Synthesis and activity studies of N-[omega-N'-(adamant-1'-yl)aminoalkyl]- 2-(4'-dimethylaminophenyl)acetamides: in the search of selective inhibitors for the different molecular forms of acetylcholinesterase.
A series of N-[omega-N'-(adamant-1'-yl)aminoalkyl]-2-(4'- dimethylaminophenyl)acetamides were synthesized and tested as acetylcholinesterase inhibitors. A significant selectivity toward acetylcholinesterases from various natural sources, mainly differing in their quaternary structure and solubility, was pointed out. The interest of this kind of molecules as potential therapeutic agents for Alzheimer's disease is discussed.


The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα.
DNA mismatch repair (MMR) ensures replication fidelity by correcting mismatches generated during DNA replication. Although human MMR has been reconstituted in vitro, how MMR occurs in vivo is unknown. Here, we show that an epigenetic histone mark, H3K36me3, is required in vivo to recruit the mismatch recognition protein hMutSα (hMSH2-hMSH6) onto chromatin through direct interactions with the hMSH6 PWWP domain. The abundance of H3K36me3 in G1 and early S phases ensures that hMutSα is enriched on chromatin before mispairs are introduced during DNA replication. Cells lacking the H3K36 trimethyltransferase SETD2 display microsatellite instability (MSI) and an elevated spontaneous mutation frequency, characteristic of MMR-deficient cells. This work reveals that a histone mark regulates MMR in human cells and explains the long-standing puzzle of MSI-positive cancer cells that lack detectable mutations in known MMR genes.


Adolescent girls' physiological reactivity to real-world peer feedback: A pilot study to validate a Peer Expressed Emotion task.
Peer feedback becomes highly salient during adolescence, especially for girls. The way in which adolescents react to social feedback is associated with psychosocial adjustment and mental health. Consequently, researchers are increasingly interested in understanding the physiological and neural underpinnings of adolescent response to feedback by simulating the experience of rejection and acceptance using computer-based paradigms. However, these paradigms typically use nonfamiliar peers and the facade of internet chatrooms or games to present artificial peer feedback. The current study piloted the use of a novel and potentially more ecologically valid peer expressed emotion paradigm in which participants listen to prerecorded clips of ostensible personalized feedback made by their close friend. Physiological data measuring autonomic nervous system response were collected as an index of emotional reactivity/arousal and cognitive-affective processing. Results show promising preliminary evidence validating the task for future use. Participants (N = 18 girls, aged 11-17 years) reported feeling more positive following praise, relative to critical and neutral feedback, and reported feeling more upset following criticism, relative to praise and neutral feedback. Girls exhibited greater pupillary dilation, skin conductance levels (N = 17), and/or heart rate (N = 17) while listening to affectively charged, peer feedback compared with neutral yet personally relevant statements. Girls also exhibited variable physiological response when listening to praising versus critical feedback. Findings from this pilot study validate the use of this novel Peer Expressed Emotion task for the investigation of adolescents' emotional and physiological reactivity in response to real-world peer evaluation. However, it is important to recognize that this study provides only preliminary findings and that future research is needed to replicate the results in larger samples.


HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4.
After tissue damage, inflammatory cells infiltrate the tissue and release proinflammatory cytokines. HMGB1 (high mobility group box 1), a nuclear protein released by necrotic and severely stressed cells, promotes cytokine release via its interaction with the TLR4 (Toll-like receptor 4) receptor and cell migration via an unknown mechanism. We show that HMGB1-induced recruitment of inflammatory cells depends on CXCL12. HMGB1 and CXCL12 form a heterocomplex, which we characterized by nuclear magnetic resonance and surface plasmon resonance, that acts exclusively through CXCR4 and not through other HMGB1 receptors. Fluorescence resonance energy transfer data show that the HMGB1-CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone. Mononuclear cell recruitment in vivo into air pouches and injured muscles depends on the heterocomplex and is inhibited by AMD3100 and glycyrrhizin. Thus, inflammatory cell recruitment and activation both depend on HMGB1 via different mechanisms.


Oncocytoid artifact of the parotid gland: a newly reported artifact.
Electrocautery can induce significant alterations in the connective tissues and epithelium of specimens removed for diagnostic or therapeutic purposes. When electrocautery is used during parotid surgery, it can cause an oncocytoid artifact. The alterations described in this article are enlarged, tightly packed serous acinar cells with coarse to granular eosinophilic cytoplasm, distinct cell borders, and round basal nuclei that on cursory microscopic examination resemble oncocytes with respect to morphology. These changes are seen in conjunction with other, more recognized changes secondary to electrocautery and are believed to occur as a consequence of the electrothermal discharge. On the basis of our findings, this artifact is common is parotid surgical specimens and was misdiagnosed as benign oncocytic lesions in 5 cases.


Effect of reduction of phosphoric acid concentration on the shear bond strength of brackets.
The purpose of this study was to evaluate in vitro the effect of the reduction of phosphoric acid concentration on the shear bond strength of brackets to enamel. Twelve pairs of contralateral maxillary premolars were randomly divided into group 1 and group 2. Twelve additional upper premolars formed group 3. The three acid concentrations examined were 37% in group 1, 2% in group 2, and 5% in group 3. The buccal surfaces of the teeth were etched for 30 seconds, and metal brackets were bonded were Concise adhesive (3M Dental Products, St. Paul, Minn.). After storage of teeth in water at 37 degrees C for 1 week, a shear force was applied to the occlusal bracket wings in a direction parallel to the bracket base. The results showed that the mean shear bond strength after etching with 37% acid (x = 18.30 MPa) was significantly higher than that after etching with 2% acid (x = 15.28 MPa). The mean bond strength after etching with 5% acid (x = 16.49 MPa) was not significantly different from that after the use of the two other acids. The assessment of the Adhesive Remnant Index (ARI) showed that the amount of adhesive left on the teeth after debonding was smaller after etching with 2% acid than after etching with 37% acid or 5% acid. It was concluded that 2% phosphoric acid solution is appropriate for bonding of brackets. The reduced etching could be favorable in preventing enamel damage during the treatment and at the time of debonding.


Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease.
Impaired degradation of amyloid beta (Abeta) peptides could lead to Abeta accumulation, an early trigger of Alzheimer's disease (AD). How Abeta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered Abeta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced Abeta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Abeta levels, the relative abundance of Abeta1-42, and plaque load. CysC removal also attenuated Abeta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble Abeta and Abeta-associated neuronal deficits through inhibiting CatB-induced Abeta degradation.


[Going Beyond the Known: Pilot Study on Prevalence, Situational Context and Consequences of Sexual Abuse of Children and Adolescents in Germany].
The current study assesses prevalence rates, circumstances and consequences of sexual abuse in childhood and adolescence. A random sample from an urban population (18-69 years) was surveyed by postal or online questionnaire. Instruments included WHO-5 well-being index, knowledge on support services for children and adolescents experiencing sexual abuse, incidents and consequences of sexual abuse. 159 persons returned the questionnaire (17.3%). 18.2% experienced sexual abuse. Of these, 34.5% disclosed sexual abuse for the first time. Psychological well-being was significantly lower in sexually abused persons. There was a lack of knowledge regarding support services for sexually abused ones. The present design is applicable in the context of a nationwide representative survey on childhood sexual abuse and provides insights into the field of concealed sexual abuse.


Morphometric parameters of living human in-vitro fertilization embryos; importance of the asynchronous division process.
A total of 304 human pronuclear zygotes and cleaved embryos from the 2- to 9-cell stages, obtained during invitro fertilization attempts, were photographed and retrospectively analysed after transfer for their morphology and size in relation to their developmental stage, using the Imagenia programme of a Biocom 500 image analyser. Morphometric parameters were calculated from the perimeters, surface measurements, theoretical diameters and circularity factors for the different structures analysed. This report provides the morphometric characteristics of living embryos. For the whole population the mean values were: 157.4 microns for the external zona pellucida diameter, 121.8 microns for the internal zona pellucida diameter, 17.9 microns for the thickness of the zona pellucida and 117.2 microns for the embryo cell mass diameter. The morphometric characteristics of the pronuclear-stage population were significantly different from the cleaved cell stages. If the zona pellucida and cell mass embryo diameters increased slowly from the 2- to 9-cell stages, embryonic external diameters were higher and zona pellucida thicknesses were lower in odd than even number blastomere embryos. Preliminary results show that in cases where implantation occurs, the embryo has a lower zona pellucida thickness. A comparison of the different embryo cell stages confirmed the existence of an asynchronous division process during early embryo development. Global results show no evidence of morphometric differences between subpopulations of the embryos according to their microscopic grading. Deviations from the normal asynchronous division process, however, appear to be a new parameter to take into account during embryo scoring.(ABSTRACT TRUNCATED AT 250 WORDS)


The capacity of Th2 lymphocytes to deliver B-cell help requires expression of the transcription factor STAT3.
CD4(+) T-cell help for B cells is crucial for effective Ab responses. Although follicular T helper (Tfh) cells have emerged as the main providers of T-cell help to B lymphocytes during the germinal center reaction, much less is known about the helper capacities of other effector CD4(+) T cells. The purpose of the present study was to evaluate the acquisition of B-cell help capacity of canonically derived T helper 2 (Th2) cells, a Th-cell subset originally considered responsible for B-cell help in vivo. We demonstrate herein that developing Th2 cells in mice co-express activated forms of signal transducer and activator of transcription 6 (STAT6) and STAT3 and that STAT3 expression was required for the capacity of Th2 cells to provide B-cell help. Thus, Th2 lymphocytes share a common, STAT3-mediated activation program for the acquisition of optimal B-cell help capacity with Tfh cells. Moreover, the expression of STAT3 in Th2 cells enhanced the IgG1-to-IgE class switch ratio in vivo, a finding with important implications for understanding the molecular basis of allergic diseases.


Kinetics of Schiff base formation between the cholesterol ozonolysis product 3-beta-hydroxy-5-oxo-5,6-secocholestan-6-al and phosphatidylethanolamine.
The kinetics of Schiff base formation between the cholesterol ozonolysis product 3beta-hydroxy-5-oxo-5,6-secocholestan-6-al and dimyristoyl phosphatidylethanolamine was investigated. The activation energy of Schiff base formation at temperatures above and below the phase transition of the phospholipid was calculated. Increase in the activation energy derived from perturbation of the surface structure by the process of Schiff base formation was demonstrated. The presence of the Schiff base with the aldolization product of the oxysterol was also observed and its significance is discussed.


Single agent infusional 5-fluorouracil is not effective second-line therapy after raltitrexed (Tomudex) in advanced colorectal cancer.
Raltitrexed (Tomudex) is currently licensed for first-line treatment of advanced colorectal cancer. We evaluated 101 patients treated with raltitrexed whose data were collected prospectively, in order to study the outcome of second-line treatments used after this drug. Of 98 evaluable patients, 50 received second-line treatments, the commonest being 5-fluorouracil (5-FU)-based therapy (22 patients with 20 evaluable) and mitomycin-c (MMC) (22 patients with 18 evaluable). Only 1 response was seen in a patient treated with 5-FU and MMC and none following other treatments. This patient was not evaluable for outcome of raltitrexed treatment, having stopped after two courses. Patients who had responded to raltitrexed and later progressed off treatment were more likely to be offered second-line 5-FU, but despite the earlier sensitivity to thymidylate synthase inhibition, response rates were minimal. Underlying mechanisms for this lack of activity and proposals for future studies are discussed.


The development of burn scar contractures and impact on joint function, disability and quality of life in low- and middle-income countries: A prospective cohort study with one-year follow-up.
The aim of this study was to assess the development of burn scar contractures and their impact on joint function, disability and quality of life in a low-income country. Patients with severe burns were eligible. Passive range of motion (ROM) was assessed using lateral goniometry. To assess the development of contractures, the measured ROM was compared to the normal ROM. To determine joint function, the normal ROM was compared to the functional ROM. In addition, disability and quality of life (QoL) were assessed. Assessments were from admission up to 12 months after injury. Thirty-six patients were enrolled, with a total of 124 affected joints. The follow-up rate was 83%. Limited ROM compared to normal ROM values was observed in 26/104 joints (25%) at 12 months. Limited functional ROM was observed in 55/115 joints (48%) at discharge and decreased to 22/98 joints (22%) at 12 months. Patients who had a contracture at 12 months reported more disability and lower QoL, compared to patients without a contracture (median disability 0.28 versus 0.17 (p = 0.01); QoL median 0.60 versus 0.76 (p = 0.001)). Significant predictors of developing joint contractures were patient delay and the percentage of TBSA deep burns. The prevalence of burn scar contractures was high in a low-income country. The joints with burn scar contracture were frequently limited in function. Patients who developed a contracture reported significantly more disability and lower QoL. To limit the development of burn scar contractures, timely access to safe burn care should be improved in low-income countries.


[Narratives created by images: photography, collective health and the construction of memory in the writing of local history].
An analysis is made of the meanings that emanate from a set of photographs collected by Luiz Palmier (1893-1955) relating to São Gonçalo Hospital, named after the municipality in Greater Rio de Janeiro. The images comprise a narrative that points to the progress experienced at the hospital, especially in healthcare, which was a paradigm for the modern period in the 1930s and 1940s. Luiz Palmier, who was the doctor and founder of the hospital, was a public figure that played a key role in the local history and its impacts on a regional and national scale.


Epidermolysis bullosa naevi reveal a distinctive dermoscopic pattern.
Large, asymmetrical and irregularly pigmented naevi in patients with epidermolysis bullosa (EB) have been reported often to mimic cutaneous melanoma clinically. As the biological course of these peculiar moles is benign, we assessed EB naevi with a dermatoscope to determine whether they could be reliably differentiated from cutaneous melanoma. We evaluated digital dermoscopic images of 23 EB naevi from 11 patients with EB and analysed these pigmented lesions according to pattern analysis, ABCD rule of dermoscopy and the seven-point checklist. Melanoma-associated dermoscopic criteria such as multicomponent pattern (20 of 23), atypical pigment network (17 of 23), irregular dots/globules (16 of 23), irregular pigmentation (22 of 23) and an atypical vascular pattern (seven of 23) were frequently seen in EB naevi. In contrast, other criteria frequently associated with melanoma progression, such as irregular streaks, blue-whitish veil, regression structures (blue-whitish areas) or black dots, were rarely seen. Most lesions gave false-positive results when the scores of the dermoscopic diagnostic algorithms were calculated. Recurring dermoscopic structures in EB naevi reveal a distinctive dermoscopic pattern of this recently defined entity. Although EB naevi represent an exception to dermoscopic diagnostic algorithms, their dermoscopic evaluation most often allows us to estimate their benign nature. Nevertheless, as an unequivocal discrimination from malignant melanoma in vivo is sometimes not possible, regular clinical follow up of EB naevi with histopathological evaluation of highly suspicious lesions is mandatory.


Identification of two distinct allergenic sites on ryegrass-pollen allergen, Lol p IV.
Lol p IV is an important allergen of ryegrass pollen. For the immunochemical identification of antigenic and/or allergenic site(s), murine monoclonal antibodies (MAbs) were prepared against Lol p IV. The hybridoma cell-culture supernatants were screened for anti-Lol p IV antibodies by a combination of ELISA and Western immunoblot analyses. The MAbs were finally purified from ascites on a Mono Q ion-exchange column. In a competitive radioimmunoassay with Lol p IV as the solid phase and 125I-labeled MAbs, it was established that MAbs 90, 91, 92, 93, and 94, although they differed in their relative affinities, recognized in common with one another an epitope designated as antigenic site A, whereas MAb 12 recognized a different epitope referred to as site B. Sites A and B were also demonstrated to constitute allergenic determinants of Lol p IV. Differences in the repertoire of specificities of the human IgE antibodies directed to Lol p IV were also demonstrated. Interestingly, it was found that sera from both allergic as well as from nonatopic individuals had IgG antibodies to sites A and/or B.


Alternatives for skin sensitisation: Hazard identification and potency categorisation: Report from an EPAA/CEFIC LRI/Cosmetics Europe cross sector workshop, ECHA Helsinki, April 23rd and 24th 2015.
In the two years since the last workshop report, the environment surrounding the prediction of skin sensitisation hazards has experienced major change. Validated non-animal tests are now OECD Test Guidelines. Accordingly, the recent cross sector workshop focused on how to use in vitro data for regulatory decision-making. After a review of general approaches and six case studies, there was broad consensus that a simple, transparent stepwise process involving non-animal methods was an opportunity waiting to be seized. There was also strong feeling the approach should not be so rigidly defined that assay variations/additional tests are locked out. Neither should it preclude more complex integrated approaches being used for other purposes, e.g. potency estimation. All agreed the ultimate goal is a high level of protection of human health. Thus, experience in the population will be the final arbiter of whether toxicological predictions are fit for purpose. Central to this is the reflection that none of the existing animal assays is perfect; the non-animal methods should not be expected to be so either, but by integrated use of methods and all other relevant information, including clinical feedback, we have the opportunity to continue to improve toxicology whilst avoiding animal use.


Effect of complement inhibition and heparin coating on artificial surface-induced leukocyte and platelet activation.
Exposure of blood to artificial surfaces, as in cardiopulmonary bypass, induces an inflammatory response involving complement, leukocyte and platelet activation. To elucidate the specific role of complement in this process, studies were performed on blood circulated in polyvinyl chloride tubing in the absence and presence of complement inhibitors. Parallel experiments were performed with heparin-coated polyvinyl chloride tubing, which is known to prevent complement and cell activation. A novel experimental model was used, based on human whole blood anticoagulated with lepirudin. Complement activation products, myeloperoxidase, lactoferrin, and thrombospondin were quantified in enzyme immunoassays. Leukocyte CD11b expression and leukocyte-platelet conjugates were detected by flow cytometry. Increased levels of C3 activation products, alternative pathway convertase, and the terminal SC5b-9 complex, combined with unchanged levels of C1rs-C1-inhibitor complexes and marginal changes in C4 activation demonstrated that complement was activated through the alternative pathway. Granulocyte and monocyte CD11b expression and granulocyte-platelet conjugate formation were efficiently attenuated by blocking either factor D, C3, C5, or C5a receptor. In contrast, monocyte-platelet conjugate formation and release of myeloperoxidase, lactoferrin, and thrombospondin were not reduced by complement inhibition. Heparin-coated polyvinyl chloride tubing efficiently reduced all inflammatory markers studied, except for C1rs-C1-inhibitor complexes, which increased, consistent with the enhancing effect of heparin on C1-inhibitor function. This effect did not, however, reduce fluid-phase classic pathway activation induced by heat-aggregated immunoglobulin G. Leukocyte and platelet activation in response to artificial materials occur by mechanisms that vary in their dependence on complement. Heparin coating precludes both the complement-dependent and complement-independent reactions.


Blocked metabotropic glutamate receptor 5 enhances chemosensitivity in hepatocellular carcinoma and attenuates chemotoxicity in the normal liver by regulating DNA damage.
DNA damaging agents are used as chemotherapeutics in many cancers, including hepatocellular carcinoma (HCC). However, they are associated with problems such as low sensitivity to chemotherapy and the induction of liver injury, underscoring the need to identify new therapies. Here, we investigated the differential regulatory effect of metabotropic glutamate receptor 5 (mGlu5) on chemosensitivity in HCC and chemotoxicity to the normal liver. The expression of mGlu5 was higher in HCC than in the normal liver, and correlated with poor prognosis according to The Cancer Genome Atlas database and Integrative Molecular Database of Hepatocellular Carcinoma. Cisplatin, oxaliplatin or methyl methanesulfonate (MMS) caused cell death by decreasing mGlu5 expression in HCC cells and increased mGlu5 expression in hepatic cells. In HCC cells, inhibition of mGlu5 aggravated MMS-induced DNA damage by increasing intracellular Ca2+ overload and mitogen-activated protein kinase (MAPK) activation, thereby promoting cell death, and activation of mGlu5 rescued the effect of MMS. However, in hepatic cells, mGlu5 inhibition alleviated MMS-induced DNA damage by downregulating Ca2+-derived MAPK pathways to advance hepatic cell survival. The opposite effects of mGlu5 overexpression or knockdown on MMS-induced DNA damage supported that cell death is a result of the differential regulation of mGlu5 expression. Inhibition of mGlu5 increased chemosensitivity and decreased chemotoxicity in a rat tumor model. This study suggests that mGlu5 inhibition could act synergistically with HCC chemotherapeutics with minimal side effects, which may improve the treatment of patients with HCC in the future.


The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response.
Arthropod-borne (arbo-) viruses have emerged as a major human health concern. Viruses transmitted by mosquitoes are the cause of the most serious and widespread arbovirus diseases worldwide and are ubiquitous in both feral and urban settings. Arboviruses, including dengue and West Nile virus, are injected into vertebrates within mosquito saliva during mosquito feeding. Mosquito saliva contains anti-haemostatic, anti-inflammatory and immunomodulatory molecules that facilitate the acquisition of a blood meal. Collectively, studies investigating the effects of mosquito saliva on the vertebrate immune response suggest that at high concentrations salivary proteins are immmunosuppressive, whereas lower concentrations modulate the immune response; specifically, T(H)1 and antiviral cytokines are downregulated, while T(H)2 cytokines are unaffected or amplified. As a consequence, mosquito saliva can impair the antiviral immune response, thus affecting viral infectiousness and host survival. Mounting evidence suggests that this is a mechanism whereby arbovirus pathogenicity is enhanced. In a range of disease models, including various hosts, mosquito species and arthropod-borne viruses, mosquito saliva and/or feeding is associated with a potentiation of virus infection. Compared with arbovirus infection initiated in the absence of the mosquito or its saliva, infection via mosquito saliva leads to an increase in virus transmission, host susceptibility, viraemia, disease progression and mortality.


Driven Dynamics of Long-Time Bond-Breaking Events.
We present a predict-correct trajectory propagation (PCTP) method for simulating nonequilibrium driven dynamics of the long-time bond-breaking event in an atomic force microscope (AFM). Whereas the parallel replica method can extend the time scale of molecular dynamics (MD) simulations of infrequent-event systems with high parallel efficiency, the second aspect of the time scale difficulty in MD simulations for slow-driven systems, namely, the unphysically high attempt frequency of an infrequent event, cannot be resolved by this method. Here, we take a gold nanojunction under mechanical pulling as a simulation system and demonstrate that the PCTP simulation is capable of capturing key transition dynamics of bond breaking predicted by accurate MD simulations in the activationless regime, such as at cryogenic temperature with high pulling rates. The PCTP algorithm includes three steps: (i) the trajectory prediction of the AFM tip, (ii) the atomic structural relaxation of the nanojunction, and (iii) the trajectory correction of the tip motion predicted by step (i). Application of the PCTP simulation to the bond breaking at AFM experimental pulling rates reveals different rupture mechanisms, depending on temperature and single-atom nanojunction structures, which are consistent with recent AFM bond-breaking observations.


Flortaucipir tau PET imaging in semantic variant primary progressive aphasia.
The semantic variant of primary progressive aphasia (svPPA) is typically associated with frontotemporal lobar degeneration (FTLD) with longTAR DNA-binding protein (TDP)-43-positive neuropil threads and dystrophic neurites (type C), and is only rarely due to a primary tauopathy or Alzheimer's disease. We undertook this study to investigate the localisation and magnitude of the presumed tau Positron Emission Tomography (PET) tracer [18F]Flortaucipir (FTP; also known as T807 or AV1451) in patients with svPPA, hypothesising that most patients would not show tracer uptake different from controls. FTP and [11C]Pittsburgh compound B PET imaging as well as MRI were performed in seven patients with svPPA and in 20 controls. FTP signal was analysed by visual inspection and by quantitative comparison to controls, with and without partial volume correction. All seven patients showed elevated FTP uptake in the anterior temporal lobe with a leftward asymmetry that was not observed in healthy controls. This elevated FTP signal, largely co-localised with atrophy, was evident on both visual inspection and quantitative cortical surface-based analysis. Five patients were amyloid negative, one was amyloid positive and one has an unknown amyloid status. In this series of patients with clinical profiles, structural MRI and amyloid PET imaging typical for svPPA, FTP signal was unexpectedly elevated with a spatial pattern localised to areas of atrophy. This raises questions about the possible off-target binding of this tracer to non-tau molecules associated with neurodegeneration. Further investigation with autopsy analysis will help illuminate the binding target(s) of FTP in cases of suspected FTLD-TDP neuropathology.


Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a.
Human mast cells (huMC) increase surface expression of FcgammaRI (CD64) in response to IFNgamma. Subsequent receptor aggregation of FcgammaR1 using CD64-specific F(ab')(2) or antibody directed against FcgammaR1-bound IgG results in cell activation. Human mast cells may be observed degranulating in inflammation associated with autoimmune disease and where IFNgamma is produced. We sought to determine if human mast cells cultured in IFNgamma would degranulate in response to aggregated IgG, what mediators might be generated (i.e., cytokines and eicosanoids), and whether C3a might enhance such activation. Activation of IFNgamma-treated huMC sensitized with 1 microg/ml aggregated IgG(1) resulted in 15-30% degranulation (beta-hexosaminidase release), which was half-maximal by 7.5 min; no degranulation was observed using heat-generated aggregates of IgG(2), IgG(3), or IgG(4). Activation using aggregated IgG(1) led to PGD(2) and LTC(4) generation as well as enhanced IL-3, IL-13, GM-CSF, and TNFalpha production. Preincubation of cells with F(ab')(2) from CD64-specific clone 10.1 reduced aggregated IgG(1)-mediated beta-hexosaminidase release by 38% while degranulation was unaffected by blocking FcgammaRII with F(ab')(2)-specific antibody (clone 7.3). Simultaneous activation of huMC via aggregated IgG and C3a led to additive degranulation. These data support a mechanism by which mast cells may contribute to the inflammatory component in fibrosis, vasculitis, and arthritis.


Molecular and clinical significance of FLT3, NPM1, DNMT3A and TP53 mutations in acute myeloid leukemia patients.
Acute myeloid leukemia (AML) is a type of blood cancer that affects the bone marrow and blood cells. AML is characterized by the rapid growth and accumulation of abnormal white blood cells, known as myeloblasts, which interfere with the production of normal blood cells. The main aim was to determine the relationship between these genetic alterations and the clinico-haematological parameters and prognostic factors with therapy for Iraqi patients with AML. We used Sanger Sequencing to detect the mutations in 76 AML patients. Clinical data of AML patients were retrospectively analysed to compare the prognosis of each gene mutation group. Somatic mutations were identified in 47.4% of the enrolled patients in a core set of pathogenic genes, including FLT3 (18 patients, 23.7%), DNMT3A (14, 18.4%), NPM1 (11, 14.5%) and TP53 (5, 6.8%). As multiple mutations frequently coexisted in the same patient, we classified patients into 10 further groups. Two novel mutations were detected in FLT3-ITD, with new accession numbers deposited into NCBI GenBank (OP807465 and OP807466). These two novel mutations were computationally analysed and predicted as disease-causing mutations. We found significant differences between patients with and without the detected mutations in disease progression after induction therapy (remission, failure and death; pv = < 0.001) and statistically significant differences were reported in total leukocyte count (pv = < 0.0001). These genes are among the most frequently mutated genes in AML patients. Understanding the molecular and clinical significance of these mutations is important for guiding treatment decisions and predicting patient outcomes.


Impact of Abnormal Potassium on Arrhythmia Risk During Pediatric Digoxin Therapy.
Digoxin is used in children with heart failure and tachyarrhythmia. Its use in patients with single ventricle anatomy has increased following evidence of improved interstage survival after the Norwood procedure. Digoxin has a narrow therapeutic window and may alter serum potassium balance, inducing arrhythmias. We hypothesized digoxin use in the setting of abnormal serum potassium levels is associated with arrhythmias. We reviewed all patients ≤ 18 years who received digoxin while admitted at our institution from 2014 to 2021. Admissions < 2 nights were excluded. We compared patients with a hemodynamically significant arrhythmia to those without. We performed adjusted mixed-effects logistic regression with arrhythmia as the outcome variable and potassium status as the predictor variable; adjusting for weight, route of digoxin administration, digoxin indication, serum creatinine, and number of interacting drugs prescribed. Abnormal potassium was defined as serum levels < 3.5 mmol/L or > 6.0 mmol/L. There were 268 encounters in 171 patients. Potassium levels were abnormal in 75.5% of patients who experienced an arrhythmia during digoxin administration, compared to 42.6% who did not (p < 0.001). Odds of arrhythmia was 138% higher in patients with abnormal potassium receiving digoxin (AOR = 2.38, 95% CI 1.07-5.29, p = 0.03). Receiving intravenous digoxin was also associated with a 7.35 odds of cardiac arrhythmia (AOR 7.35, p = 0.006, 95% CI 1.79-30.26). Odds of arrhythmia is increased during digoxin administration when pediatric patients have abnormal potassium levels. Vigilant attention to potassium levels is essential to prevent adverse outcomes during digoxin therapy.


Addiction to protein kinase Cɩ due to PRKCI gene amplification can be exploited for an aptamer-based targeted therapy in ovarian cancer.
PRKCI, the gene for protein kinase Cι (PKCι), is frequently amplified in ovarian cancer and recent studies have shown that PKCι participates in ovary tumorigenesis. However, it is unknown whether PKCι is differentially involved in the growth/survival between PRKCI-amplified and non-amplified ovarian cancer cells. In this study, we analyzed ovarian cancer patient dataset and revealed that PRKCI is the only PKC family member significantly amplified in ovarian cancer and PRKCI amplification is associated with higher PKCι expression. Using a panel of ovarian cancer cell lines, we found that abundance of PKCι is generally associated with PRKCI amplification. Interestingly, silencing PKCι led to apoptosis in PRKCI-amplified ovarian cancer cells but not in those without PRKCI amplification, thus indicating an oncogenic addiction to PKCɩ in PRKCI-amplified cells. Since small-molecule inhibitors characterized to selectively block atypical PKCs did not offer selectivity nor sensitivity in PRKCI-amplified ovarian cancer cells and were even cytotoxic to non-cancerous ovary surface or fallopian tube epithelial cells, we designed an EpCAM aptamer-PKCι siRNA chimera (EpCAM-siPKCι aptamer). EpCAM-siPKCι aptamer not only effectively induced apoptosis of PRKCI-amplified ovarian cancer cells but also greatly deterred intraperitoneal tumor development in xenograft mouse model. This study has demonstrated a precision medicine-based strategy to target a subset of ovarian cancer that contains PRKCI amplification and shown that the EpCAM aptamer-delivered PKCι siRNA may be used to suppress such tumors.


Effect of solubility enhancement on nasal absorption of meloxicam.
Besides the opioids the standard management of the World Health Organization suggests NSAIDs (non-steroidal anti-inflammatory drugs) alone or in combination to enhance analgesia in malignant and non-malignant pain therapy. The applicability of NSAIDs in a nasal formulation is a new approach in pharmaceutical technology. In order to enhance the nasal absorption of meloxicam (MX) as an NSAID, its salt form, meloxicam potassium monohydrate (MXP), registered by Egis Plc., was investigated in comparison with MX. The physico-chemical properties of the drugs (structural analysis, solubility and dissolution rate) and the mucoadhesivity of nasal formulations were controlled. In vitro and in vivo studies were carried out to determine the nasal applicability of MXP as a drug candidate in pain therapy. It can be concluded that MX and MXP demonstrated the same equilibrium solubility at the pH5.60 of the nasal mucosa (0.017mg/ml); nonetheless, MXP indicated faster dissolution and a higher permeability through the synthetic membrane. The animal studies justified the short Tmax value (15min) and the high AUC of MXP, which is important in acute pain therapy. It can be assumed that the low mucoadhesivity of MXP spray did not increase the residence time in the nasal cavity, and the elimination from the nasal mucosa was therefore faster than in the case of MX. Further experiments are necessary to prove the therapeutic relevance of this MXP-containing innovative intranasal formulation.


Increased PMN CD11b/CD18 expression following post-traumatic ARDS.
We investigated the role of polymorphonuclear leukocytes (PMN) in the pathogenesis of post-traumatic adult respiratory distress syndrome (ARDS). Two groups of patients were studied: Group I (n = 29) represents trauma patients studied within 24 hr of admission to the SICU, and Group II (n = 10) represents a subset of Group I patients who subsequently developed ARDS. Circulating pulmonary artery PMN were then assayed for CD11b/CD18 expression, MTT-Formazan production, intracellular H2O2 production, and superoxide anion release. PMN from Group II patients were upregulated with regard to all of the PMN functions assayed within 24 hr of the diagnosis of ARDS being made. Subsequently, longitudinal assays were performed on 17 patients at risk for the development of ARDS. In 6 of 7 patients prior to the clinical recognition of ARDS, CD11b/CD18 expression and MTT-Formazan production increased significantly over baseline. These results suggest that: (i) ARDS coincides with increased CD11b/CD18 expression on PMN cell surfaces, (ii) PMN oxidative metabolism increases at the onset of ARDS, and (iii) changes in circulating pulmonary artery PMN may provide markers for the development of ARDS in the traumatized patient.


Tetracycline removal via adsorption and metal-free catalysis with 3D macroscopic N-doped porous carbon nanosheets: Non-radical mechanism and degradation pathway.
Recently, metal-based carbon materials have been verified to be an effective persulfate activator, but secondary pollution caused by metal leaching is inevitable. Hence, a green metal-free 3D macroscopic N-doped porous carbon nanosheets (NPCN) was synthesized successfully. The obtained NPCN showed high adsorption capacity of tetracycline (TC) and excellent persulfate (PS) activation ability, especially when calcined at 700 °C (NPCN-700). The maximum adsorption capacity of NPCN-700 was 121.51 mg/g by H-bonds interactions. Moreover, the adsorption process followed pseudo-second-order kinetics model and Langmuir adsorption isotherm. The large specific surface area (365.27 mg/g) and hierarchical porous structure of NPCN-700 reduced the mass transfer resistance and increased the adsorption capacity. About 96.39% of TC was removed after adding PS. The effective adsorption of the catalyst greatly shortened the time for the target organic molecules to migrate to the catalyst. Moreover, the NPCN-700 demonstrated high reusability with the TC removal rate of 80.23% after 4 cycles. Quenching experiment and electron paramagnetic resonance (EPR) test confirmed the non-radical mechanism dominated by 1O2. More importantly, the C = O groups, defects and Graphitic N acted as active sites to generate 1O2. Correspondingly, electrochemical measurement revealed the direct electron transfer pathway of TC degradation. Finally, multiple degradation intermediates were recognized by the LC-MS measurement and three possible degradation pathways were proposed. Overall, the prepared NPCN had excellent application prospects for removal of antibiotics due to its remarkable adsorption and catalytic degradation capabilities.


Effect of inhalation anesthesia with isoflurane on circadian rhythm of murine intraocular pressure.
For research on circadian intraocular pressure (IOP), rebound tonometers are widely used with or without general anesthesia as a non-invasive approach to obtain IOP values. However, whether general anesthesia such as inhalation anesthesia with isoflurane affects the circadian rhythm of IOP and in turn IOP measurements is currently unclear. As such, data reporting IOP values obtained under general anesthesia should be interpreted with caution. The purpose of this study was to evaluate how general anesthesia with isoflurane inhalation affects the circadian rhythm of IOP. C57Bl/6J strain mice maintained using a 12h:12h light/dark cycle (lights on and off at ZT0 and ZT12, respectively) were used. IOPs were measured using a rebound tonometer (Icare TonoLab) before and 3, 5, 10, 15, and 30 min after initiating anesthesia in both light and dark phases (ZT 2-6 and ZT 14-18, respectively). Awake IOPs and IOPs at 3 and 5 min after anesthesia initiation were also obtained at ZT5, 8, 11, 14, 17, and 20 to assess IOP diurnal curves under gas anesthesia. IOP values gradually decreased after anesthesia initiation in both light and dark phases (P < 0.001) and there was no interaction between light/dark phase and anesthesia time (P = 0.88). There was a slight, but not significant, reduction in IOP 3 min after initiating anesthesia (P = 0.23), and significant decreases in IOP occurred at subsequent timepoints (P ≤ 0.001). Both awake and anesthetized mice showed a robust IOP rhythm that reached a peak and trough in the dark and light phase, respectively. Awake IOP levels did not significantly differ from those for anesthetized mice at 3 min after anesthesia initiation at all time points (P ≥ 0.07). Both awake and anesthetized mice demonstrated a robust circadian rhythm for IOP. Murine IOP showed similar gradual decreases under inhalation anesthesia with isoflurane in both the light and dark phases. IOPs measured using a rebound tonometer within 3 min of initiating isoflurane anesthesia were comparable to awake IOPs, and thus may be useful to monitor the circadian rhythm of IOP in mice.


Effects of processing moisture on the physical properties and in vitro digestibility of starch and protein in extruded brown rice and pinto bean composite flours.
The influence of pinto bean flour and processing moisture on the physical properties and in vitro digestibility of rice-bean extrudates has been investigated. Brown rice: pinto bean flour (0%, 15%, 30%, and 45% bean flour) were extruded under 5 moisture conditions (17.2%, 18.1%, 18.3%, 19.5%, and 20.1%). Physical properties [bulk density, unit density, radial expansion, axial expansion, overall expansion, specific volume, hardness, color, water solubility index, and water absorption index] and in vitro starch and protein digestibilities were determined. Increasing bean flour and processing moisture increased density and hardness while decreasing expansion. Rapidly digestible starch decreased and resistant starch increased as bean substitution and processing moisture increased. In vitro protein digestibility increased with increasing bean flour or with decreasing processing moisture. Incorporating bean flour into extruded snacks can negatively affect physical attributes (hardness, density, and expansion) while positively affecting in vitro starch (decrease) and protein (increase) digestibilities.


Anatomy of the posterior antebrachial cutaneous nerve: practical information for the surgeon operating on the lateral aspect of the elbow.
To investigate the anatomic relationships of the posterior antebrachial cutaneous nerve (PABCN) to anatomic landmarks on the lateral side of the elbow. The PABCN was explored in 30 cadaveric upper extremities. Distances were noted from easily identifiable structures including the lateral epicondyle, the lateral intermuscular septum, and the radial nerve. The path of the PABCN follows the spiral groove initially, diverging as the radial nerve pierces the lateral intermuscular septum. The PABCN emerges from the posterior compartment through a hiatus in the deep fascia at a mean of 6.6 cm proximal to the lateral epicondyle and passes a mean of 2.1 cm anterior to the lateral epicondyle. The anatomic relationships determined in this study should enable the surgeon to avoid injuring the PABCN when performing surgery in the lateral elbow region.


Detection of specific IgE antibodies in the sera of patients allergic to birch pollen using recombinant allergens Bet v 1, Bet v 2, Bet v 4: evaluation of different IgE reactivity profiles.
Birch pollen is a significant cause of immediate hypersensitivity among susceptible subjects in temperate climates, affecting 5-54% of the population in western Europe. We examined the specific serum IgE antibodies towards recombinant allergens Bet v 1, Bet v 2 and Bet v 4 in birch-sensitive patients from the province of Cuneo, north-west Italy. Sera were obtained from 372 patients with symptomatic birch pollen-induced allergic rhinitis and/or asthma. A subgroup of these patients suffered from oral allergy syndrome after eating apple. Their sera were evaluated for specific IgE against natural birch pollen and apple extract, as well as Bet v 1, Bet v 2 and Bet v 4 using Pharmacia CAP system (Pharmacia, Uppsala, Sweden). Of 372 patients 215 (57.80%) had serum-specific IgE towards Bet v 1. A total of 166 sera (44.62%) contained serum-specific IgE to Bet v 2, while Bet v 4 IgE reactivity was documented in 35 subjects (9.41%). Moreover, 146 (39.25%) patients were monosensitized to Bet v 1; 96 (25.81%) patients were monosensitized to Bet v 2; only four sera (1.08%) contained specific IgE towards Bet v 4. Thirty-nine sera (11.02%) did not contain specific IgE to these individual birch pollen allergens. Of course, all 372 sera (100%) had specific IgE against natural birch pollen extract, of which 162 (43.55%) contained specific IgE to apple extract (75.35% of Bet v 1 positive sera). In this study we observed that three birch pollen recombinant allergens alone, could sufficiently identify 90% of birch pollen-sensitive patients. Therefore, for a more precise IgE profile of patients allergic to birch, further purified birch pollen allergens (i.e. Bet v 6, Bet v 7, Bet v 8) will be required.


The interplay of matching and non-matching job demands and resources on emotional exhaustion among teachers.
We investigated how matching and non-matching demands and resources are related to emotional exhaustion (EE) in teachers. Theoretically, we draw on the Demand-Induced Strain Compensation (DISC) model that proposes that demands, resources, and strains are multidimensional and comprise emotional, cognitive, and physical components. We first tested whether resources compensate aversive effects of demands. Second, as proposed by the triple-match principle, we tested whether interaction effects between job demands and resources are most likely if demands, resources, and outcomes relate to the same dimension. We retrieved data from 177 school teachers; a subsample was re-examined after a time lag of about 21 month (N = 56). Linear regression analyses reveal concurrent and longitudinal main and interaction effects of teacher-specific emotional and cognitive job demands and resources on EE. Results support the compensation principle and triple-match principle. Therefore, the DISC model seems to provide a valuable framework for the study of interaction effects in job stress research and, in particular, for interventions to reduce job strain in teachers.


Development of sentinel lymph node biopsy technique in patients with salivary gland cancer using the IDEAL framework.
Salivary cancer is rare and comprises a variety of histological subtypes and clinical behaviors. There is no agreed method of estimating the risk of occult metastasis or managing the clinically N0 neck.Sentinel node biopsy (SNB) may offer a solution but previous studies have not produced a reliable imaging protocol. This study uses novel technology and trial methodology to develop a reliable SNB technique, with primary aim to identify peri-and intraglandular sentinel nodes. IDEAL framework was used to undertake SNB in clinically node negative salivary gland cancer. Patients with cT1-2 N0 salivary cancer were eligible. Lymphoscintigraphy was undertaken using Tc-99 m labelled nanocoll. Injection technique as well as adjunctive use of freehand SPECT (fhSPECT), near-infrared (NIR) fluorescence imaging, and navigation-guided surgery were used and optimisied during the study protocol. 10 patients were recruited. Initial protocol of peritumoural injection of Tc99 m nanocoll showed poor image resolution. Subsequent adjustment to single intratumoural injection allowed identification of intraglandular sentinel nodes. Fh/SPECT and NIR fluorescence imaging found intraglandular lymph nodes otherwise not recognizable to the naked eye. In two cases occult lymph node metastasis were identified. This study has shown the IDEAL framework is vital in allowing iterative changes in surgical protocol in the light of experience. This study has produced a reliable method for detection of sentinel nodes, in particular the ability to identify intra- and periglandular nodes with diagnosis of occult metastatic deposits and no false negative results. Our protocol can be readily transferred in to larger scale studies.


Destabilization of cationic lipid vesicles by an anionic hydrophobically modified poly(N-isopropylacrylamide) copolymer: a solid-state 31P NMR and 2H NMR study.
The effect of binding PNIPAM-Py-Gly, a copolymer of N-isopropylacrylamide, N-[4-(1-pyrenyl)butyl]-N-n-octadecylacrylamide and N-glycydyl-acrylamide, on membrane stability in cationic multilamellar vesicles (MLVs) was examined using solid-state phosphorus (31P) and deuterium (2H) nuclear magnetic resonance (NMR) spectroscopy. For MLVs of composition n-octadecyldiethylene oxide (ODEO)+cholesterol (CHOL)+1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)+dimethyldioctadecylammonium bromide (DODAB) (molar ratios 75:10.5:10.5:4), PNIPAM-Py-Gly induced a complete conversion from a bilayer-type 31P NMR spectrum to one characteristic of lipids undergoing isotropic motional averaging, indicating the existence of regions of high local membrane curvature. This response was sustained even at elevated temperatures. For MLVs of composition POPC+1,2-dioleoyloxy-3-(trimethylammonio)-propane (DOTAP), only at high levels of DOTAP and ionic strength did PNIPAM-Py-Gly induce even a partial conversion to an isotropic-type 31P NMR spectrum. At lower pH this effect was diminished. Raising the temperature eliminated the isotropic 31P NMR spectral component, and this effect was not reversible upon returning to room temperature. 2H NMR spectroscopy of headgroup-deuterated DOTAP and POPC confirmed the 31P NMR results, but did not provide specific surface electrostatic information. We conclude that the binding of PNIPAM-Py-Gly to phospholipid-based vesicles is dominated by electrostatic attraction between cationic lipids and the polymer's glycine residues. At high binding levels, the polymer assumes a collapsed conformation at the surface, resulting in regions of high local curvature of the lipid assembly. For ODEO-based liposomes, these effects are magnified by the additional contribution of hydrogen bonding to the strength of polymer binding.


The role of intra-specific mechanisms and predation in regulating the numbers of the lime aphid, Eucallipterus tiliae L.
Analysis of changes in numbers of the lime aphid, Eucallipterus tiliae L., reveals that there is an overcompensated density dependent factor acting within years, and an inverse density dependent factor acting between years. Because of its effect on the aphid's rate of development and reproduction the variation in temperature from year to year acts as a density disturbing factor.There is no evidence from laboratory experiments to suggest that the quality of its food influences the numbers of the lime aphid. However, qualitative changes in the aphid following period of aphid abundance are shown to be important in the overcompensated density dependent response. The more prevalent insect predators influence the regulating process as they eat most of the aphids that remain after an aphid population has declined from a very high level of abundance. Their action results in a more overcompensated response than would occur in their absence.


The probability of causal conditionals.
Conditionals in natural language are central to reasoning and decision making. A theoretical proposal called the Ramsey test implies the conditional probability hypothesis: that the subjective probability of a natural language conditional, P(if p then q), is the conditional subjective probability, P(q/p). We report three experiments on causal indicative conditionals and related counterfactuals that support this hypothesis. We measured the probabilities people assigned to truth table cases, P(pq), P(p notq), P( notpq) and P( notp notq). From these ratings, we computed three independent predictors, P(p), P(q/p) and P(q/ notp), that we then entered into a regression equation with judged P(if p then q) as the dependent variable. In line with the conditional probability hypothesis, P(q/p) was by far the strongest predictor in our experiments. This result is inconsistent with the claim that causal conditionals are the material conditionals of elementary logic. Instead, it supports the Ramsey test hypothesis, implying that common processes underlie the use of conditionals in reasoning and judgments of conditional probability in decision making.


Gender differences in social reactions to abuse disclosures, post-abuse coping, and PTSD of child sexual abuse survivors.
This research examines the understudied issue of gender differences in disclosure, social reactions, post-abuse coping, and PTSD of adult survivors of child sexual abuse (CSA). Data were collected on a cross-sectional convenience sample of 733 college students completing a confidential survey about their demographic characteristics, sexual abuse experiences, disclosure characteristics, post-abuse coping, and social reactions from others. Female students reported greater prevalence and severity of CSA, more distress and self-blame immediately post-assault, and greater reliance on coping strategies of withdrawal and trying to forget than male students. Women were more likely to have disclosed their abuse to others, to have received positive reactions, and to report greater PTSD symptom severity, but were no more likely to receive negative reactions upon disclosure than men. Women delaying disclosure had greater PTSD symptom severity, whereas men's symptoms did not vary by timing of disclosure. Additional regression analyses examined predictors of PTSD symptom severity and negative and positive social reactions to abuse disclosures. Several gender differences were observed in this sample of college students in terms of sexual abuse experiences, psychological symptoms, coping, PTSD, and some aspects of disclosure and social reactions from others.


Developing psychiatric competence during medical education and internship: contributing factors.
The study describes the learning process in psychiatry of medical students through their clerkship and internship, It focused upon the development of students' attitudes to psychiatry, subjective psychiatric competence and self-confidence. The relationships between the participants' background, aspects of the learning environment, their attitudes to psychiatry, psychiatric competence and psychiatric self-confidence were explored in order to develop an empirical model of the learning process.The participants were medical students at the University of Tromsoe, Norway. The study was prospective and based on students' self-reports, Structural panel modelling and growth curve analyses were used to explore the complex interactions between the variables over time and to create a model of the learning processes. The medical students significantly increased their subjective competence and psychiatric self-confidence during their clerkship in psychiatry and maintained them during their internship. Previous psychiatric experience, attitudes towards psychiatry and current psychiatric experience contributed to subjective psychiatric competence, Competence in turn had a positive effect on self-confidence. Interestingly, those with greater subjective competence also appeared to have more psychiatric experience during their internship. An empirical model of the important aspects of the learning process was developed.


COVID-19 vaccine safety monitoring in Republic of Korea from February 26, 2021 to October 31, 2021.
This study aimed to present data on reported adverse events following coronavirus disease 2019 (COVID-19) vaccination in Republic of Korea from February 26 to October 31, 2021, and to determine whether any significant patterns emerged from an analysis of the characteristics of suspected adverse event cases for each type of vaccine. Adverse events following COVID-19 vaccination reported by medical doctors and forensic pathologists were analyzed. Cases of suspected anaphylaxis were classified using the Brighton Collaboration definition. By October 31, 2021, a total of 353,535 (0.45%) adverse events were reported after 78,416,802 COVID-19 vaccine doses. Of the adverse events, 96.4% were non-serious and 3.6% were serious. The most frequently reported adverse events were headache, myalgia, and dizziness. Of the 835 reported deaths after COVID-19 vaccination, 2 vaccine-related deaths were confirmed. Suspected anaphylaxis was confirmed in 454 cases using the Brighton Collaboration definition. The commonly reported symptoms were similar to those described in clinical trials. Most reported adverse events were non-serious, and the reporting rate of adverse events following COVID-19 vaccination was higher in women than in men (581 vs. 315 per 100,000 vaccinations). Confirmed anaphylaxis was reported in 5.8 cases per 1,000,000 vaccinations.


Postoperative Pancreatic Fistula After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Update on Incidence, Risk Factors, Management, and Clinical Sequelae in 1,141 Patients.
An update on the incidence, risk factors, clinical sequalae, and management of postoperative pancreatic fistula (POPF) following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Retrospective analysis of prospectively collected data from the St George CRS/HIPEC database. Sixty-five (5.7%) out of 1,141 patients developed a POPF. Patients with POPFs were older, had a higher peritoneal cancer index, longer operation time, and required more units of blood intraoperatively. Splenectomy and distal pancreatectomy were significant risk factors for developing POPFs. While there was no effect on overall long-term survival in POPF patients, they did suffer higher rates of Clavien-Dindo grade 3/4 complications, in-hospital deaths, and longer hospital length of stay. Of the 65 POPF patients, 23 were taken back to theatre, 48 required radiological drains and 7 underwent endoscopic retrograde cholangiopancreatography. There are multiple risk factors for developing POPFs that are non-modifiable. While POPFs are associated with increased postoperative morbidity, long-term survival does not appear to be affected.


Treatment patterns and outcomes of patients with locally advanced vulvar or vaginal cancer in British Columbia.
As vulvar and vaginal cancers are rare malignancies, treatment is extrapolated from the cervical cancer field. Further studies are necessary to evaluate whether surgery, radiotherapy (RT), or combined chemoRT is most beneficial. A retrospective chart review was conducted on patients diagnosed with vulvar or vaginal cancer in 2000-2017. Descriptive statistics was used to summarize demographic factors. Kaplan-Meier curves, log-rank tests, multivariate analysis with hazard ratios (HR) were conducted to compare survival outcomes, including overall survival (OS), disease-free survival, and cancer-specific survival, between surgery, RT, and chemoRT. This study included 688 patients with either vulvar (n = 560, 81%) or vaginal cancer (n = 128, 19%). Median age of diagnosis was 68 (27-98) years. In multivariate survival analysis, vulvar cancer was associated with more likelihood of death (HR: 1.50, p = 0.042) compared to vaginal cancer. For patients who received definitive RT, median OS was 63.8 months with concurrent chemotherapy vs. 46.3 months without for vulvar cancer (p = 0.75); for vaginal, median OS 100.4 with chemotherapy vs. 66.6 months without (p = 0.31). For vulvar cancer patients who received RT (n = 224), adding chemotherapy (n = 100) was not associated with statistically significant OS improvement (HR: 0.989, p = 0.957). Similarly, vaginal cancer patients who received chemoRT (n = 51) did not have significant OS benefit (HR: 0.720, p = 0.331) over patients who received RT (n = 49). In this retrospective study, chemoRT was not associated with significant improvements in survival compared to RT in vulvar or vaginal cancer. Future studies investigating novel therapies to treat these cancers are needed to improve patient outcomes.


Premarital mental health screening among the Saudi population.
This study was aimed at exploring attitudes and knowledge regarding, and acceptance of, premarital mental health screening among the Saudi population. A cross-sectional study was performed via an online survey distributed through social media. The survey comprised a set of 14 questions to be answered by individuals over 18 years of age living in KSA. A convenience sampling strategy was followed, and chi-square tests were used to establish associations. A P-value of 0.05 was considered to indicate significance. A total of 955 responses were received, most of which were from participants with no history of mental illness. However, most individuals were in favor of premarital mental health screening, because they did not want their children to inherit hereditary diseases or mental health problems. Higher parental education levels significantly contributed to respondents' acceptance of premarital screening. Most participants were aware of the concept of premarital screening but not for mental health disorders. This study highlighted a positive and accepting attitude among the Saudi population towards premarital mental health screening. Arranged marriages in the community and mental health stigma can create hesitancy towards screening measures. Healthcare professionals, public health officials, and policymakers are highly encouraged to increase awareness of premarital mental health screening and provide counseling regarding screening consultations before marriages.


Association between discrepancy in objective and subjective cognitive abilities and treatment response in patients with major depressive disorder: A CAN-BIND-1 study report.
Major Depressive Disorder (MDD) is characterized by objective and subjective cognitive deficits. Discrepancies between objective and subjective cognitive performance can reflect under- to over-estimations of cognitive abilities, and these discrepancies are referred to as cognitive self-appraisals. Despite evidence that low self-appraisals are associated with depression, the modifiability of self-appraisals and their association with treatment outcome remains unclear. The current study examined whether self-appraisals change following antidepressant treatment. Furthermore, we investigated the association of self-appraisals with treatment outcome. As part of the CAN-BIND-1 clinical trial, 154 patients with MDD completed measures of objective and subjective cognitive abilities, depressive symptoms, and functional outcomes (work productivity, psychosocial functioning, and quality of life) at baseline and post-escitalopram treatment. Self-appraisals were calculated based on discrepancies between objective and subjective cognitive abilities, with higher scores indicating overestimation of cognitive abilities. Baseline self-appraisals were not predictive of treatment outcomes. However, self-appraisals increased from pre- to post-treatment. Moreover, pre-post treatment increases in self-appraisals were associated with positive treatment response and remission, decreases in depressive symptoms, and improvements in work productivity, psychosocial functioning, and quality of life. The pre-post intervention design precluded examining the temporal precedence of change in self-appraisals versus depressive symptoms and functional outcomes. Findings are the first to demonstrate that self-appraisals are treatment-sensitive and are associated with treatment outcomes and recovery from MDD. Cognitive self-appraisals may represent a key marker of treatment response and a valuable target for assessment and intervention, as well as a potential mechanism underlying risk and recovery.


A Prospective Analysis of Radiation Oncologist Compliance With Early Peer Review Recommendations.
We conducted a prospective observational cohort study of physician compliance with daily early pretreatment planning peer review recommendations and quantified factors associated with compliance. All patient cases in our department are presented at 2 peer review conferences: (1) "early" preplanning, occurring daily for patients who have undergone simulation review, and (2) "late" (chart rounds), occurring weekly for patients who have started treatment. Peer review recommendations were prospectively recorded during early review, and compliance with recommendations was determined at chart rounds. Recommendations were assigned magnitude scores (minor, moderate, or major). We analyzed the association of patient, physician, and recommendation characteristics and compliance (scored as a binary variable) with early peer review recommendations, using logistic regression with a mixed effects model. From February 2017 to May 2018, 1271 patient cases underwent early peer review, and 326 (26%) received peer-based recommendations. Of 356 recommendations, 37% were minor, 36% were moderate, and 27% were major. Overall compliance was 59% (95% confidence interval, 54%-64%). On univariate analysis, compliance decreased as the recommendation magnitude increased (minor, 65%; moderate, 60%; major, 47%; P = .019; odds ratio, 0.71 per increase in magnitude). Compliance also differed among different treating physicians (range, 38%-73%, χ2 test, P = .003) but was not associated with other physician characteristics. Disease group and treatment technique were not associated with compliance. On multivariable analysis, increasing recommendation magnitude remained significantly associated with decreased compliance (multivariate P = .042; odds ratio, 0.74). Daily early peer review resulted in a substantial proportion of recommended changes. Compliance with early peer review recommendations was fair but varied among physicians. Compliance declined with increasing recommendation magnitude, suggesting that physicians may be reluctant to adopt major changes. These results highlight the potential importance of peer review timing.


Multisystem Lewy body disease and the other parkinsonian disorders.
Here we prioritize as multisystem Lewy body disease (MLBD) those genetic forms of Parkinson's disease that point the way toward a mechanistic understanding of the majority of sporadic disease. Pathological diagnosis of genetic subtypes offers the prospect of distinguishing different mechanistic trajectories with a common mutational etiology, differing outcomes from varying allelic bases, and those disease-associated variants that can be used in gene-environment analysis. Clearly delineating parkinsonian disorders into subclasses on the basis of molecular mechanisms with well-characterized outcome expectations is the basis for refining these forms of neurodegeneration as research substrate through the use of cell models derived from affected individuals while ensuring that clinically collected data can be used for therapeutic decisions and research without increasing the noise and confusion engendered by the collection of data against a range of historically defined criteria.


The ultrastructure of the epicardium epithelium of the slug, Arion ater (Linnaeus, 1758), (Pulmonata, Stylommatophora).
In the present paper we investigated the fine structure of terrestial slug Arion ater (L.) Interacisternal microtubules were formed in Arion ater, however they do not correspond to interacisternal polycylinders because they differ in size and they are not continuous with the membrane cistern. From our study it may be concluded that these intracisternal microtubules suggest an accumulation of protein.


Vulvar Crohn's Disease: Clinical Features and Outcomes.
Vulvar involvement is a rare complication of Crohn's disease (CD). The optimal treatment of vulvar CD is unknown. We conducted a 25-year retrospective cohort study of vulvar CD from 3 referral centers. Clinical features and outcomes were studied. Fifty patients were identified. The most common vulvar symptoms were pain (74%), edema (60%), ulcerations (46%), nodules (36%), and abscess (34%). Medical management leading to symptomatic improvement varied, and 5 patients ultimately required surgery. Vulvar CD manifests with a broad spectrum of symptoms. Aggressive medical management was frequently effective, although surgery was required in 10% of cases.


Remnant preservation technique versus standard technique for anterior cruciate ligament reconstruction: a meta-analysis of randomized controlled trials.
This meta-analysis was performed to compare the clinical outcomes of primary anterior cruciate ligament (ACL) reconstruction using the ACL remnant preservation technique versus the standard technique. PubMed, Embase, and the Cochrane Library were searched through December 24, 2017, to identify randomized controlled studies that compared the use of the ACL remnant preservation technique versus the standard technique for primary ACL reconstruction. Statistical heterogeneity among the trials was evaluated with chi-square and I-square tests. A sensitivity analysis was conducted to explore sources of heterogeneity. Subgroup analysis was performed to identify potential differences according to type of ACL remnant tissue (remnant bundle or remnant fibers). Seven studies with a combined 412 patients (208 in the remnant preservation technique group and 204 in the standard technique group) were included in the meta-analysis. There was a significant difference between the groups in Lysholm score (mean difference (MD), 2.20; 95% confidence interval (CI), 0.95-3.45; P = 0.0006) and side-to-side difference (MD, - 0.71; 95% CI, - 0.87 to - 0.55; P < 0.01). There was no significant difference between the groups in subjective International Knee Documentation Committee (IKDC) score, complications, pivot shift test, Lachman test, or overall IKDC score. Subgroup analysis demonstrated that for primary ACL reconstruction with preservation of remnant fibers, the remnant preservation technique was superior to the standard technique based on Lysholm scores (P < 0.01) and side-to-side difference (P < 0.01). Based on the current literature, using the remnant preservation technique showed a better clinical outcome than using the standard technique for patients undergoing primary ACL reconstruction with respect to Lysholm score and side-to-side difference. However, it remains unclear that there is a definite advantage to use the remnant preservation technique compared with the standard technique.


A case of aggressive angiomyxoma of the vulva.
Aggressive angiomyxoma (AA) is a rare mesenchymal neoplasm of the female pelvis and vulva, which has a tendency for local recurrence. AA is occasionally misdiagnosed as Bartholin's gland cyst or abscess, lipoma, simple labial cyst, or soft tissue tumors. We describe a case of AA on the outside of the left labium majus pudendi in a 28-year-old female. We were able to make the preoperative diagnosis of AA by magnetic resonance imaging (MRI) and ultrasound (US), and to perform complete surgical excision with a transperineal minimally invasive approach. The novelty of this case is the use of ultrasound for the diagnostic workup of the perineal tumor and determination of the incision line.


Pharmacokinetics of ginsenosides following repeated oral administration of red ginseng extract significantly differ between species of experimental animals.
We aimed to investigate ginsenoside pharmacokinetics in mice and rats following the repeated oral administration of red ginseng extract (RGE) (2 g/kg/day for 7 days). In mouse plasma, seven protopanaxadiol (PPD)-type ginsenosides (20(S)-ginsenoside Rb1, Rb2, Rc, Rd, Rg3, 20(S)-compound K, and 20(S)-PPD) and one protopanaxatriol (PPT)-type 20(S)-ginsenoside Re were detected, whereas 20(S)-ginsenoside Rb1, Rb2, Rc, Rd, 20(S)-PPD, and 20(S)-PPT were detected in rat plasma. The tetra- or tri-glycosylated PPD-type ginsenosides Rb1, Rb2, Rc, and Rd, high content ginsenosides in RGE, showed high plasma exposure, a short absorption time (Tmax), and a long elimination time (T1/2) among the ginsenosides detected in both species. Among the deglycosylated metabolites existing in the feces, 20(S)-compound K and 20(S)-PPD in mice and 20(S)-PPD and 20(S)-PPT in rats were found in the plasma samples. In addition to the differences in the ginsenosides detected in mice and rats, the Tmax and T1/2 of 20(S)-PPD and 20(S)-PPT in rats were greater than those in mice, suggesting the species-dependent difference in the gut metabolism and absorption of ginsenosides in the pathway from 20(S)-ginsenoside Rd to 20(S)-PPD and from 20(S)-ginsenoside Re to 20(S)-PPT. In conclusion, the choice of animal model should be the subject of careful consideration when exploring the pharmacology of RGE with specific focus on the plasma profile of an individual ginsenoside.


Influence of trem-1 gene polymorphisms on cytokine levels during malaria by Plasmodium vivax in a frontier area of the Brazilian Amazon.
The immunopathology during malaria depends on the level of inflammatory response generated. In this scenario, the TREM-1 has been associated with the severity of infectious diseases and could play an important role in the inflammatory course of malaria. We aimed to describe the allelic and genotypic frequency of four polymorphisms in the trem-1 gene in Plasmodium vivax-infected patients and to verify the association of these polymorphisms with clinical and immunological factors in a frontier area of the Brazilian Amazon. We included 76 individuals infected with P. vivax and 144 healthy controls living in the municipality of Oiapoque, Amapá, Brazil. The levels of TNF-α, IL-10, IL-2, IL-4, IL-5, and IFN-γ were measured by flow cytometry, while IL-6, sTREM-1, and antibodies against PvMSP-119 were evaluated by ELISA. The SNPs were genotyped by qPCR technique. Polymorphisms analysis, allelic and genotype, frequencies, and HWE calculation were determined by x2 test in R Software. The association between the parasitemia, gametocytes, antibodies, cytokines, and sTREM-1 with the genotypes of malaria and control groups was performed using the Kruskal-Wallis test, these analyzes were conducted in SPSS Software, at 5% significance level. All SNPs were successfully genotyped. Allelic and genotypic distribution was in Hardy-Weinberg Equilibrium. Furthermore, several associations were identified between malaria and control groups, with increased levels of IL-5, IL-6, IL-10, TNF-α, and IFN-γ in the infected individuals with rs6910730A, rs2234237T, rs2234246T, rs4711668C alleles compared to the homozygous wild-type and heterozygous genotypes of the controls (p-value < 0.05). No association was found for these SNPs and the levels of IL-2, and sTREM-1. The SNPs on the trem-1 gene are associated with the effector molecules of the innate immunity and may contribute to the identification and effective participation of trem-1 in the modulation of the immune response. This association may be essential for the establishment of immunization strategies against malaria.


Block copolymer-mediated synthesis of gold nanoparticles in aqueous solutions: segment effect on gold ion reduction, stabilization, and particle morphology.
We report here on the segment effects of poly(ethylene oxide)-containing block copolymers (PEO-BCP) on the reduction activity for tetrachloride gold(III) ([AuCl(4)](-)), interfacial activity for gold surface, colloidal stability, and morphology of gold nanoparticles formed in aqueous solutions. In particular, the effects of poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), polyethylene (PE) segments and amino group (NH(2)) on the rate of [AuCl(4)](-) reduction, adsorption of PEO-BCP onto gold surface, colloidal stability, and morphology of gold nanoparticles formed in aqueous solutions were examined using a poly(ethylene oxide)-poly(propylene oxide) triblock copolymer (PEO-PPO-PEO, Pluronic L44), an amino-terminated poly(ethylene oxide)-poly(propylene oxide) block copolymer (PEO-PPO-NH(2), SURFONAMINE® L-207), a poly(ethylene oxide) homopolymer (PEO, poly(ethylene glycol)2000), and a polyethylene-poly(ethylene oxide) block copolymer (PE-PEO). We found that the reduction activity of PEO-BCP for [AuCl(4)](-) became higher with the order of PEO-PPO-NH(2)<PE-PEO<PEO<PEO-PPO-PEO. The interfacial activity (affinity) of PEO-BCP for gold surface increased with the order of PEO<PE-PEO<PEO-PPO-PEO≪PEO-PPO-NH(2). Consequently, the colloidal stability of gold nanoparticles formed in aqueous PEO-PPO-NH(2) solutions was extremely high compared with that in PEO, PEO-PPO-PEO, and PE-PEO solutions. In addition, the size of gold nanoparticles formed in aqueous PEO-PPO-NH(2) solutions was much smaller than that in aqueous solutions of PEO-PPO-PEO, PEO or PE-PEO.


The vitamin D receptor as a potential target for the toxic effects of per- and polyfluoroalkyl substances (PFASs): An in-silico study.
Due to their persistence and toxicity, perfluoroalkyl and polyfluoroalkyl substances (PFASs) constitute significant hazards to human health and the environment. Their effects include immune suppression, altered hormone levels, and osteoporosis. Recently, the most studied PFAS, perfluorooctanoic acid (PFOA), was shown to competitively binding to the Vitamin D receptor (VDR). VDR plays a crucial role in regulating genes involved in maintaining immune, endocrine, and calcium homeostasis, suggesting it may be a target for at least some of the health effects of PFAS. Hence, this study examined the potential binding of 5206 PFASs to VDR using molecular docking, molecular dynamics, and free energy binding calculations. We identified 14 PFAS that are predicted to interact strongly with VDR, similar to the natural ligands. We further investigated the interactions of VDR with 256 PFASs of established commercial importance. Eighty-three (32%) of these 256 commercially important PFAS were predicted to be stronger binders to VDR than PFOA. At least 16 PFASs of regulatory importance, because they have been identified in water supplies and human blood samples, were also more potent binders to VDR than PFOA. Further, PFASs are usually found together in contaminated drinking water and human blood samples, which raises the concern that multiple PFASs may act together as a mixture on VDR function, potentially producing harmful effects on the immune, endocrine, and bone homeostasis.


Cryoablation of Lung Metastases: Review of Recent Literature and Ablation Technique.
This article reviews the current indications for image-guided thermal ablation of pulmonary metastatic disease. It also summarizes data regarding the efficacy and complications of lung cryoablation and present techniques for performing lung cryoablation as informed by the recent literature.


Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice.
Iodine is an essential component of thyroid hormones; high intake may lead to thyroid disease. Epidemiologic researches have shown that exposure to iodine may be involved in the onset and development of autoimmune thyroiditis. Iodine may induce hypothyroidism in patients with autoimmune thyroiditis in a dose-dependent manner. The aim of the present study was to investigate the effects of dosages of iodine on thyroid autoimmunity, morphology, structure, and function in autoimmune-prone animals. NOD.H-2h4 mice were randomly divided into normal iodine, 5-fold, 10-fold, 100-fold, 1,000-fold iodine excess group, anesthetized by diethyl ether and bleed from eye socket vein at 4, 8, 16, and 24 weeks after the commencement of experiment. Iodine and thyroid hormone levels in the thyroid tissue and sera, serum thyroglobulin antibody levels, as well as thyroid gland histological appearance were measured. Excessive iodine caused thyroid goiter, and there was a positive correlation between the thyroid weight and the dosage of iodine (r = 0.64-0.92, P < 0.01). Iodine overdose ultrastructurally damaged thyroid epithelial cells in a dose-dependent manner. The incidence of thyroiditis, as well as the degree of lymphocytic infiltration in the thyroid gradually increased as the dosage increased (r = 0.87-0.98, P </= 0.05). Excessive iodine intake might induce goiter, lead to thyroiditis, worsen lymphocytic infiltration, as well as damage to the thyroid follicular structure in a dose-dependent manner in autoimmune-prone NOD.H-2h4 mice.


Detecting exacerbations using the Clinical COPD Questionnaire.
Early treatment of COPD exacerbations has shown to be important. Despite a non-negligible negative impact on health related quality of life, a large proportion of these episodes is not reported (no change in treatment). Little is known whether (low burden) strategies are able to capture these unreported exacerbations. The Clinical COPD Questionnaire (CCQ) is a short questionnaire with great evaluative properties in measuring health status. The current explorative study evaluates the discriminative properties of weekly CCQ assessment in detecting exacerbations. In a multicentre prospective cohort study, 121 patients, age 67.4 ± 10.5 years, FEV1 47.7 ± 18.5% pred were followed for 6 weeks by daily diary card recording and weekly CCQ assessment. Weeks were retrospectively labeled as stable or exacerbation (onset) weeks using the Anthonisen symptom diary-card algorithm. Change in CCQ total scores are significantly higher in exacerbation-onset weeks, 0.35 ± 0.69 compared to -0.04 ± 0.37 in stable weeks (p < 0.001). Performance of the Δ CCQ total score discriminating between stable and exacerbation onset weeks was sufficient (area under the ROC curve 0.75). At a cut off point of 0.2, sensitivity was 62.5 (50.3-73.4), specificity 82.0 (79.3-84.4), and a positive and negative predictive value of 43.5 (35.0-51.0) and 90.8 (87.8-93.5), respectively. Using this cut off point, 22 (out of 38) unreported exacerbations were detected while 39 stable patients would have been false positively 'contacted'. Weekly CCQ assessment is a promising, low burden method to detect unreported exacerbations. Further research is needed to validate discriminative performance and practical implications of the CCQ in detecting exacerbations in daily care.


Culture model for the study of cerebral malaria: antibodies from Plasmodium falciparum-infected comatose patients inhibit the dendritic development of Purkinje cells.
The in vitro development of kitten Purkinje cells was inhibited by sera or IgG from cerebral malaria (CM) patients but not by sera from acute non-complicated malaria (NCM) cases. This inhibitory effect, quantified by computer-assisted methods, concerned the dendritic (though not the axonal) development and was found to be related to the presence of CM sera of self-reactive antibodies of the IgG class. These results suggest that protection acquired against the major complication of Plasmodium falciparum malaria may correspond to the repression of an abnormal stimulation of autoreactive B cells.


Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012.
Neonatal abstinence syndrome (NAS), a postnatal opioid withdrawal syndrome, increased threefold from 2000 to 2009. Since 2009, opioid pain reliever prescriptions and complications increased markedly throughout the United States. Understanding recent changes in NAS and its geographic variability would inform state and local governments in targeting public health responses. We utilized diagnostic and demographic data for hospital discharges from 2009 to 2012 from the Kids' Inpatient Database and the Nationwide Inpatient Sample. NAS-associated diagnoses were identified utilizing International Classification of Diseases, Ninth Revision, Clinical Modification codes. All analyses were conducted with nationally weighted data. Expenditure data were adjusted to 2012 US dollars. Between-year differences were determined utilizing least squares regression. From 2009 to 2012, NAS incidence increased nationally from 3.4 (95% confidence interval (CI): 3.2 to 3.6) to 5.8 (95% CI 5.5 to 6.1) per 1000 hospital births, reaching a total of 21,732 infants with the diagnosis. Aggregate hospital charges for NAS increased from $732 million to $1.5 billion (P<0.001), with 81% attributed to state Medicaid programs in 2012. NAS incidence varied by geographic census division, with the highest incidence rate (per 1000 hospital births) of 16.2 (95% CI 12.4 to 18.9) in the East South Central Division (Kentucky, Tennessee, Mississippi and Alabama) and the lowest in West South Central Division Oklahoma, Texas, Arkansas and Louisiana 2.6 (95% CI 2.3 to 2.9). NAS incidence and hospital charges grew substantially during our study period. This costly public health problem merits a public health approach to alleviate harm to women and children. States, particularly, in areas of the country most affected by the syndrome must continue to pursue primary prevention strategies to limit the effects of opioid pain reliever misuse.


Field dependence, laterality and the EEG.
There is evidence that an individual's 'cognitive style' is related to lateralization of function in the brain, and that this in turn is associated with characteristic EEG coherence spectra. We tested the hypothesis that field dependence (a measure of cognitive organization) and hand preference (a measure of functional organisation) relate to EEG coherence measures in a specific way. The predicted associations were based on the proposal that right preferent individuals have a more specific, and left preferents a more diffuse, system of functional units in the cortex. The association between alpha band resting EEG coherence (sampled on two occasions for both hemispheres from 12 right and 12 left preferent individuals), field dependence (Nyborg's criterion of frame dependence on a rod and frame test), and laterality scores (questionnaire and manual performance), was measured by Kendall's coefficient of concordance (W). Significant associations support the proposed model except for coherence within the left preferents' right hemisphere. It is argued that the right hemisphere is more specifically organised in strong sinistrals than the general model would predict. These and other results support the use of EEC coherence measures in the study of cerebral functional organisation.


Sonocatalytic and sonophotocatalytic degradation of Rhodamine 6G containing wastewaters.
The present work deals with degradation of aqueous solution of Rhodamine 6G (Rh 6G) using sonocatalytic and sonophotocatalytic treatment schemes based on the use of cupric oxide (CuO) and titanium dioxide (TiO2) as the solid catalysts. Experiments have been carried out at the operating capacity of 2 L and constant initial pH of 12.5. The effect of catalyst loading on the sonochemical degradation has been investigated by varying the loading over the range of 1.5-4.5 g/L. It has been observed that the maximum degradation of 52.2% was obtained at an optimum concentration of CuO as 1.5 g/L whereas for TiO2 maximum degradation was observed as 51.2% at a loading of 4 g/L over similar treatment period. Studies with presence of radical scavengers such as methanol (CH3OH) and n-butanol (C4H9OH) indicated lower extents of degradation confirming the dominance of radical mechanism. The combined approach of ultrasound, solid catalyst and scavengers has also been investigated at optimum loadings to simulate real conditions. The optimal solid loading was used for studies involving oxidation using UV irradiations where 26.4% and 28.9% of degradation was achieved at optimal loading of CuO and TiO2, respectively. Studies using combination of UV and US irradiations have also been carried out using the optimal concentration of the catalysts. It has been observed that maximum degradation of 63.3% is achieved using combined US and UV with TiO2 (4 g/L) as the photocatalyst. Overall it can be said that the combined processes give higher extent of degradation as compared to the individual processes based on US or UV irradiations.


Age-related vulnerabilities along the hippocampal longitudinal axis.
Evidence for an anterior-posterior gradient of age-related volume reduction along the hippocampal longitudinal axis has been reported in normal aging, but functional changes have yet to be systematically investigated. The current study applied an advanced brain mapping technique, large deformation diffeomorphic metric mapping (LDDMM), automatically delineating the hippocampus into the anterior and posterior segments based on anatomical landmarks. We studied this anterior-posterior gradient in terms of structural and functional MRI in 66 participants aged from 19 to 79 years. The results showed age-related structural volume reduction in both anterior and posterior hippocampi, with greater tendency for anterior decrease. FMRI task contrasts that robustly activated the anterior (associative/relational processing) and posterior (novelty) hippocampus independently, showed only significant reduction of activation in the anterior hippocampus as age increased. Our results revealed positive correlation between structural atrophy and functional decrease in the anterior hippocampi, regardless of task performance in normal aging. These findings suggest that anatomy and functions related to the anterior hippocampus may be more vulnerable to aging, than previously thought.


The updates and implications of cutaneous microbiota in acne.
Acne is a chronic inflammatory skin disorder that profoundly impacts the quality of life of patients worldwide. While it is predominantly observed in adolescents, it can affect individuals across all age groups. Acne pathogenesis is believed to be a result of various endogenous and exogenous factors, but the precise mechanisms remain elusive. Recent studies suggest that dysbiosis of the skin microbiota significantly contributes to acne development. Specifically, Cutibacterium acnes, the dominant resident bacterial species implicated in acne, plays a critical role in disease progression. Various treatments, including topical benzoyl peroxide, systemic antibiotics, and photodynamic therapy, have demonstrated beneficial effects on the skin microbiota composition in acne patients. Of particular interest is the therapeutic potential of probiotics in acne, given its direct influence on the skin microbiota. This review summarizes the alterations in skin microbiota associated with acne, provides insight into its pathogenic role in acne, and emphasizes the potential of therapeutic interventions aimed at restoring microbial homeostasis for acne management.


Collagen hemostat significantly reduces time to hemostasis compared with cellulose: COBBANA, a single-center, randomized trial.
This single-center, randomized trial compares the hemostatic effectiveness of microfibrillar collagen and oxidized cellulose in arterial bypass surgery. In patients undergoing arterial bypass surgery, 2 hemostats, microfibrillar collagen and oxidized cellulose, were randomly used to achieve hemostasis. The primary endpoint was the time to hemostasis. The secondary endpoints were the complication rate, mortality, number of hemostats required, handling, and adhesion. Collagen achieved hemostasis significantly faster than cellulose, with considerably less hemostats. In addition, its ease of use was rated substantially better. In arterial bypass surgery, microfibrillar collagen is more effective than oxidized cellulose in achieving hemostasis.


Color discrimination in schizophrenia.
Neuropsychiatric conditions that involve dopaminergic depletion have been associated with color discrimination deficits along the blue-hue (tritan, or short-wavelength-sensitive) axis. Because dopamine dysregulation may be a major factor in schizophrenia, we investigated color vision in this disorder. The performance of males with schizophrenia (SZ, n = 16) and normal male control subjects (CS, n = 14) was evaluated on five measures of color discrimination. SZ made more hue discrimination errors than CS, but no pattern emerged regarding a hue-specific axis of deficit. Dosage of anti-psychotic medication was not correlated with performance on hue discrimination. These results suggest that in medicated patients with schizophrenia, the dopaminergic disturbance, which may involve system hyperactivity, does not produce tritan-specific color deficits that have been observed in disorders involving dopaminergic hypoactivity.


Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin.
Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis. The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus. Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.


Differential expression of the Candida glabrata CgRTA1 and CgRSB1 genes in response to various stress conditions.
Candida glabrata, a human opportunistic pathogen is characterized by intrinsic, low susceptibility to fluconazole and a high capacity for acquiring high-level azole resistance. This is related to the elevated expression of genes belonging to the CgPdr1-governed regulon, comprising numerous genes, of which the multidrug ABC transporter-encoding CgCDR1, CgCDR2, CgSNQ2 are the best characterized. The function of certain PDR loci, such as CgRTA1 and CgRSB1 is poorly understood. These are homologs of ScRTA1 and ScRSB1 from Saccharomyces cerevisiae, members of the LTE family of plasma membrane proteins characteristic of fungi. While overproduced, they are involved in tolerance to 7-aminocholesterol or phytosphingosine, respectively. In this report we shed light on the differential regulation of CgRTA1 and CgRSB1 in C. glabrata. CgRTA1 expression positively correlated with intrinsic azole tolerance in clinical isolates. In contrast to CgRSB1, a high induction of CgRTA1 was observed upon fluconazole exposure, which was accompanied by a parallel up-regulation of its transcriptional activator CgPDR1. Hypoxia or presence of ketoconazole, both leading to ergosterol depletion, resulted in increased level of CgRTA1 transcript, whereas CgRSB1 was highly responsive to mitochondrial dysfunction. On the other hand, the expression of CgRTA1 was suppressed during growth in pseudohyphae formation promoting media. Our results are the first report linking the divergent regulation of LTE family members and azole sensitivity in C. glabrata.