Deformable image registration for cone-beam CT guided transoral robotic base-of-tongue surgery.
Transoral robotic surgery (TORS) offers a minimally invasive approach to resection of base-of-tongue tumors. However, precise localization of the surgical target and adjacent critical structures can be challenged by the highly deformed intraoperative setup. We propose a deformable registration method using intraoperative cone-beam computed tomography (CBCT) to accurately align preoperative CT or MR images with the intraoperative scene. The registration method combines a Gaussian mixture (GM) model followed by a variation of the Demons algorithm. First, following segmentation of the volume of interest (i.e. volume of the tongue extending to the hyoid), a GM model is applied to surface point clouds for rigid initialization (GM rigid) followed by nonrigid deformation (GM nonrigid). Second, the registration is refined using the Demons algorithm applied to distance map transforms of the (GM-registered) preoperative image and intraoperative CBCT. Performance was evaluated in repeat cadaver studies (25 image pairs) in terms of target registration error (TRE), entropy correlation coefficient (ECC) and normalized pointwise mutual information (NPMI). Retraction of the tongue in the TORS operative setup induced gross deformation >30 mm. The mean TRE following the GM rigid, GM nonrigid and Demons steps was 4.6, 2.1 and 1.7 mm, respectively. The respective ECC was 0.57, 0.70 and 0.73, and NPMI was 0.46, 0.57 and 0.60. Registration accuracy was best across the superior aspect of the tongue and in proximity to the hyoid (by virtue of GM registration of surface points on these structures). The Demons step refined registration primarily in deeper portions of the tongue further from the surface and hyoid bone. Since the method does not use image intensities directly, it is suitable to multi-modality registration of preoperative CT or MR with intraoperative CBCT. Extending the 3D image registration to the fusion of image and planning data in stereo-endoscopic video is anticipated to support safer, high-precision base-of-tongue robotic surgery.


Postoperative Respiratory Complications After Cleft Palate Closure in Patients With Pierre Robin Sequence: Operative Considerations.
In cleft palate surgery, there is currently no consensus on the management of patients with Pierre Robin Sequence (PRS). The authors aimed to evaluate the treatment strategy of cleft palate in our centers, with emphasis on patients with PRS, as the authors noted some patients with severe respiratory distress. Moreover, the authors aimed to investigate the prevalence of postoperative respiratory complications, using a modified-Furlow palatoplasty in combination with intravelar veloplasty in both patients with PRS and patients with non-PRS. The authors retrospectively identified all consecutive patients, both PRS and non-PRS, who underwent palate repair between January 1, 2012 and December 15, 2014 at 2 cooperating cleft centers (Bruges, Belgium; Budapest, Hungary). The treatment modality was uniform and performed by the same 2 surgeons. In 92 consecutive patients, 4 patients experienced respiratory distress after palate repair. The female-to-male ratio was 1:1. The mean age at surgery in these 4 patients was 15 months (range 13-19 months). Fifteen percent (2/13) of patients with PRS experienced respiratory distress in comparison to 3% (2/79) of non-PRS (χ = 4.43; P = 0.035). This is the first report of postoperative respiratory difficulties, while using a modified-Furlow palatoplasty in combination with intravelar veloplasty. In the present author's experience, the authors suggest to perform a 2-stage closure of the cleft palate in patients with PRS and to do so at a later age, when the palatal tissues and airway structures are more mature. Moreover, patients with PRS should be monitored closely, as they can present with different degrees of respiratory distress after palatoplasty.


A clinical approach to non-A, non-B hepatitis.
Non-A, non-B agents are currently the major cause of posttransfusion hepatitis and a major cause of chronic active hepatitis in the United States. Recent investigations suggest the clinical entity of non-A, non-B hepatitis results from infection with one of at least two distinct viruses. These viruses produce hepatitis with different incubation periods, induce different histopathologic characteristics, and have different antigenic determinants. The clinical and virologic aspects of non-A, non-B hepatitis are reviewed.


A comparative analysis of collagen III, IV, laminin and fibronectin in Duchenne muscular dystrophy biopsies and cell cultures.
The role of collagen type III and IV (Coll III, IV) in Duchenne muscular dystrophy (DMD) was investigated by the indirect immunofluorescence technique (IIF) both in muscle biopsies and derived cell cultures. Ten dystrophic cases were studied and compared with twelve suitable control cases, extending the IIF analysis to two other representative non-collagenous proteins of the extracellular matrix (ECM), namely fibronectin (FN) and laminin (LM). DMD biopsies generally displayed a thickening of endomysial and/or perimysial connective, as compared to control specimens. All the markers analyzed were found to contribute to this connective proliferation, although from a quantitative point of view the relative involvement decreases progressively from FN through Coll III and IV to LM. However, due to Coll IV selective endomysial localization, Coll IV alteration can be considered a specific indicator of a muscle cell defect. Results from DMD muscle cultures revealed no significant changes in comparison to control cultures, except for Coll IV. A well-organized, Coll IV-containing pericellular matrix was noted in a fraction of DMD cultures as a unique feature seen in no control culture. This alteration was again considered significant since Coll IV is the only marker clearly associated with the myotube component still expressed in vitro. The negative results obtained on the other marker proteins should not however be considered definitive, due to the lack in the simplified in vitro system used of humoral and/or neuronal factors which may be needed to express gene defect(s) in differentiated cells.


Determining the threshold for alcohol-induced brain damage: new evidence with gliosis markers.
Chronic intake of ethanol (EtOH) has been linked to serious health consequences such as cardiac and liver problems, cognitive impairments, and brain damage. Alcohol's detrimental effects depend upon the dose, duration, and pattern of exposure with binge drinking as one of the most common, but most damaging, patterns of intake. Little is known about the threshold of the damaging effects of alcohol. Therefore, these experiments sought to determine a threshold for brain damage using various markers of neurodegeneration. Adult male Sprague-Dawley rats were administered nutritionally complete liquid diet containing either EtOH (25% w/v) or isocaloric dextrose every 8 hours for either 1 (mean dose, 13.4 ± 0.3 g/kg/d; mean blood EtOH concentration (BEC), 336.2 ± 18.8 mg/dl) or 2 days (mean dose, 10.9 ± 0.3 g/kg/d; mean BEC, 369.8 ± 18.1 mg/dl). On the basis of a known time course of various neurodegeneration-associated events, rats were perfused transcardially immediately following, 2 days after, or 7 days post EtOH exposure. To label actively dividing cells, some animals were injected with BromodeoxyUridine (BrdU) 2 hours prior to perfusion. Tissue was then analyzed for the presence of BrdU (cell proliferation), FluoroJade B (degenerative neurons), and vimentin (reactive astrogliosis) immunoreactivity. One or 2 days of EtOH exposure failed to alter cell proliferation at any of the time points analyzed. However, significant 2- to 9-fold increases in neuronal degeneration in limbic cortex and clear evidence of reactive gliosis as indicated by a 2- to 8-fold upregulation in vimentin immunoreactivity in the hippocampus were observed following as little as 1 day of binge EtOH exposure. These results indicate that as little as 1 day (24 hours) of high BEC, binge-like EtOH exposure is enough to elicit signs of alcohol-induced brain damage in adult rats. Further, reactive gliosis may be a more sensitive marker of alcohol-induced damage in the hippocampus.


CDS-DB, an omnibus for patient-derived gene expression signatures induced by cancer treatment.
Patient-derived gene expression signatures induced by cancer treatment, obtained from paired pre- and post-treatment clinical transcriptomes, can help reveal drug mechanisms of action (MOAs) in cancer patients and understand the molecular response mechanism of tumor sensitivity or resistance. Their integration and reuse may bring new insights. Paired pre- and post-treatment clinical transcriptomic data are rapidly accumulating. However, a lack of systematic collection makes data access, integration, and reuse challenging. We therefore present the Cancer Drug-induced gene expression Signature DataBase (CDS-DB). CDS-DB has collected 78 patient-derived, paired pre- and post-treatment transcriptomic source datasets with uniformly reprocessed expression profiles and manually curated metadata such as drug administration dosage, sampling time and location, and intrinsic drug response status. From these source datasets, 2012 patient-level gene perturbation signatures were obtained, covering 85 therapeutic regimens, 39 cancer subtypes and 3628 patient samples. Besides data browsing, download and search, CDS-DB also supports single signature analysis (including differential gene expression, functional enrichment, tumor microenvironment and correlation analyses), signature comparative analysis and signature connectivity analysis. This provides insights into drug MOA and its heterogeneity in patients, drug resistance mechanisms, drug repositioning and drug (combination) discovery, etc. CDS-DB is available at http://cdsdb.ncpsb.org.cn/.


Cronobacter sakazakii and Microbiological Parameters in Dairy Formulas Associated With a Food Alert in Chile.
The objective of this study was to evaluate the presence of Cronobacter sakazakii and microbiological parameters in dairy products associated with a food alert. Ninety dairy product samples were analyzed, including seven commercial brands and two product types (liquid and powdered) from four countries. Aerobic plate count (APC) and Enterobacteriaceae count were performed according to Chilean standards. Cronobacter spp. and C. sakazakii were identified by polymerase chain reaction real time amplification of rpoB and cgcA genes and the genotype by multilocus sequence typing. Eighty-eight percent of dairy products showed APC higher than the detection limit. Fifty percent of liquid commercial brand samples contained APC: 2.6, 2.3, 1.1, and 2.9 CFU/mL in brands A, C, E, and G, respectively. Results for powdered commercial brands were 3.0, 3.6, and 5.7 CFU/g in brands B, D, and F, respectively. Maximum count (5.7 CFU/g) occurred in brand F dairy product manufactured in Chile. Enterobacteriaceae were found in 55% of the samples, 64% in liquid and 51% in powdered commercial brands. In 50% of brands B, D, and E, samples contained 2.9, 2.8, and 2.7 log CFU/g, respectively. Only liquid commercial brands from the United States had Enterobacteriaceae values between 0.1 and 4.5 CFU/mL. Seventeen suspicious strains were isolated and nine were identified as Enterobacter spp. Only eight suspicious strains from four powdered commercial brands (Chile and Singapore) were confirmed as C. sakazakii by rpoB and cgcA gene amplification and fusA sequencing. C. sakazakii prevalence in the analyzed samples was 8.8%. There were 11% of powdered milk brands that contained APC between 4.0 and 4.7 log CFU/g and 55% of the samples contained Enterobacteriaceae. C. sakazakii was found in dairy products manufactured in Chile and Singapore. On the basis of this information, the Chilean Ministry of Health (RSA) decreed a national and international food alert and recalled all the product batches that resulted positive in the present study from supermarkets and pharmacies.


The role of STI-related attitudes on screening attendance in young adults.
This study assessed whether attitudes towards STI screening, visiting a clinic and having an STI (STI stigma) predict STI screening attendance in young adults. Participants (N = 217) rated each of these attitudes and completed measures assessing their STI knowledge, past sexual behaviour and sexual health. STI stigma and having favourable attitudes towards STI screening positively predicted screening attendance. People were less likely to attend if they had a negative attitude towards visiting sexual health clinics. Researchers should assess attitudes towards the attitude object (screening), condition (STI stigma) and process (visiting a clinic) to understand the different ways that attitudes predict behaviour.


Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake.
The induction of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a key regulator of mitochondriogenesis, is well-established under multiple physical exercise regimens, including, endurance, resistance, and sprint training. We wanted to determine if increased expression of PGC-1alpha in muscle is sufficient to improve performance during exercise in vivo. We demonstrate that muscle-specific expression of PGC-1alpha improves the performance during voluntary as well as forced exercise challenges. Additionally, PGC-1alpha transgenic mice exhibit an enhanced performance during a peak oxygen uptake exercise test, demonstrating an increased peak oxidative capacity, or whole body oxygen uptake. This increased ability to perform in multiple exercise paradigms is supported by enhanced mitochondrial function as suggested by increased mitochondrial gene expression, mitochondrial DNA, and mitochondrial enzyme activity. Thus this study demonstrates that upregulation of PGC-1alpha in muscle in vivo is sufficient to greatly improve exercise performance under various exercise paradigms as well as increase peak oxygen uptake.


BMP4 is dispensable for skeletogenesis and fracture-healing in the limb.
Bone morphogenetic proteins (BMPs) are potent bone-forming agents that show clinical efficacy when used in patients to augment fracture-healing. Molecular profiling of fracture tissues has confirmed that BMPs 2, 3, 4, 5, 6, and 7 are expressed during the healing process, and it has identified a specific temporal pattern of expression for each BMP. Mice engineered to express increased levels of BMP antagonists have fragile bones that are prone to fracture, suggesting that BMPs not only mediate bone formation in the context of repair, but may also have a role in maintaining adult bone. In this study, mice carrying floxed Bmp4 alleles were bred with Prx1-cre transgenic mice to establish limb-specific removal of Bmp4. We compared these mice to mice in which Bmp2 was specifically deleted from the limb, and we then assessed limb skeletogenesis and fracture-healing. Limb skeletogenesis occurs normally in the absence of BMP4, and postnatal skeletal growth was also unaffected when BMP4 was removed. When mice lacking BMP4 were challenged to repair fractures, they were able to mount a successful healing response. We concluded that BMP4 is not required for formation of the limb skeleton and that femur fracture-healing is unaffected by the absence of BMP4. This study demonstrates that BMP4 is not required for bone formation and function in the limb, giving us further insights into the utility of recombinant human BMPs as therapeutic agents.


Complexity of T cell receptor recognition sites for defined alloantigens.
Three monoclonal antibodies react with the T cell receptor on the tumor line HPB-ALL and in addition with 3 to 13% of human peripheral blood T cells of normal donors. These antibodies are shown to react with an epitope encoded by the V beta 5 family of T cell receptor beta-chain variable region gene segments. Cells expressing V beta 5 gene segments can have cytotoxic or helper function, be of the T4+ or T8+ phenotype, and have specificity for either class I or class II major histocompatibility complex alloantigens. Seven T cell clones were generated, which express V beta 5 and are specific for the HLA-A2 molecule. With the use of these clones, we illustrate how isoelectric focusing can be used to analyze T cell receptor alpha- and beta-chain structure. The seven clones recognize five distinct conformational determinants on HLA-A2. They procure different binding sites by the use of different alpha-chains, J beta sequences, or both.


The effect of an active implementation of a disease management programme for chronic obstructive pulmonary disease on healthcare utilization--a cluster-randomised controlled trial.
The growing population living with chronic conditions calls for efficient healthcare-planning and effective care. Implementing disease-management-programmes is one option for responding to this demand. Knowledge is scarce about the effect of implementation processes and their effect on patients; only few studies have reported the effectiveness of disease-management-programmes targeting patients with chronic obstructive pulmonary disease (COPD). The objective of this paper was to determine the effect on healthcare-utilization of an active implementation model for a disease-management-programme for patients with one of the major multimorbidity diseases, COPD. The standard implementation of a new disease-management-programme for COPD was ongoing during the study-period from November 2008 to November 2010 in the Central Denmark Region. We wanted to test a strategy using Breakthrough Series, academic detailing and lists of patients with COPD. It targeted GPs and three hospitals serving approx. 60,000 inhabitants aged 35 or older and included interventions directed at professionals, organisations and patients. The study was a non-blinded block- and cluster-randomised controlled trial with GP-practices as the unit of randomisation. In Ringkoebing-Skjern Municipality, Denmark, 16 GP-practices involving 38 GPs were randomised to either the intervention-group or the control-group. A comparable neighbouring municipality acted as an external-control-group which included nine GP-practices with 25 GPs. An algorithm based on health-registry-data on lung-related contacts to the healthcare-system identified 2,736 patients who were alive at the end of the study-period. The population included in this study counted 1,372 (69.2%) patients who responded to the baseline questionnaire and confirmed their COPD diagnosis; 458 (33.4%) patients were from the intervention-group, 376 (27.4%) from the control-group and 538(39.2%) from the external-control-group. The primary outcome was adherence to the disease-management-programme measured at patient-level by use of specific services from general practice. Secondary outcomes were use of out-of-hours-services, outpatient-clinic, and emergency-department and hospital-admissions. The intervention practices provided more planned preventive consultations, additional preventive consultations and spirometries than non-intervention practices. A comparison of the development in the intervention practices with the development in the control-practices showed that the intervention resulted in more planned preventive-consultations, fewer conventional consultations and fewer patients admitted without a lung-related-diagnosis. Use of the active implementation model for the disease-management-programme for COPD changed the healthcare utilization in accordance with the programme. Clinicaltrials.gov identifier: NCT01228708.


Exploring iron-based multifunctional catalysts for Fischer-Tropsch synthesis: a review.
The continuous increase in oil prices together with an increase in carbon dioxide concentration in the atmosphere has prompted an increased interest in the production of liquid fuels from non-petroleum sources to ensure the continuation of our worldwide demands while maximizing CO(2) utilization. In this sense, the Fischer-Tropsch (FT) technology provides a feasible option to render high value-added hydrocarbons. Alternative sources, such as biomass or coal, offer a real possibility to realize these purposes by making use of H(2)-deficient or CO(2)-rich syngas feeds. The management of such feeds ideally relies on the use of iron catalysts, which exhibit the unique ability to adjust the H(2)/CO molar ratio to an optimum value for hydrocarbon synthesis through the water-gas-shift reaction. Taking advantage of the emerging attention to hybrid FT-synthesis catalysts based on cobalt and their associated benefits, an overview of the current state of literature in the field of iron-based multifunctional catalysts is presented. Of particular interest is the use of zeolites in combination with a FT catalyst in a one-stage operation, herein named multifunctional, which offer key opportunities in the modification of desired product distributions and selectivity, to eventually overcome the quality limitations of the fuels prepared under intrinsic FT conditions. This review focuses on promising research activities addressing the conversion of syngas to liquid fuels mediated by iron-based multifunctional materials, highlights their preparation and properties, and discusses their implication and challenges in the area of carbon utilization through H(2)/CO(+CO(2)) mixtures.


Membrane potential drives direct translocation of cell-penetrating peptides.
Cell-penetrating peptides (CPPs) are frequently employed as drug delivery agents with rapid cellular uptake, however, the uptake mechanism and the detailed translocation pathway are at present not completely understood. Both endocytosis and direct translocation through membrane pores have been observed in experiments and simulations under different conditions. Here we report the molecular dynamics simulations providing evidence for the direct translocation of CPPs across the membrane driven by the membrane electrostatic potential. The local membrane potential can be produced by the ion concentration imbalance across the membrane, which is ubiquitous in biological environments. Moreover, if positively charged CPPs are adsorbed on the membrane, this further enhances the membrane potential, opening membrane pores through which CPPs can be instantly transported in a chain-like configuration. The classical nucleation theory is applied to estimate the translocation time by calculating the changes in the free energy upon transferring CPPs across the membrane at different potentials, showing good agreement with available experimental measurements. The revealed CPP translocation mechanism can be broadly relevant for cellular processes in biology.


A noninvasive hemoglobin monitor in the pediatric intensive care unit.
Critically ill pediatric patients frequently require hemoglobin monitoring. Accurate noninvasive Hb (SpHb) would allow practitioners to decrease anemia from repeated blood draws, traumatic blood draws, and a decreased number of laboratory Hb (LabHb) medical tests. The Food and Drug Administration has approved the Masimo Pronto SpHb and associated Rainbow probes; however, its use in the pediatric intensive care unit (PICU) is controversial. In this study, we define the degree of agreement between LabHb and SpHb using the Masimo Pronto SpHb Monitor and identify clinical and demographic conditions associated with decreased accuracy. We performed a prospective, observational study in a large PICU at an academic medical center. Fifty-three pediatric patients (30-d and 18-y-old), weighing >3 kg, admitted to the PICU from January-April 2013 were examined. SpHb levels measured at the time of LabHb blood draw were compared and analyzed. Only 83 SpHb readings were obtained in 118 attempts (70.3%) and 35 readings provided a result of "unable to obtain." The mean LabHb and SpHb were 11.1 g/dL and 11.2 g/dL, respectively. Bland-Altman analysis showed a mean difference of 0.07 g/dL with a standard deviation of ±2.59 g/dL. Pearson correlation is 0.55, with a 95% confidence interval between 0.38 and 0.68. Logistic regression showed that extreme LabHb values, increasing skin pigmentation, and increasing body mass index were predictors of poor agreement between SpHb and LabHb (P < 0.05). Separately, increasing body mass index, hypoxia, and hypothermia were predictors for undetectable readings (P < 0.05). The Masimo Pronto SpHb Monitor provides adequate agreement for the trending of hemoglobin levels in critically ill pediatric patients. However, the degree of agreement is insufficient to be used as the sole indicator for transfusion decisions and should be used in context of other clinical parameters to determine the need for LabHb in critically ill pediatric patients.


Measuring the temperature dependence of individual two-level systems by direct coherent control.
We demonstrate a new method to directly manipulate the state of individual two-level systems (TLSs) in phase qubits. It allows one to characterize the coherence properties of TLSs using standard microwave pulse sequences, while the qubit is used only for state readout. We apply this method to measure the temperature dependence of TLS coherence for the first time. The energy relaxation time T1 is found to decrease quadratically with temperature for the two TLSs studied in this work, while their dephasing time measured in Ramsey and spin-echo experiments is found to be T1 limited at all temperatures.


The Role of the Immune Microenvironment in Bone Regeneration.
Bone is an active tissue, being constantly renewed in healthy individuals with participation of the immune system to a large extent. Any imbalance between the processes of bone formation and bone resorption is linked to various inflammatory bone diseases. The immune system plays an important role in tissue formation and bone resorption. Recently, many studies have demonstrated complex interactions between the immune and skeletal systems. Both of immune cells and cytokines contribute to the regulation of bone homeostasis, and bone cells, including osteoblasts, osteoclasts, osteocytes, also influence the cellular functions of immune cells. These crosstalk mechanisms between the bone and immune system finally emerged, forming a new field of research called osteoimmunology. Therefore, the immune microenvironment is crucial in determining the speed and outcome of bone healing, repair, and regeneration. In this review, we summarise the role of the immune microenvironment in bone regeneration from the aspects of immune cells and immune cytokines. The elucidation of immune mechanisms involved in the process of bone regeneration would provide new therapeutic targets for improving the curative effects of bone injury treatment.


Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals.
The primary genetic risk factor in multiple sclerosis (MS) is the HLA-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has yet to be elucidated. Several lines of evidence support a role for neuroendocrine system involvement in autoimmunity which may, in part, be genetically determined. Here, we comprehensively investigated variation within eight candidate hypothalamic-pituitary-adrenal (HPA) axis genes and susceptibility to MS. A total of 326 SNPs were investigated in a discovery dataset of 1343 MS cases and 1379 healthy controls of European ancestry using a multi-analytical strategy. Random Forests, a supervised machine-learning algorithm, identified eight intronic SNPs within the corticotrophin-releasing hormone receptor 1 or CRHR1 locus on 17q21.31 as important predictors of MS. On the basis of univariate analyses, six CRHR1 variants were associated with decreased risk for disease following a conservative correction for multiple tests. Independent replication was observed for CRHR1 in a large meta-analysis comprising 2624 MS cases and 7220 healthy controls of European ancestry. Results from a combined meta-analysis of all 3967 MS cases and 8599 controls provide strong evidence for the involvement of CRHR1 in MS. The strongest association was observed for rs242936 (OR = 0.82, 95% CI = 0.74-0.90, P = 9.7 × 10(-5)). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted.


Perfusion network shift during seizures in medial temporal lobe epilepsy.
Medial temporal lobe epilepsy (MTLE) is associated with limbic atrophy involving the hippocampus, peri-hippocampal and extra-temporal structures. While MTLE is related to static structural limbic compromise, it is unknown whether the limbic system undergoes dynamic regional perfusion network alterations during seizures. In this study, we aimed to investigate state specific (i.e. ictal versus interictal) perfusional limbic networks in patients with MTLE. We studied clinical information and single photon emission computed tomography (SPECT) images obtained with intravenous infusion of the radioactive tracer Technetium- Tc 99 m Hexamethylpropyleneamine Oxime (Tc-99 m HMPAO) during ictal and interictal state confirmed by video-electroencephalography (VEEG) in 20 patients with unilateral MTLE (12 left and 8 right MTLE). Pair-wise voxel-based analyses were used to define global changes in tracer between states. Regional tracer uptake was calculated and state specific adjacency matrices were constructed based on regional correlation of uptake across subjects. Graph theoretical measures were applied to investigate global and regional state specific network reconfigurations. A significant increase in tracer uptake was observed during the ictal state in the medial temporal region, cerebellum, thalamus, insula and putamen. From network analyses, we observed a relative decreased correlation between the epileptogenic temporal region and remaining cortex during the interictal state, followed by a surge of cross-correlated perfusion in epileptogenic temporal-limbic structures during a seizure, corresponding to local network integration. These results suggest that MTLE is associated with a state specific perfusion and possibly functional organization consisting of a surge of limbic cross-correlated tracer uptake during a seizure, with a relative disconnection of the epileptogenic temporal lobe in the interictal period. This pattern of state specific shift in metabolic networks in MTLE may improve the understanding of epileptogenesis and neuropsychological impairments associated with MTLE.


Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42 998 Individuals: A Meta-analysis.
Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits. To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders. This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the UK, the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019. Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI). Regression meta-analyses were used to test associations between PGS and attention-deficit/hyperactivity disorder (ADHD) symptoms and internalizing and social problems measured repeatedly across childhood and adolescence and whether these associations depended on childhood phenotype, age, and rater. The sample included 42 998 participants aged 6 to 17 years. Male participants varied from 43.0% (1040 of 2417 participants) to 53.1% (2434 of 4583 participants) by age and across all cohorts. The PGS of adult major depression, neuroticism, BMI, and insomnia were positively associated with childhood psychopathology (β estimate range, 0.023-0.042 [95% CI, 0.017-0.049]), while associations with PGS of subjective well-being and educational attainment were negative (β, -0.026 to -0.046 [95% CI, -0.020 to -0.057]). There was no moderation of age, type of childhood phenotype, or rater with the associations. The exceptions were stronger associations between educational attainment PGS and ADHD compared with internalizing problems (Δβ, 0.0561 [Δ95% CI, 0.0318-0.0804]; ΔSE, 0.0124) and social problems (Δβ, 0.0528 [Δ95% CI, 0.0282-0.0775]; ΔSE, 0.0126), and between BMI PGS and ADHD and social problems (Δβ, -0.0001 [Δ95% CI, -0.0102 to 0.0100]; ΔSE, 0.0052), compared with internalizing problems (Δβ, -0.0310 [Δ95% CI, -0.0456 to -0.0164]; ΔSE, 0.0074). Furthermore, the association between educational attainment PGS and ADHD increased with age (Δβ, -0.0032 [Δ 95% CI, -0.0048 to -0.0017]; ΔSE, 0.0008). Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.


Proinsulin is an independent predictor of coronary heart disease: Report from a 27-year follow-up study.
Some, but not all, studies have reported a relationship between plasma insulin and coronary heart disease (CHD). Conventional nonspecific insulin assays are also measuring various fractions of proinsulin-like molecules due to cross-reactivity. The long-term relationship between proinsulin-like molecules and CHD is largely unknown. For this reason, the longitudinal relationships between intact proinsulin, split proinsulin, specific insulin, immunoreactive insulin, and CHD, were studied in a population-based cohort of 50-year-old men (n=874), with a follow-up of 27 years. Fasting proinsulin-like molecule and specific-insulin concentrations were measured in plasma (stored frozen since baseline 1970 to 1973) by specific 2-site immunometric assays. Immunoreactive insulin concentrations were determined at baseline. The associations between proinsulin-like molecules, specific insulin, immunoreactive insulin, and CHD mortality (International Classification of Diseases [9th revision] codes 410 to 414) were analyzed using Cox's proportional hazards regression and presented as hazard ratios (HRs) with their 95% confidence intervals (CIs) for a 1-SD increase in a predictor variable. In the univariate analysis, intact proinsulin (HR, 1.69; 95% CI, 1.41 to 2.01) was the strongest predictor of death from CHD. In the multivariate analysis, smoking (HR, 1.57; 95% CI, 1.03 to 2.38), intact proinsulin (HR, 1.47; 95% CI, 1.18 to 1.82), systolic blood pressure (HR, 1.38; 95% CI, 1.14 to 1.66), and LDL/HDL cholesterol ratio (HR, 1.31; 95% CI, 1.12 to 1.53) were independent predictors of CHD mortality (adjusted for body mass index, triglycerides, and fasting glucose), whereas specific insulin and immunoreactive insulin were not (HR, 1.12; 95% CI, 0.90 to 1.40). The increased risk was restricted to the upper third of the proinsulin distribution. Increased proinsulin concentrations predict death and morbidity caused by CHD over a period of 27 years, independent of other major cardiovascular risk factors.


Systemic nickel allergy after internal fixation of a bunionectomy.
Allergic reactions to implanted metals have been estimated to occur in 1% to 5% of orthopedic cases. Stainless steel screws, which contain 14% nickel, are commonly used for internal fixation in an array of podiatric procedures. We present a rare case of a systemic allergic reaction to nickel secondary to stainless steel screw fixation in a bunionectomy procedure.


Improving the Affordability of Anticancer Medicines Demands Evidence-Based Policy Solutions.
The high cost of many new anticancer medicines significantly impedes breakthrough discoveries from reaching patients. A commonly heard refrain is that high prices are necessary to compensate for the high costs of research and development (R&D). Yet, there are promising policy proposals aimed at improving affordability without compromising innovation. In seeking new policy solutions, we argue for a shift away from entrenched opinion toward an evidence-based discourse that is grounded in experiments and real-world pilot studies. We offer a novel perspective and practical recommendations on how empirical evidence could and should be gathered to inform evidence-based policy interventions that lead to sustainable medicine prices in oncology.See related article by Franzen et al. (Cancer Res Commun 2022;2:39-47).


Glycophase glass revisited: protein adsorption and cell growth on glass surfaces bearing immobilized glycerol monosaccharides.
Gamma-Glycerylpropylsilyl or "glycophase" glass has been promoted as a non-fouling surface, resistant to protein adsorption and cell attachment, on which one can immobilize oligopeptide ligands, and thus create cell-type-specific culture surfaces. The present study confirmed that the glycerol-rich glycophase surface is a useful support for peptide immobilization. But glycophase glass was observed to adsorb more albumin than glass. At pH 7.4, desorption studies revealed that albumin bound more tightly to glycophase glass than to glass. Moreover, the growth rates, morphologies, and functions of transgenic betaG I/17 insulinoma cell cultures were equivalent on the two surfaces. Glycophase glass is neither protein- nor cell-repellant.


Wideband absorbance tympanometry using pressure sweeps: system development and results on adults with normal hearing.
A system with potential for middle-ear screening and diagnostic testing was developed for the measurement of wideband energy absorbance (EA) in the ear canal as a function of air pressure, and tested on adults with normal hearing. Using a click stimulus, the EA was measured at 60 frequencies between 0.226 and 8 kHz. Ambient-pressure results were similar to past studies. To perform tympanometry, air pressure in the ear canal was controlled automatically to sweep between -300 and 200 daPa (ascending/descending directions) using sweep speeds of approximately 75, 100, 200, and 400 daPas. Thus, the measurement time for wideband tympanometry ranged from 1.5 to 7 s and was suitable for clinical applications. A bandpass tympanogram, calculated for each ear by frequency averaging EA from 0.38 to 2 kHz, had a single-peak shape; however, its tympanometric peak pressure (TPP) shifted as a function of sweep speed and direction. EA estimated at the TPP was similar across different sweep speeds, but was higher below 2 kHz than EA measured at ambient pressure. Future studies of EA on normal ears of a different age group or on impaired ears may be compared with the adult normal baseline obtained in this study.


Ideas About Resourcing Health Care in the United States: Can Economic Evaluation Achieve Meaningful Use?
The United States is one of the few high-income countries not to apply economic evaluation routinely to health care decision making on a national level, yet it excels at spending least efficiently on health care. In the interest of continuing to develop new solutions to curb spending on health care and reduce waste in the United States, perhaps now is an important moment to reconsider the benefits of economic evaluation and the barriers that must be overcome to have it emerge as a solution for health care institutions and the patients they serve. This article offers several distinct considerations to make economic evaluation methods (such as cost-effectiveness analysis) an effective component of value-based decision making in the United States. These considerations include overcoming the barriers presented by opportunity costs, spending on health care services versus biomedical technologies, phasing out low-value care, using value of information to prioritize resources, and determining what to do with the quality-adjusted life-year. These issues need to be addressed to achieve a collective purpose for economic evaluation at state and national levels.


Knowledge of osteoporosis in middle-aged and elderly women.
To determine knowledge of osteoporosis in middle-aged and elderly Saudi women, and to identify women in need of education on osteoporosis. We conducted this cross-sectional analytical study of 368 women who attended the well-person clinic in a primary health care center (PHCC) in the Dirab area, Riyadh, Saudi Arabia between January and July 2006, using a validated questionnaire. Seventy-six percent of women were postmenopausal, 62% had heard of osteoporosis, and younger women had more knowledge of this disease. The identification of risk factors by the participants ranged from poor to fair. Sixty percent of women identified low calcium intake, lack of exercise was identified as a risk factor in 39%, and 22% identified family history of osteoporosis. Only 48% of the participants could correctly identify calcium rich foods. A considerable number of the Saudi middle-aged and elderly women are unaware of osteoporosis risk factors. Information resources should be easily available for those at high risk.


Mineral-Doped Poly(L-lactide) Acid Scaffolds Enriched with Exosomes Improve Osteogenic Commitment of Human Adipose-Derived Mesenchymal Stem Cells.
Exosomes derived from mesenchymal stem cells are extracellular vesicles released to facilitate cell communication and function. Recently, polylactic acid (PLA), calcium silicates (CaSi), and dicalcium phosphate dihydrate (DCPD) have been used to produce bioresorbable functional mineral-doped porous scaffolds-through thermally induced phase separation technique, as materials for bone regeneration. The aim of this study was to investigate the effect of mineral-doped PLA-based porous scaffolds enriched with exosome vesicles (EVs) on osteogenic commitment of human adipose mesenchymal stem cells (hAD-MSCs). Two different mineral-doped scaffolds were produced: PLA-10CaSi-10DCPD and PLA-5CaSi-5DCPD. Scaffolds surface micromorphology was investigated by ESEM-EDX before and after 28 days immersion in simulated body fluid (HBSS). Exosomes were deposited on the surface of the scaffolds and the effect of exosome-enriched scaffolds on osteogenic commitment of hAD-MSCs cultured in proximity of the scaffolds has been evaluated by real time PCR. In addition, the biocompatibility was evaluated by direct-contact seeding hAD-MSCs on scaffolds surface-using MTT viability test. In both formulations, ESEM showed pores similar in shape (circular and elliptic) and size (from 10-30 µm diameter). The porosity of the scaffolds decreased after 28 days immersion in simulated body fluid. Mineral-doped scaffolds showed a dynamic surface and created a suitable bone-forming microenvironment. The presence of the mineral fillers increased the osteogenic commitment of hAD-MSCs. Exosomes were easily entrapped on the surface of the scaffolds and their presence improved gene expression of major markers of osteogenesis such as collagen type I, osteopontin, osteonectin, osteocalcin. The experimental scaffolds enriched with exosomes, in particular PLA-10CaSi-10DCPD, increased the osteogenic commitment of MSCs. In conclusion, the enrichment of bioresorbable functional scaffolds with exosomes is confirmed as a potential strategy to improve bone regeneration procedures.


Humic substances alleviate the aquatic toxicity of polyvinylpyrrolidone-coated silver nanoparticles to organisms of different trophic levels.
The present study investigated how humic substances (HS) modify the aquatic toxicity of silver nanoparticles (AgNPs) as these particles agglomerate in water and interact with HS. An alga species (Raphidocelis subcapitata), a cladoceran species (Chydorus sphaericus), and a freshwater fish larva (Danio rerio), representing organisms of different trophic levels, were exposed to colloids of the polyvinylpyrrolidone-coated AgNPs in the presence and absence of HS. Results show that the presence of HS alleviated the aquatic toxicity of the AgNP colloids to all the organisms in a dose-dependent manner. The particle size distribution of the AgNPs' colloidal particles shifted to lower values due to the presence of HS, implying that the decrease in the toxicity of the AgNP colloids cannot be explained by the variation of agglomeration size. The surface charge of the AgNPs was found to be more negative in the presence of high concentrations of HS, suggesting an electrostatic barrier by which HS might limit interactions between particles and algae cells; indeed, this effect reduced the algae toxicity. Observations on silver ions (Ag(+)) release show that HS inhibit AgNP dissolution, depending on the concentrations of HS. When toxic effects were expressed as a function of each Ag-species, toxicity of the free Ag(+) was found to be much higher than that of the agglomerated particles.


Rare presentation of intracranial vascular blowout after tumor resection and radiation therapy.
A middle-aged patient presented with a rapidly growing right dural-based extra-axial posterior clinoid mass extending to the right cavernous sinus that was surgically resected. Histological examination showed solid growth of primitive neuroectodermal tumor arising from the third nerve. Following surgical resection, the patient was further managed by radiation and chemotherapy. Two years later the patient developed new intracranial hemorrhage in the area adjacent to the previous surgical cavity. A cerebral angiogram showed contrast extravasation at the junction of the posterior communicating artery (Pcom) and the right posterior cerebral artery (PCA), with an expanding pseudoaneurysm. This was managed with N-butyl cyanoacrylate embolization. Autopsy showed microscopic recurrence of tumor into the PCA/PCom region with invasion of the wall of the Pcom. This case report illustrates the concept of vascular blowout in intracranial cerebral vasculature. It appears that, in the presence of risk factors that contribute to weakening of vessel walls (surgery, radiation, tumor recurrence), a blowout can occur intracranially.


Clinical significance of 14-3-3 zeta in human esophageal cancer.
We recently found 14-3-3 zeta to be overexpressed in esophageal squamous cell carcinomas (ESCCs) by differential display. In the present study we determined the clinical significance of 14-3-3 zeta in esophageal tumorigenesis. Immunohistochemical analysis was carried out in 61 ESCCs, 33 dysplasia samples, 14 hyperplasia samples and 7 matched histologically normal esophageal tissues and correlated with clinicopathological parameters. Cytoplasmic expression of 14-3-3 zeta protein was observed in 95% of ESCCs; 63% of tumors also showed nuclear localization. All hyperplastic and dysplastic tissues distant from ESCCs as well as dysplastic endoscopic biopsies showed cytoplasmic immunopositivity for 14-3-3 zeta, while nuclear localization was observed in 58% of dysplasia and 36% of hyperplasia samples. Matched distant histologically normal epithelia either showed basal cytoplasmic expression of 14-3-3 zeta or no detectable nuclear expression of the protein. Interestingly, immunopositivity observed in normal esophageal tissues and early hyperplasia was confined to cytoplasm only, though significant nuclear expression was detected in dysplasia and ESCC. Immunoblotting and RT-PCR analyses further confirmed 14-3-3 zeta expression in dysplasia and ESCC. To our knowledge, this is the first report demonstrating overexpression of 14-3-3 zeta in esophageal hyperplasia, dysplasia and squamous cell carcinoma, suggesting that alteration in its expression occurs in early stages and is associated with esophageal tumorigenesis.


Differentiation of steroid isomers by steroid analogues adducted trapped ion mobility spectrometry-mass spectrometry.
Steroids are one of the important indicators of health and disease. However, due to the high similarity of steroid structures, there are several potential obstacles in the differentiation of steroids, especially for their isomers. Herein, we described a trapped ion mobility spectrometry-mass spectrometry (TIMS-MS) approach based on the steroid analogue adduction for isomer-specific identification of steroids. The application of dexamethasone (DEX) to form heterodimers with steroids enhanced the separation of their isomers in TIMS. Two isomer pairs including 17-hydroxyprogesterone/11-deoxycorticosterone and androsterone/epiandrosterone were successfully separated as the heterodimers with DEX by TIMS. The stability of DEX-adducted heterodimers is comparable with steroid dimers. Owing to the high separation efficiency and stability, the relative quantification of steroid isomers was demonstrated with the proposed method.


Abnormal biochemistry of subcellular membranes isolated from nonvascular smooth muscles of spontaneously hypertensive rats.
Microsomal fractions enriched in plasma membranes and endoplasmic reticulum were isolated from stomach fundus and vas deferens from age-matched Okamoto spontaneously hypertensive (SHR) rats and corresponding Kyoto-Wistar normotensive rats (KWR). Alterations of several enzyme activities and Ca2+ accumulation of the isolated microsomal fraction from these nonvascular smooth muscles provide direct evidence of abnormal smooth muscle membrane biochemistry in SHR. Decreased Ca2+ accumulation in the presence of but not in the absence of adenosine triphosphate by the microsomal fractions of both fundus and vas deferens from SHR is consistent with previous findings using plasma membranes from vascular smooth muscles from SHR and cannot be explained in terms of adaptation induced by elevation of blood pressure in SHR. Defective Ca2+ handling now observed in both vascular and nonvascular smooth muscles from hypertensive animals not only provides a cellular basis for the altered reactivity and contractility of smooth muscles observed in SHR, but also supports the hypothesis that spontaneous hypertension is associated with a generalized widespread alteration in smooth muscle membrane fraction.


When phosphorylated at Thr148, the β2-subunit of AMP-activated kinase does not associate with glycogen in skeletal muscle.
The 5'-AMP-activated protein kinase (AMPK), a heterotrimeric complex that functions as an intracellular fuel sensor that affects metabolism, is activated in skeletal muscle in response to exercise and utilization of stored energy. The diffusibility properties of α- and β-AMPK were examined in isolated skeletal muscle fiber segments dissected from rat fast-twitch extensor digitorum longus and oxidative soleus muscles from which the surface membranes were removed by mechanical dissection. After the muscle segments were washed for 1 and 10 min, ∼60% and 75%, respectively, of the total AMPK pools were found in the diffusible fraction. After in vitro stimulation of the muscle, which resulted in an ∼80% decline in maximal force, 20% of the diffusible pool became bound in the fiber. This bound pool was not associated with glycogen, as determined by addition of a wash step containing amylase. Stimulation of extensor digitorum longus muscles resulted in 28% glycogen utilization and a 40% increase in phosphorylation of the downstream AMPK target acetyl carboxylase-CoA. This, however, had no effect on the proportion of total β2-AMPK that was phosphorylated in whole muscle homogenates measured by immunoprecipitation. These findings suggest that, in rat skeletal muscle, β2-AMPK is not associated with glycogen and that activation of AMPK by muscle contraction does not dephosphorylate β2-AMPK. These findings question the physiological relevance of the carbohydrate-binding function of β2-AMPK in skeletal muscle.


Preservation of aortic valve in type A aortic dissection complicated by aortic regurgitation.
Two hundred fifty-two patients underwent operation for type A aortic dissection at Stanford University Medical Center from 1963 to 1987 and Duke University Medical Center from 1975 to 1988. Sixty-seven percent had an acute type A dissection and 33% had a chronic type A dissection. In addition to repair or replacement of the ascending aorta, 121 patients (48%) required an aortic valve procedure. Valve resuspension was performed in 46 (39 acute type A and 7 chronic type A), with an operative mortality rate of 13% +/- 5% (+/- 70% confidence limits), and aortic valve replacement in 75 (36 acute type A and 39 chronic type A), with an operative mortality rate of 20% +/- 5% (p = not significant versus resuspension). The operative mortality rate for patients requiring only repair or replacement of the ascending aorta was 32% +/- 4%. Indications for valve replacement included coexistent (nonacute) aortic valve disease, Marfan's syndrome, annuloaortic ectasia, and cases in which successful resuspension could not be accomplished. The overall actuarial survival rate for all patients was 59% +/- 3% (+/- 1 standard error of the mean), 40% +/- 4%, and 25% +/- 5% at 5, 10, and 15 years, respectively. Survival rates at these same times for patients with valve resuspension were 67% +/- 8%, 52% +/- 10%, and 26% +/- 19%, respectively; for patients who required aortic valve replacement, these survival rates were 70% +/- 5%, 39% +/- 8%, and 21% +/- 11%; finally, patients who received only an ascending aortic procedure had survival probabilities of 51% +/- 5%, 37% +/- 6%, and 23% +/- 6% (p = not significant versus resuspension versus aortic valve replacement). Multivariate analysis showed advanced age (p less than 0.001), previous cardiac or aortic operation (p less than 0.001), more preoperative dissection complications (p = 0.002), and earlier operative date (p = 0.038) to be the only significant, independent factors that increased the likelihood of early or late death. The type of aortic valve procedure (resuspension versus aortic valve replacement versus none) was not a significant predictor of mortality. Two of 46 patients with valve resuspension required late aortic valve replacement (freedom from aortic valve replacement: 100% and 80% +/- 13% at 5 and 10 years, respectively), as did 4 of 75 patients with initial aortic valve replacement (freedom from repeat aortic valve replacement: 98% +/- 2% and 73% +/- 13%, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)


Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms.
Cumulative evidence collected in recent decades suggests that lysosomal dysfunction contributes to neurodegenerative diseases, especially if amyloid proteins are involved. Among these, alpha-synuclein (aSyn) that progressively accumulates and aggregates in Lewy bodies is undisputedly a main culprit in Parkinson disease (PD) pathogenesis. Lysosomal dysfunction is evident in brains of PD patients, and mutations in lysosomal enzymes are a major risk factor of PD. At first glance, the role of protein-degrading lysosomes in a disease with pathological protein accumulation seems obvious and should guide the development of straightforward and rational therapeutic targets. However, our review demonstrates that the story is more complicated for aSyn. The protein can possess diverse posttranslational modifications, aggregate formations, and truncations, all of which contribute to a growing known set of proteoforms. These interfere directly or indirectly with lysosome function, reducing their own degradation, and thereby accelerating the protein aggregation and disease process. Conversely, unbalanced lysosomal enzymatic processes can produce truncated aSyn proteoforms that may be more toxic and prone to aggregation. This highlights the possibility of enhancing lysosomal function as a treatment for PD, if it can be confirmed that this approach effectively reduces harmful aSyn proteoforms and does not produce novel, toxic proteoforms.


Physicochemical and functional characteristics of glycated collagen protein from giant salamander skin induced by ultrasound Maillard reaction.
Chinese giant salamander skin collagen (CGSSC) was successfully conjugated with glucose (Glu)/xylose (Xy) by ultrasound Maillard reaction (MR) in nature deep eutectic solvents (NADES). The effects of ultrasound and reducing sugar types on the degree graft (DG) of MR products (MRPs), as well as the influence of DG on the structure and functional properties of MRPs were investigated. The results indicated that the ultrasound assisted could markedly enhance the MR of CGSSC, and low molecular weight reducing sugars were more reactive in MR. The ultrasound MR significantly changed the microstructure, secondary and tertiary structures of CGSSC. Moreover, the free sulfhydryl content of MRPs were increased, thus enhancing the surface hydrophobicity, emulsifying properties and antioxidant activity, which were positively correlated with DG. These findings provided theoretical insights into the effects of ultrasound assisted and different sugar types on the functional properties of collagen induced by MR.


Can determination of extractable organofluorine (EOF) be standardized? First interlaboratory comparisons of EOF and fluorine mass balance in sludge and water matrices.
The high proportion of unidentified extractable organofluorine (EOF) observed globally in humans and the environment indicates widespread occurrence of unknown per- and polyfluoroalkyl substances (PFAS). However, efforts to standardize or assess the reproducibility of EOF methods are currently lacking. Here we present the first EOF interlaboratory comparison in water and sludge. Three participants (four organizations) analyzed unfortified and PFAS-fortified ultrapure water, two unfortified groundwater samples, unfortified wastewater treatment plant effluent and sludge, and an unfortified groundwater extract. Participants adopted common sample handling strategies and target lists for EOF mass balance but used in-house combustion ion-chromatography (CIC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. EOF accuracy ranged from 85-101% and 76-109% for the 60 and 334 ng L-1 fluorine (F) - fortified water samples, respectively, with between-laboratory variation of 9-19%, and within-laboratory variation of 3-27%. In unfortified sludge and aqueous samples, between-laboratory variation ranged from 21-37%. The contribution from sum concentrations of 16 individual PFAS (∑PFAS-16) to EOF ranged from 2.2-60% but extended analysis showed that other targets were prevalent, in particular ultra-short-chain perfluoroalkyl acids (e.g. trifluoroacetic acid) in aqueous samples and perfluoroalkyl acid-precursors (e.g. polyfluoroalkyl phosphate diesters) in sludge. The EOF-CIC method demonstrated promising accuracy, robustness and reporting limits but poor extraction efficiency was observed for some targets (e.g. trifluoroacetic acid).


New variants of alpha 1-antitrypsin: comparison of Pi typing techniques.
Four new rare inherited variants (Pi types) of alpha 1-antitrypsin (alpha 1-protease inhibitor) are described. Each variant has been compared with previously reported genetic variants by several techniques used for Pi typing: isoelectric focusing in polyacrylamide gel, starch gel electrophoresis, and agarose gel electrophoresis. Some variants are identical or very similar by one technique but can be clearly distinguished by another technique. Crossed immunoelectrophoresis and gel immunofixation have been used to identify the gel bands as alpha 1-antitrypsin.


Relative contributions of neural mechanisms versus muscle mechanics in promoting finger extension deficits following stroke.
The origins of impaired finger and hand function were examined in 10 stroke survivors with chronic spastic hemiparesis, with the intent of assessing whether mechanical restraint or altered neurophysiological control mechanisms are responsible for the well-known impairment of finger extension. Simultaneous extension of all four metacarpophalangeal (MCP) joints of the impaired hand was either externally imposed using a rotary actuator or attempted voluntarily by the subject. Trials were conducted both before and after administration of a local anesthetic, blocking the median and ulnar nerves at the elbow. The anesthetic was administered to reduce the activity of the muscles flexing the MCP joints, in order to distinguish mechanical from neuronal resistance to imposed MCP rotation. We found that the nerve blockade resulted in a reduction in velocity-dependent torque (P = 0.01), thereby indicating significant joint impedance due to spasticity. Blockade also produced a posture-dependent reduction in static torque in declaratively relaxed subjects (P = 0.04), suggesting some tonic flexor activity for specific hand postures. No change in either extensor isometric (P = 0.33) or isokinetic (0.53) torque was apparent, but 3 of the 10 subjects did exhibit substantial (>10 degrees ) improvement in voluntary MCP extension following the blockade. This improvement seemed largely due to a decrease in inappropriate flexor activity during the movement, rather than an increase in extensor activity. We argue that persistent and inappropriate flexor activation plays a role in limiting voluntary finger extension, and that this activation is potentially a reflection of altered supraspinal control of key spinal pathways. In all cases, this inappropriate activation was compounded by weakness, apparent in both the extensor and flexor muscles.


MISAGA: An Algorithm for Mining Interesting Subgraphs in Attributed Graphs.
An attributed graph contains vertices that are associated with a set of attribute values. Mining clusters or communities, which are interesting subgraphs in the attributed graph is one of the most important tasks of graph analytics. Many problems can be defined as the mining of interesting subgraphs in attributed graphs. Algorithms that discover subgraphs based on predefined topologies cannot be used to tackle these problems. To discover interesting subgraphs in the attributed graph, we propose an algorithm called mining interesting subgraphs in attributed graph algorithm (MISAGA). MISAGA performs its tasks by first using a probabilistic measure to determine whether the strength of association between a pair of attribute values is strong enough to be interesting. Given the interesting pairs of attribute values, then the degree of association is computed for each pair of vertices using an information theoretic measure. Based on the edge structure and degree of association between each pair of vertices, MISAGA identifies interesting subgraphs by formulating it as a constrained optimization problem and solves it by identifying the optimal affiliation of subgraphs for the vertices in the attributed graph. MISAGA has been tested with several large-sized real graphs and is found to be potentially very useful for various applications.


Oncologic outcomes of selective neck dissection in HPV-related oropharyngeal squamous cell carcinoma.
To examine outcomes of selective neck dissection (SND) in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) who present with clinical neck disease. Multi-institutional retrospective review. Two institutional databases of patients with HPV-related OPSCC were reviewed to identify patients with clinical (c) N1-N3 neck disease who underwent SND ± adjuvant therapy. Three hundred and twenty-four patients were identified with a median follow-up of 49 months (range 3-199 months). All patients underwent transoral resection of the primary tumor and SND, including levels II-IV and ± levels I or V, with resection of additional nonlymphatic tissue (extended SND) as indicated by extent of disease, including the spinal accessory nerve (7%), the internal jugular vein (13%), and the sternocleidomastoid muscle (8%). Two hundred and seventy (83%) patients underwent adjuvant radiation. There were 13 (4%) regional recurrences and 19 (6%) distant recurrences. Regional control following salvage was 98%. On univariable analysis, absence of radiation was associated with regional recurrence (odds ratio [OR] 9.2, 95% confidence interval [CI] 2.9-29.4). On multivariable analysis, adjuvant radiation was associated with improved disease-free survival (DFS) (OR 0.27, 95% CI 0.14-0.53) but lost significance for overall (OS) and disease-specific survival (DSS) (P > 0.05). Five-year Kaplan-Meier estimates for OS, DSS, and DFS were 88% (95% CI 84%-92%), 93% (95% CI 89%-96%), and 83% (95% CI 78%-87%), respectively. In HPV-related OPSCC presenting with clinical neck disease, a SND ± additional tissue resection and adjuvant therapy, when indicated, provides excellent long-term regional control. Omission of radiotherapy increases the risk of regional recurrence, although it may not significantly impact OS or DSS. It appears unnecessary to routinely perform a comprehensive neck dissection. 4. Laryngoscope, 127:623-630, 2017.


[The role of clinical and economic indices in shaping the criteria for registering schizophrenic patients].
This work is a fragment of a study into expenditures in schizophrenia. The purpose of the work was to distinguish groups of "economic risk" in the population of schizophrenic patients in order to use in future the clinico-economic criteria for the design of the principles of patients' observation and to define approaches to the optimization of the functioning of psychiatric aid services. Depending on the total expenditures per patient during one year all the patients examined were distributed in 4 groups. It is shown that attribution of the patients to one or other group of "economic risk" is related to a definite complex of clinical signs. The authors discuss the problem of the potential orienting of psychiatric services in accordance with the priorities elaborated on that basis, formation of the economic effect commensurable with the expenditures, varying whatever the changes in investments.


Sex pheromone perception in male pine sawflies, Neodiprion sertifer (Hymenoptera; Diprionidae).
Electroantennographic and single sensillum recordings were performed on male pine sawfly, Neodiprion sertifer, antennae. Responses to the sex pheromone component (2S, 3S, 7S)- 3,7-dimethyl-2-pentadecenyl (diprionyl) acetate (SSS:OAc), to the behavioral inhibitor (2S, 3R, 7R)-diprionyl acetate (SRR:OAc), to the six other enantiomers of diprionyl acetate, and to the biosynthetic precursor diprionol were recorded. Responses to trans-perillenal, a monoterpene identified in female gland extracts and to (2S, 3S, 7S)-diprionyl propionate (SSS:OPr), a field attractant for N. sertifer and some related sawfly species were also recorded. EAG recordings demonstrated a high antennal sensitivity to SSS:OAc and to SSS:OPr. A somewhat lower response was elicited by SRR:OAc. Single sensillum recordings revealed 8-12 different cells firing in each sensillum, corresponding to the number of cells observed in earlier morphological investigations. Out of these cells all, except one, responded to SSS:OAc and to SSS:OPr. No differences in the response to the two components could be observed. The largest amplitude cell in each sensillum was specifically tuned to the behavioral antagonist, SRR:OAc. The pheromone perception system encountered in male pine sawflies thus differs clearly from that observed in moths.


Study of ligand-receptor binding using SPME: investigation of receptor, free, and total ligand concentrations.
The theoretical background and practical approaches for studying ligand-receptor (protein) binding by solid phase microextraction (SPME) are investigated, along with methods for simultaneous calculation of receptor, free, and total ligand concentrations. With the introduction of new extraction phases (restricted access materials, molecularly imprinted polymers, and immobilized antibodies), SPME allows better separation of small molecules of ligand from larger molecules of receptor, and improved accuracy. This sample preparation method based on nonexhaustive extraction is well suited as a general method to study and quantify systems involving multiple equilibriums, with significant advantages over currently used methods. SPME was used previously for the determination of protein binding constants, but only with conventional extraction phases and in simple cases, with a 1:1 combination ratio between the ligand and the receptor or when negligible depletion conditions were met. The new theoretical approach presented in this study allows the quantification of any binding equilibrium, regardless of the extent of depletion. Restricted-access particles are used as extraction phase, and if the amount of receptor is limited, selected regions of the binding curve may be obtained using a single sample, with a volume as low as 10 muL. The equations developed here are simple and independent of the analytical method used for the quantification of the amount of ligand. Three different practical approaches are presented: the method of multiple standard solutions, the method of successive extractions from the same sample and the method of successive additions to the same sample. The usefulness of this novel approach is demonstrated by using it to determine the binding parameters of some selected drugs to human serum albumin. These parameters are subsequently used to calculate albumin, free drug, and total drug concentrations from unknown mixtures. The results are in good agreement with previously published data. Quantification of the amount of ligand extracted by SPME is done by liquid chromatography coupled with tandem mass spectrometry.


Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3'UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3'UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3'UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3'UTR functional variants altering miRNAs-BDNF binding.


Surgical management of calcified hydatid cysts of the liver.
Hydatid disease of the liver is still a major cause of morbidity in Greece. Beside the common complications of rupture and suppuration, calcification of the hepatic cysts represent a not well studied, less frequent and sometimes difficult surgical problem. In the present study 75 cases with calcified symptomatic liver echinococcosis were operated on in the 1st Propedeutic Surgical Clinic between 1964 to 1996. Twenty-eight patients were male and 47 female with ages from 23 to 78 years. The diagnosis was based mainly on the clinical picture and radiological studies. In 5 cases the operative method was cystopericystectomy. We performed evacuation of the cystic cavity and partial pericystectomy and primary closure of the residual cavity in 6 cases, omentoplasty or filling of the residual cavity with a piece of muscle of the diaphragm in 4 cases and external drainage by closed tube, in 60 cases. In 12 of those with drainage, after a period of time, a second operation with easy, removal of most of the calcareous wall plaques was performed. The mortality rate was 2%. Our results could be considered satisfactory. In the calcified parasitic cysts of the liver the proposed technique is cystopericystectomy. An alternative procedure is pericystectomy and drainage with a "planned" reoperation with a bloodless, due to intervening inflammation, chiseling of the calcification.


Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells.
Slit, which mediates its function by binding to the Roundabout (Robo) receptor, has been shown to regulate neuronal and CXCR4-mediated leukocyte migration. Slit-2 was shown to be frequently inactivated in lung and breast cancers because of hypermethylation of its promoter region. Furthermore, the CXCR4/CXCL12 axis has been reported recently to be actively involved in breast cancer metastasis to target organs such as lymph nodes, lung, and bone. In this study, we sought to characterize the effect of Slit (=Slit-2) on the CXCL12/CXCR4-mediated metastatic properties of breast cancer cells. We demonstrate here that breast cancer cells and tissues derived from breast cancer patients express Robo 1 and 2 receptors. We also show that Slit treatment inhibits CXCL12/CXCR4-induced breast cancer cell chemotaxis, chemoinvasion, and adhesion, the fundamental components that promote metastasis. Slit had no significant effect on the CXCL12-induced internalization process of CXCR4. In addition, characterization of signaling events revealed that Slit inhibits CXCL12-induced tyrosine phosphorylation of focal adhesion components such as RAFTK/Pyk2 at residues 580 and 881, focal adhesion kinase at residue 576, and paxillin. We found that Slit also inhibits CXCL12-induced phosphatidylinositol 3-kinase, p44/42 MAP kinase, and metalloproteinase 2 and 9 activities. However, it showed no effect on JNK and p38 MAP kinase activities. To our knowledge, this is the first report to analyze in detail the effect of Slit on breast cancer cell motility as well as its effect on the critical components of the cancer cell chemotactic machinery. Studies of the Slit-Robo complex may foster new anti-chemotactic approaches to block cancer cell metastasis.


Cell surface antigen induced by venezuelan equine encephalomyelitis virus.
By immunofluorescence staining, a specific surface antigen induced by Venezuelan equine encephalomyelitis virus was detected on L-929 cells. Formation of the antigen was independent of viral ribonucleic acid synthesis.


[Can meniscal suture repair in athletes prevent early development of osteoarthritis without compromising the preinjury sports activity level].
In a retrospective study we evaluated the outcome of arthroscopic assisted meniscal repair in athletes on different competitive sports levels. Examination included early osteoarthritic changes and full recovery in sports activities. Fifty athletes were followed up with an average of 6,5 years after meniscal refixation from 1984 through 1998. Twenty-three patients had isolated full-thickness meniscal tears, twenty-seven an associated rupture of the anterior cruciate ligament. Preoperative sports levels were evaluated with Tegners score. Reexamination included Lysholm score, IKDC score and Fairbanks score. With no persisting anterior knee instability 86 % of the professional athletes returned to former full sports activities on competitive levels. Noncompetitive athletes returned in all cases (100 %) to their former level. Fairbanks score increased by 0,1 observing minimal osteoarthitic signs. However, persisting anterior knee instability showed on reexamination poor results. Only one third of all athletes were able to return to former activity levels. Osteoarthritic changes were observed in all patients. Professional athletes had the most severe osteoarthritic changes with an increase of 0,8 in the Fairbanks score. The results demonstrate that complete recovery on sports activities is not possible without reconstruction of the anterior cruciate ligament. Isolated meniscal repair shows poor results in persisting anterior knee instability and does not prevent increasing osteoarthritic changes in athletes.


Production, isolation, and preliminary toxicity studies of brevianamide A from cultures of Penicillium viridicatum.
Brevianamide A, one of a novel group of alkaloids first obtained from Penicillium brevi-compactum, has also been isolated as a principal metabolite from two key isolates of P. viridicatum. Procedures for bioproduction and purification are described. This compound was not toxic when fed or injected into mice and had no antibiotic properties against several common bacterial and fungal microorganisms. Brevianamides A and B are among at least four yellow metabolites that may be formed by isolates of P. viridicatum.


Does smoking exposure alter the effect of non-surgical periodontal therapy?
This prospective longitudinal observational study aimed to explore the impact of varying levels of smoking exposure on periodontal healing over a 12-month period following non-surgical periodontal therapy. The study included 80 individuals in the age range of 20-70 years, who were both, smokers at baseline, and also diagnosed with periodontitis. Initially, all participants were enrolled in a smoking cessation program and were provided with non-surgical periodontal therapy (NSPT). Subsequently, all patients were recalled after every 3 months for supportive periodontal care and data collection. Socio-demographic features and periodontal health parameters were recorded, which included clinical attachment level (CAL), periodontal pocket depth (PPD), bleeding on probing, etc. For smoking, data about frequency, duration and salivary carbon monoxide and cotinine levels were recorded. Descriptive statistics was used to depict and compare periodontal health and smoking parameters at different time intervals. In addition, exploratory factor analysis method was employed to identify distinct patterns of smoking behavior over a 1-year study period. Accordingly, patients were classified into three categories. Lastly, in order to assess the impact of NSPT among patients in different smoking categories, mixed-effects regression modeling was used. The distribution of smokers was light smokers/quitters (46 individuals), moderate smokers (17 individuals) and heavy smokers (17 individuals). With NSPT an improvement in the mean CAL, PPD, and number of sites with PPD ≥4/5/6/7 mm was observed in all light, moderate and heavy smokers. Mean CAL (±SD) changed from 3.2 ± 1.5 to 2.5 ± 1.3, 3.5 ± 1.6 to 2.6 ± 1.3, and 4.2 ± 1.5 to 3.6 ± 1.3 and mean PPD changed from 2.5 ± 0.8 to 1.9 ± 0.4, 2.6 ± 1.0 to 2.0 ± 0.7, and 2.7 ± 0.8 to 2.1 ± 0.5 in light, moderate and heavy smokers respectively. Similar changes were observed in other periodontal and smoking parameters, e.g., salivary cotinine levels changed from baseline to 1 year, from 276.0 ± 155.7 to 213.8 ± 160.6, 564.8 ± 77.8 to 518.6 ± 197.6, and 764.0 ± 205.9 to 728.9 ± 116.7 in different smoking categories. Lastly, regression coefficients (RCs) were evaluated using regression modeling. RCs (and confidence intervals) for light and moderate smokers were CAL = -0.7 (-0.9 to -0.6), PPD -0.6 (-0.7 to -0.5) and CAL -0.4 (-0.1 to 0.3), PPD -0.4 (-0.8 to -0.1) respectively. In heavy smokers, a positive value of the regression coefficient for CAL was observed, indicating a trend of "increase in CAL value" (RC = 0.5, -0.1 to 1.2). The study concluded that in smokers, NSPT done along with SPC yielded positive results. However, these results were influenced by the level of smoking exposure in a dose-response manner.


Long-term survival patients with acute and severe renal failure due to multiple myeloma.
We selected 37 cases, followed-up for more than 36 months or until death, from a series of 45 patients affected by acute renal failure due to multiple myeloma in order to identify the parameters that could allow the outcome to be predicted. The patients were allocated to group 1, consisting of 27 patients who died within one year and to group 2, consisting of 10 patients who survived for more than 36 months. Renal failure was severe enough to require dialysis in 28 patients, 16 of whom were oliguric. Renal biopsy was performed in 23 cases, whereas light chain isoelectric point and serum beta 2-microglobulin levels were evaluated in each patient. All the patients underwent chemotherapy, which was associated with plasma exchange in 16 patients. Statistical analysis of the potential prognostic factors in the 2 groups showed that the incidence of hypercalcemia, infection, irreversible renal failure and severe tubulo-interstitial damage was significantly higher in group 1. Sex, tumor load, severity of renal failure and light chain isoelectric point had no prognostic significance. Finally, the number of patients treated by plasma exchange was significantly higher in group 2. Our results underline the prognostic role of both hypercalcemia and infection and justify aggressive treatment consisting of chemotherapy, plasma exchange and dialysis, even in cases of severe renal failure and high tumor load.


Efficacy of Oryza sativa husk and Quercus phillyraeoides extracts for the in vitro and in vivo control of fungal rot disease of white yam (Dioscorea rotundata Poir).
Tuber rot disease is a major constraint to white yam (Dioscorea rotundata) production, accounting for 50-60% of annual yield losses in Nigeria. The main method of control using synthetic fungicides is being discouraged due to human and environmental health hazards. The potential of Oryza sativa husk (OSH) and Quercus phillyraeoides (QP) extracts for the in vitro and in vivo control of six virulent rot-causing fungal pathogens, Lasiodiplodia theobromae, Aspergillus niger, Rhizoctonia solani, Penicillium oxalicum, Sclerotium rolfsii, and Fusarium oxysporum was evaluated, using five different extract concentrations of 0.5%, 1.0%, 1.5%, 2.5%, and 3.5% w/v. These fungi were isolated from rotted tubers of D. rotundata, across three agroecological zones in Nigeria-the Humid rainforest, Derived savanna, and southern Guinea savanna. All treatments were subjected to three methods of inoculation 48 hours before the application of both extracts and stored at 28 ± 2°C for 6 months. Radial mycelial growth of the test pathogens was effectively inhibited at concentrations ≤ 3.5% w/v in vitro for both OSH and QP extracts. Rotting was significantly reduced (P ≤ 0.05) to between 0 to 18.8% and 0% to 20.9% for OSH and QP extracts respectively. The extracts significantly (P ≤ 0.05) inhibited percent rot of the test pathogens at 3.5% concentration w/v in vivo. Rot incidence was, however, lower in replicate tubers that were inoculated, treated with extracts and exposed than treatments that were covered. Phytochemical analysis of OSH and QP extracts revealed the presence of secondary metabolites such as alkaloids, flavonoids, saponins, tannins, ferulic acid, phlobatanins, Terpenoids, phenols, anthraquinone and pyroligneous acid. The efficacy of both extracts in reducing rot in this study recommends their development as prospective biopesticide formulation and use in the management of post-harvest rot of yam tubers.


[Participation of cyclic nucleotides in immunogenesis and immune reactions of lymphocytes].
The paper deals with generalized literary and author's own data testifying to the role of cyclic nucleotides as mediators in the effect of specific and nonspecific factors on immunogenesis, from the proliferation of stem hemopoietic cell of bone marrow to the reaction of T and B lymphocytes to antigens. It is shown that changes in the system of lymphocytes cyclic nucleotides are most probably secondary in response to changes in intracellular concentration and distribution of calcium ions. Certain evidence is presented on immunopharmacological preparations based on cyclic nucleotides, their analogs and preparations modulating the activity of phosphodiesterases.


Anti-Inflammatory, Antimicrobial and Insecticidal Properties of Daucus Gracilis Steinh Flowers Essential Oil.
Daucus gracilis Steinh belongs to the Apiaceae family. The flowers of this plant have been used by the population of western Algeria for the treatment of mouth ulcers. However, very few studies exist concerning the biological properties of essential oil of Daucus gracilis Steinh flowers. The purpose of this work was to study the chemical composition of the essential oil of Daucus gracilis flowers and to evaluate their antimicrobial, insecticidal and anti-inflammatory properties. The distilled essential oil was analyzed by GC and GC-MS. The antimicrobial activity of the essential oil was evaluated using two methods i) diffusion method, and ii) micro dilution technique. The insecticidal activity of essential oil was evaluated against adults of Tribolium confusum by fumigant test. The in vitro assessment of the anti-inflammatory property of essential oil was assessed by the protein denaturation method. Daucus gracilis flowers essential oil mainly represented oxygenated monoterpenes such as geranyl acetate (18.3%), lavandulyl acetate (15.2%), lavandulyl isobutyrate (13.6%) and citronellyl isobutyrate (6.8%). According to the results of antimicrobial activity, the essential oil of flowers presented prominent inhibitory action against Aspergillus flavus (0.06 μg/mL), followed by Staphylococcus aureus, Escherichia faecalis, Bacillus cereus and Candida albicans with MIC values of 0.125 μg/mL. The Daucus gracilis essential oil flowers proved to be very biocidal toward adults of Tribolium confusum; mortality of 100% of the population was noted with a dose of 2 μl/L air after 24 hours of exposure. Furthermore, the oil has shown a very good inhibition of protein denaturation comparable to Diclofenac at a concentration of 30 μL/mL. Daucus gracilis essential oil can be used as a pharmacological tools for inflammatory, antimicrobial and insecticidal properties.


Low-Dose Radiation Can Cause Epigenetic Alterations Associated With Impairments in Both Male and Female Reproductive Cells.
Humans are regularly and continuously exposed to ionizing radiation from both natural and artificial sources. Cumulating evidence shows adverse effects of ionizing radiation on both male and female reproductive systems, including reduction of testis weight and sperm count and reduction of female germ cells and premature ovarian failure. While most of the observed effects were caused by DNA damage and disturbance of DNA repairment, ionizing radiation may also alter DNA methylation, histone, and chromatin modification, leading to epigenetic changes and transgenerational effects. However, the molecular mechanisms underlying the epigenetic changes and transgenerational reproductive impairment induced by low-dose radiation remain largely unknown. In this study, two different types of human ovarian cells and two different types of testicular cells were exposed to low dose of ionizing radiation, followed by bioinformatics analysis (including gene ontology functional analysis and Ingenuity Pathway Analysis), to unravel and compare epigenetic effects and pathway changes in male and female reproductive cells induced by ionizing radiation. Our findings showed that the radiation could alter the expression of gene cluster related to DNA damage responses through the control of MYC. Furthermore, ionizing radiation could lead to gender-specific reproductive impairment through deregulation of different gene networks. More importantly, the observed epigenetic modifications induced by ionizing radiation are mediated through the alteration of chromatin remodeling and telomere function. This study, for the first time, demonstrated that ionizing radiation may alter the epigenome of germ cells, leading to transgenerational reproductive impairments, and correspondingly call for research in this new emerging area which remains almost unknown.


Dorsal Dartos Flap Prepared Before Urethroplasty, Less Bleeding of Operation: A New Perspective on Hypospadias.
The benefits of preparing the dorsal dartos flap before urethroplasty were investigated. Patients with coronal, subcoronal, and distal penile hypopadias without severe cordee who underwent surgical repair between October 2016 and September 2020 were included in the study. Tubularized incised plate urethroplasty technique was applied to all patients. The patients were divided into two groups: In Group 1, the dorsal dartos flap was prepared after urethroplasty, which is the commonly used technique today, and sutured on the neourethra. In Group 2, the dorsal dartos flap was prepared before the post-degloving urethroplasty. The amount of bleeding, the duration of the surgery, and the complications between the two groups were recorded and compared. Twenty-two patients who could be followed up for at least 3 months were examined. There were 10 patients in Group 1 and 12 patients in Group 2. A statistically significant difference was found between the amount of bleeding of the operation in the two groups. Duration of operation, hematoma, infection, skin necrosis, or glanular dehiscence were not observed in any patient. Preparing the dorsal dartos flap, before urethroplasty significantly reduces the amount of bleeding. This may be a new modification alternative in hypospadias surgery.


Protein complex prediction via dense subgraphs and false positive analysis.
Many proteins work together with others in groups called complexes in order to achieve a specific function. Discovering protein complexes is important for understanding biological processes and predict protein functions in living organisms. Large-scale and throughput techniques have made possible to compile protein-protein interaction networks (PPI networks), which have been used in several computational approaches for detecting protein complexes. Those predictions might guide future biologic experimental research. Some approaches are topology-based, where highly connected proteins are predicted to be complexes; some propose different clustering algorithms using partitioning, overlaps among clusters for networks modeled with unweighted or weighted graphs; and others use density of clusters and information based on protein functionality. However, some schemes still require much processing time or the quality of their results can be improved. Furthermore, most of the results obtained with computational tools are not accompanied by an analysis of false positives. We propose an effective and efficient mining algorithm for discovering highly connected subgraphs, which is our base for defining protein complexes. Our representation is based on transforming the PPI network into a directed acyclic graph that reduces the number of represented edges and the search space for discovering subgraphs. Our approach considers weighted and unweighted PPI networks. We compare our best alternative using PPI networks from Saccharomyces cerevisiae (yeast) and Homo sapiens (human) with state-of-the-art approaches in terms of clustering, biological metrics and execution times, as well as three gold standards for yeast and two for human. Furthermore, we analyze false positive predicted complexes searching the PDBe (Protein Data Bank in Europe) database in order to identify matching protein complexes that have been purified and structurally characterized. Our analysis shows that more than 50 yeast protein complexes and more than 300 human protein complexes found to be false positives according to our prediction method, i.e., not described in the gold standard complex databases, in fact contain protein complexes that have been characterized structurally and documented in PDBe. We also found that some of these protein complexes have recently been classified as part of a Periodic Table of Protein Complexes. The latest version of our software is publicly available at http://doi.org/10.6084/m9.figshare.5297314.v1.


Emergent endovascular treatment of ruptured vertebral artery dissecting aneurysms.
The goal of this study was to evaluate the results of endovascular and surgical treatments for ruptured vertebral artery dissecting aneurysms (VADAs) to determine which treatment is preferable. We evaluated the cases of 25 consecutive patients with ruptured VADAs treated in our institution. From 1992 to 1997, five patients were treated surgically. Since 1998, 20 patients with VADAs have been treated with endovascular therapy. The goal of the treatment was to exclude the aneurysm from the circulation. Among the five patients undergoing surgery, three aneurysms were treated with proximal clipping, one with trapping, and one with dome clipping. None of the patients were treated during the acute stage of rupture. Transient complications occurred in two patients. Of the 20 patients treated through the endovascular approach, 15 were treated within 24 h of rupture, but 12 had rebleeding before treatment. Eighteen aneurysms were occluded, along with the affected vertebral artery (VA), by using detachable coils (internal trapping), and one was occluded with the VA preserved. A stent-assisted occlusion of one aneurysm was done in a patient who had a contralateral hypoplastic VA. In both groups, the outcome of each patient depended greatly on the patient's condition before treatment and whether there was rebleeding. No posttreatment bleeding occurred. All procedures were effective, but endovascular treatment was less invasive and easier to use during the acute stage of subarachnoid hemorrhage. Although this report does not describe a controlled study, we found that endovascular treatment is preferable for treating ruptured VADAs in the acute stage.


Role of Fosinopril and Valsartan on Klotho Gene Expression Induced by Angiotensin II in Rat Renal Tubular Epithelial Cells.
Klotho gene, a new anti-aging gene, is mainly expressed in the kidney tubules. Several studies have found the relationship between klotho and emergence and development of renal diseases. This study set out to explore the role of fosinopril (Fos) and valsartan (Val) on klotho expression induced by angiotensin II (Ang II) in rat renal tubular epithelial cells (NRK-52E). NRK-52E cells were divided into five groups according to the treatment of Ang II, Fos and Val. Transforming growth factor-β1 (TGF-β1), p38, phospho-p38 (p-p38), p53, and Sp1 protein expression were determined by immunohistochemical and Western blotting analysis. Klotho expression was detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Ang II upregulated TGF-β1, p-p38 and p53 expression, and inhibited Sp1 and klotho expression in NRK-52E cells. After the intervention of Fos and/or Val, TGF-β1, p-p38 and p53 expression were downregulated, Sp1 and klotho expression were upregulated. TGF-β1 and p53, Sp1 and klotho expression exhibited a positive linear correlation, respectively. We conclude that Fos and Val have a protective role in Ang II-induced renal damage, and it may be through mechanism of inhibiting TGF-β1, p-p38 and p53 expression, thus upregulating Sp1 and klotho expression.


[Participation of peptide hydra morphogen in the regulation of proliferation processes in different tissues of white rats].
The PMH influence on proliferation processes in some tissues of white rats was studied. PMH injections in doses 10.0 mkg/kg and 100.0 mkg/kg stimulated the processes of DNA--synthesis after 24 hours in corneal and tongue epithelium. The direct dose-dependent effect was revealed. PMH in dose 10.0 mkg/kg activated the proliferative processes in the stomach epithelium and thymus cortex. after 24 hours too. The given dose of PMH caused trustworthy decreasing of proliferative activity in thymus after 4 hours. The stimulation of DNA-synthesis and acceleration of mitosis were found after 5-times application on white rat's corneal with 100 nM PMH solution.


Mobility and electrophoretic mobility of long linear polymer molecules in gels.
Theoretical expressions for mobility and specific (per unit charge) electrophoretic mobility of long linear molecules in gels are derived in one-dimensional approximations. The influence of the gel is described by a voluminal friction coefficient which is shown to be a reciprocal of specific hydrodynamic permeability of the gel. The nonmonotonous profile of liquid flow velocity in the vicinity of the molecular surface is obtained. Near the surface of the molecule, the liquid flows in the direction of electrophoretic movement. At a distance from the molecule, the direction of liquid flow is in the opposite direction. The distance of the point with zero velocity from the surface of the molecule decreases with increase of gel density. The specific electrophoretic mobility of a straight molecule in the gel is equal to half the harmonic average of the mobility of the molecule in the gel and the specific electrophoretic mobility of the same molecule in gel-free electrolyte solution. The theoretical expression for friction coefficient is given. The results will be used for theoretical analysis of PFGE experiments.


Abscisic acid induced a negative geotropic response in dark-incubated Chlamydomonas reinhardtii.
The phytohormone abscisic acid (ABA) plays a role in stresses that alter plant water status and may also regulate root gravitropism and hydrotropism. ABA also exists in the aquatic algal progenitors of land plants, but other than its involvement in stress responses, its physiological role in these microorganisms remains elusive. We show that exogenous ABA significantly altered the HCO3- uptake of Chamydomonas reinhardtii in a light-intensity-dependent manner. In high light ABA enhanced HCO3- uptake, while under low light uptake was diminished. In the dark, ABA induced a negative geotropic movement of the algae to an extent dependent on the time of sampling during the light/dark cycle. The algae also showed a differential, light-dependent directional taxis response to a fixed ABA source, moving horizontally towards the source in the light and away in the dark. We conclude that light and ABA signal competitively in order for algae to position themselves in the water column to minimise photo-oxidative stress and optimise photosynthetic efficiency. We suggest that the development of this response mechanism in motile algae may have been an important step in the evolution of terrestrial plants and that its retention therein strongly implicates ABA in the regulation of their relevant tropisms.