to plasma cells, as assessed by immunohistochemistry, flow cytometry and ELISPOT analysis, while germinal center reactions were not consistently observed. The extrafollicular nature of this B cell response and its strongly IgM-skewed isotype profile bear the hallmarks of a T-independent response. The induced B cell response does appear, however, to be largely antigen-specific. Use of a cocktail of recombinant, in vivo-expressed B. burgdorferi-antigens revealed the robust induction of borrelia-specific antibody-secreting cells by ELISPOT. Furthermore, nearly a quarter of hybridomas generated from regional lymph nodes during acute infection showed reactivity against a small number of recombinant Borrelia-antigens. Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88. Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes.


An Analysis of the Interaction Between Intelligent Software Agents and Human Users.
Interactions between an intelligent software agent (ISA) and a human user are ubiquitous in everyday situations such as access to information, entertainment, and purchases. In such interactions, the ISA mediates the user's access to the content, or controls some other aspect of the user experience, and is not designed to be neutral about outcomes of user choices. Like human users, ISAs are driven by goals, make autonomous decisions, and can learn from experience. Using ideas from bounded rationality (and deploying concepts from artificial intelligence, behavioural economics, control theory, and game theory), we frame these interactions as instances of an ISA whose reward depends on actions performed by the user. Such agents benefit by steering the user's behaviour towards outcomes that maximise the ISA's utility, which may or may not be aligned with that of the user. Video games, news recommendation aggregation engines, and fitness trackers can all be instances of this general case. Our analysis facilitates distinguishing various subcases of interaction (i.e. deception, coercion, trading, and nudging), as well as second-order effects that might include the possibility for adaptive interfaces to induce behavioural addiction, and/or change in user belief. We present these types of interaction within a conceptual framework, and review current examples of persuasive technologies and the issues that arise from their use. We argue that the nature of the feedback commonly used by learning agents to update their models and subsequent decisions could steer the behaviour of human users away from what benefits them, and in a direction that can undermine autonomy and cause further disparity between actions and goals as exemplified by addictive and compulsive behaviour. We discuss some of the ethical, social and legal implications of this technology and argue that it can sometimes exploit and reinforce weaknesses in human beings.


Can acupuncture enhance therapeutic effectiveness of antidepressants and reduce adverse drug reactions in patients with depression? A systematic review and meta-analysis.
Some depressed patients receive acupuncture as an adjunct to their conventional medications. This review aims to provide evidence on whether acupuncture can enhance the therapeutic effectiveness of antidepressants for treating depression, and explore whether acupuncture can reduce the adverse reactions associated with antidepressants. English and Chinese databases were searched for randomized controlled trials (RCTs) published until December 1, 2021. RCTs with a modified Jadad scale score ≥ 4 were included if they compared a group of participants with depression that received acupuncture combined with antidepressants with a control group that received antidepressants alone. Meta-analysis was performed, and statistical heterogeneity was assessed based on Cochran's Q statistic and its related P-value. Primary outcomes were the reduction in the severity of depression and adverse reactions associated with antidepressants, while secondary outcomes included remission rate, treatment response, social functioning, and change in antidepressant dose. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to evaluate the overall quality of evidence in the included studies. This review included 16 studies (with a total of 1958 participants). Most studies were at high risk of performance bias and at low or unclear risk of selection bias, detection bias, attrition bias, reporting bias, and other bias. Analysis of the 16 RCTs showed that, compared with antidepressants alone, acupuncture along with antidepressants reduced the Hamilton Depression Rating Scale-17 (HAMD-17) scores (standard mean difference [SMD] -0.44, 95% confidence interval [CI] -0.55 to -0.33, P < 0.01; I2 = 14%), Self-rating Depression Scale (SDS) scores (SMD -0.53, 95% CI -0.84 to -0.23, P < 0.01; I2 = 79%), and the Side Effect Rating Scale (SERS) scores (SMD -1.11, 95% CI -1.56 to -0.66, P < 0.01; I2 = 89%). Compared with antidepressants alone, acupuncture along with antidepressants improved World Health Organization Quality of Life-BREF scores (SMD 0.31, 95% CI 0.18 to 0.44, P < 0.01; I2 = 15%), decreased the number of participants who increased their antidepressant dosages (relative risk [RR] 0.32, 95% CI 0.22 to 0.48, P < 0.01; I2 = 0%), and resulted in significantly higher remission rates (RR 1.52, 95% CI 1.26 to 1.83, P < 0.01; I2 = 0%) and treatment responses (RR 1.35, 95% CI 1.24 to 1.47, P < 0.01; I2 = 19%) in terms of HAMD-17 scores. The HAMD-17, SDS and SERS scores were assessed as low quality by GRADE and the other indices as being of moderate quality. Acupuncture as an adjunct to antidepressants may enhance the therapeutic effectiveness and reduce the adverse drug reactions in patients receiving antidepressants. These findings must be interpreted with caution, as the evidence was of low or moderate quality and there was a lack of comparative data with a placebo control. INPLASY202150008.


Osteomyelitis due to multiple rare infections in a patient with idiopathic CD4 lymphocytopenia.
A 26-year-old male patient presented with features suggestive of osteomyelitis involving the entire left femur, hip joint and knee joint. Culture from the debrided tissue grew Acinetobacter spp. and he was treated with sensitivity based antibiotics but the symptoms did not resolve. The synovial biopsy showed multinucleated giant cells and acid fast bacilli on Ziehl Neelsen stain. Cartridge based nucleic acid amplification test (GeneXpert) was negative. The Mycobacteria growth indicator tube culture was found to be positive for Mycobacterium abscessus. The patient was started on imipenem, amikacin and macrolide based therapy. There was partial response initially but the patient worsened again. A girdle stone arthroplasty with cemented nail (with tobramycin) insertion after debridement of the infected tissue was done. Potassium hydroxide (KOH) mount from the debridement sample was found to be positive for aseptate hyphae suggestive of mucormycosis. He was treated with liposomal amphotericin B. He was evaluated for immunodeficiency in view of multiple atypical infections and was found to have a low CD4 count. The patient was discharged on amikacin, azithromycin, trimethoprim-sulfamethoxazole and posaconazole. Follow up showed considerable resolution both clinically and radiologically. To our knowledge, this is the first reported case of osteomyelitis with co-infection of Acinetobacter spp., M. abscessus and mucormycetes. We report this case to highlight the possibility of multiple rare infections in patients with immunodeficiency. Also, atypical complicated bone infections, such as Mycobacterium abscessus and mucormycetes might require combined medical and surgical treatment.


Investigation of the water-stimulated Mg2+ insertion mechanism in an electrodeposited MnO2 cathode using X-ray photoelectron spectroscopy.
Batteries based on magnesium chemistry are being widely investigated as an alternative energy storage system to replace lithium-ion batteries. Mg batteries have multiple challenges, especially on the cathode side. The divalent Mg ion has slow insertion kinetics in many metal oxide cathodes conventionally used in Li-ion batteries. One solution that has been explored is adding water molecules into an organic electrolyte, which has been shown to aid in Mg insertion and improve performance of manganese oxide (MnO2) cathodes. While there have been studies on Mg insertion mechanisms into MnO2 in solely aqueous or organic electrolytes for some crystalline MnO2 polymorphs, our work is focused on water-containing organic electrolyte, where an H2O to Mg ratio of 6 : 1 is present. In this study, we report results based on ex situ XPS experiments, including both angle resolved and depth profiling studies to assess the surface reactions and determine the mechanism of Mg insertion into an amorphous, electrodeposited MnO2 cathode. We propose that in this mixed electrolyte system, there is a combined insertion/conversion reaction mechanism whereby Mg and H2O molecules co-insert into the MnO2 structure and a reaction between H2O and Mg creates an observable Mg(OH)2 layer at the surface of the MnO2. A more full understanding of the role of the water molecules is important to aid in the future design of cathode materials, especially when determining potential ways to integrate metal oxides in Mg batteries.


Blocking Ca(2+)-dependent synaptic release delays motoneuron differentiation in the rat spinal cord.
Development of motoneuron electrical properties and excitability was studied in spinal cord explants of rat embryos cultured for 1-3 weeks. The morphological organization of the spinal cord and synaptic inputs onto motoneurons were maintained in organ culture. The rate of differentiation of motoneuron resting potential and increase in membrane excitability was similar in vitro and in vivo, suggesting that these properties were regulated by cellular signals or extracellular differentiation-promoting factors that were preserved in culture. However, maturation of input resistance, action potential threshold and action potential maximum rate of rise was slower than in vivo. Culturing spinal cord explants with their dorsal root ganglia attached did not facilitate motoneuron differentiation. The role of newly formed synaptic pathways in regulating the changes in motoneuron electrical properties was studied in the presence of blockers of synaptic transmission. Motoneuron differentiation was delayed in spinal cords cultured in the presence of TTX, indicating that electrical activity influenced the time course of their development. However, blocking synaptic transmission with antagonists of glutamate, glycine, and GABAA receptors did not affect the rate of motoneuron differentiation, suggesting that maturation of motoneuron phenotype was independent of activation of these transmitter-gated channels. Incubating spinal cords in medium containing high-K+, which increased the frequency of spontaneous potentials, reversed the inhibitory effect of TTX. Similar to TTX action, motoneuron development was retarded when synaptic release was chronically blocked with either tetanus toxin or omega-conotoxin, a Ca2+ channel blocker. These findings suggested that electrical activity in spinal cord explants modulated motoneuron differentiation via Ca(2+)-dependent synaptic release of neurotransmitters or neurotrophic factors.


Antarctic stratospheric chemistry of chlorine nitrate, hydrogen chloride, and ice: release of active chlorine.
The reaction rate between atmospheric hydrogen chloride (HCl) and chlorine nitrate (ClONO(2)) is greatly enhanced in the presence of ice particles; HCl dissolves readily into ice, and the collisional reaction probability for ClONO(2) on the surface of ice with HCl in the mole fraction range from approximately 0.003 to 0.010 is in the range from approximately 0.05 to 0.1 for temperatures near 200 K. Chlorine (Cl(2)) is released into the gas phase on a time scale of at most a few milliseconds, whereas nitric acid (HNO(3)), the other product, remains in the condensed phase. This reaction could play an important role in explaining the observed depletion of ozone over Antarctica; it releases photolytically active chlorine from its most abundant reservoir species, and it promotes the formation of HNO(3) and thus removes nitrogen dioxide (NO(2)) from the gas phase. Hence it establishes the necessary conditions for the efficient catalytic destruction of ozone by halogenated free radicals. In the absence of HCl, ClONO(2) also reacts irreversibly with ice with a collision efficiency of approximately 0.02 at 200 K; the product hypochlorous acid (HOCI) is released to the gas phase on a time scale of minutes.