Solanum lycopersicum cv. Heinz 1706 chromosome 6: distribution and abundance of genes and retrotransposable elements.
We studied the physical and genetic organization of chromosome 6 of tomato (Solanum lycopersicum) cv. Heinz 1706 by combining bacterial artificial chromosome (BAC) sequence analysis, high-information-content fingerprinting, genetic analysis, and BAC-fluorescent in situ hybridization (FISH) mapping data. The chromosome positions of 81 anchored seed and extension BACs corresponded in most cases with the linear marker order on the high-density EXPEN 2000 linkage map. We assembled 25 BAC contigs and eight singleton BACs spanning 2.0 Mb of the short-arm euchromatin, 1.8 Mb of the pericentromeric heterochromatin and 6.9 Mb of the long-arm euchromatin. Sequence data were combined with their corresponding genetic and pachytene chromosome positions into an integrated map that covers approximately a third of the chromosome 6 euchromatin and a small part of the pericentromeric heterochromatin. We then compared physical length (Mb), genetic (cM) and chromosome distances (microm) for determining gap sizes between contigs, revealing relative hot and cold spots of recombination. Through sequence annotation we identified several clusters of functionally related genes and an uneven distribution of both gene and repeat sequences between heterochromatin and euchromatin domains. Although a greater number of the non-transposon genes were located in the euchromatin, the highly repetitive (22.4%) pericentromeric heterochromatin displayed an unexpectedly high gene content of one gene per 36.7 kb. Surprisingly, the short-arm euchromatin was relatively rich in repeats as well, with a repeat content of 13.4%, yet the ratio of Ty3/Gypsy and Ty1/Copia retrotransposable elements across the chromosome clearly distinguished euchromatin (2:3) from heterochromatin (3:2).


Relationship between azithromycin susceptibility and administration efficacy for nontypeable Haemophilus influenzae respiratory infection.
Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.


[Accompanying symptoms in infantile spastic hemiplegia].
Various concomitant disorders in 535 children with infantile hemiplegia were evaluated; 159 of the cases were particularly well documented. The right/left distribution of the hemiplegia was 56 to 44, the ratio of boys to girls 59 to 41. Severe impairments of hand function (lack of function, first grip) were found more frequently in right hemiplegics than left; the ratio of severe to slight disorders was approx. 3 to 1 in right hemiplegics and 3 to 2 in left hemiplegics. Impairment of hand function was closely related to the quality of sensitivity, the tests of this being based on two-point discrimination and stereognosis. Sixty-two percent of the children were of normal intelligence; of the remainder, approximately equal-sized groups suffered from impairment of the learning faculty or were mentally retarded. There was a positive correlation between reduced intelligence and the severity of impairment of hand function. Impaired speech development was found in 7 percent of the children, right and left hemiplegics being equally affected. Thus, there was no evidence that the brain lesion had any special influence on development of speech. Observations of growth in the legs revealed average differences of length of 2 mm and up to 3.5 cm in isolated cases. After eight year of life there was practically no further increase in the differences in length.


MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases.
Pulmonary fibrosis is defined by an overgrowth of fibroblasts and extracellular matrix deposition, and results in respiratory dysfunction that is often fatal. It is the end stage in many chronic inflammatory interstitial lung diseases (ILD) such as sarcoidosis and idiopathic pulmonary fibrosis (IPF). The myeloid-related proteins (MRPs) belong to the S100 family of calcium-binding proteins and are highly expressed by neutrophils, macrophages and epithelial cells during chronic inflammation. MRP14 stimulates fibroblast proliferation in vitro and is expressed in granulomas from sarcoidosis patients. We hypothesized that MRP14 may be a biomarker for fibrotic interstitial lung diseases. The objective of this study was to investigate whether levels of MRP14 in the bronchoalveolar lavage fluid (BALF) of patients with sarcoidosis and IPF correlate with clinical parameters. We used an enzyme-linked immunosorbent assay (ELISA) to measure MRP14 in BALF of 74 sarcoidosis patients, 54 IPF patients and 19 controls. Mean BALF levels of MRP14 were elevated significantly in IPF (P < 0.001) and sarcoidosis (P < 0.05) patients compared to controls. MRP14 levels were associated linearly with sarcoidosis disease severity based on chest radiographic stage. Moreover, BALF MRP14 levels were correlated inversely with diffusion capacity and forced vital capacity in sarcoidosis patients. In IPF patients, a correlation with BALF neutrophil percentage was found. In conclusion, BALF MRP14 levels are elevated in IPF and sarcoidosis and are associated with disease severity in sarcoidosis. The results support the need for further studies into the role of MRP14 in the pathogenesis of lung fibrosis.


Influence of CO2 on neurovascular coupling: interaction with dynamic cerebral autoregulation and cerebrovascular reactivity.
Abstract PaCO2 affects cerebral blood flow (CBF) and its regulatory mechanisms, but the interaction between neurovascular coupling (NVC), cerebral autoregulation (CA), and cerebrovascular reactivity to CO2 (CVR), in response to hypercapnia, is not known. Recordings of cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end-tidal CO2 (EtCO2) were performed in 18 subjects during normocapnia and 5% CO2 inhalation while performing a passive motor paradigm. Together with BP and EtCO2, a gate signal to represent the effect of stimulation was used as input to a multivariate autoregressive-moving average model to calculate their separate effects on CBFv. Hypercapnia led to a depression of dynamic CA at rest and during stimulation in both hemispheres (P < 0.02) as well as impairment of the NVC response, particularly in the ipsilateral hemisphere (P < 0.01). Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The CBFv step responses to each individual input (BP, EtCO2, stimulation) allowed identification of the influences of hypercapnia and neuromotor stimulation on CA, CVR, and NVC, which have not been previously described, and also confirmed the depressing effects of hypercapnia on CA and NVC. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation. Dynamic multivariate modeling can identify the complex interplay between different CBF regulatory mechanisms and should be recommended for studies involving similar interactions, such as the effects of exercise or posture on cerebral hemodynamics.


Scientific impact: opportunity and necessity.
Recent National Institutes of Health changes have focused attention on the potential scientific impact of research projects. Research with the excellent potential to change subsequent science or health care practice may have high scientific impact. Only rigorous studies that address highly significant problems can generate change. Studies with high impact may stimulate new research approaches by changing understanding of a phenomenon, informing theory development, or creating new research methods that allow a field of science to move forward. Research with high impact can transition health care to more effective and efficient approaches. Studies with high impact may propel new policy developments. Research with high scientific impact typically has both immediate and sustained influence on the field of study. The article includes ideas to articulate potential scientific impact in grant applications as well as possible dissemination strategies to enlarge the impact of completed projects.


Familial aggregation of attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) aggregates in families. To date, the strength, pattern, and characteristics of the familial aggregation have not been thoroughly assessed in a population-based family sample. In this cohort study, we identified relative pairs of twins, full and half-siblings, and full and half cousins from 1,656,943 unique individuals born in Sweden between 1985 and 2006. The relatives of index persons were followed from their third birthday to 31 December 2009 for ADHD diagnosis. Birth year adjusted hazard ratio (HR), that is, the rate of ADHD in relatives of ADHD-affected index persons compared with the rate of ADHD in relatives of unaffected index persons, was estimated in the different types of relatives using Cox proportional hazards model. During the follow-up, 31,865 individuals were diagnosed with ADHD (male to female ratio was 3.7). The birth year adjusted HRs were as follows: 70.45 for monozygotic twins; 8.44 for dizygotic twins; 8.27 for full siblings; 2.86 for maternal half-siblings; 2.31 for paternal half-siblings; 2.24 for full cousins; 1.47 for half cousins. Maternal half-siblings had significantly higher HR than in paternal half-siblings. The HR did not seem to be affected by index person's sex. Full siblings of index persons with ADHD diagnosis present at age 18 or older had a higher rate of ADHD (HR: 11.49) than full siblings of index persons with ADHD diagnosis only before age 18 (HR: 4.68). Familial aggregation of ADHD increases with increasing genetic relatedness. The familial aggregation is driven by not only genetic factors but also a small amount of shared environmental factors. Persistence of ADHD into adulthood indexes stronger familial aggregation of ADHD.


Alpha-adrenergic supersensitivity and decreased number of alpha-adrenoceptors in heart from acute diabetic rats.
The inotropic effect of methoxamine, as well as the alpha-adrenoceptor population, were measured in cardiac tissue from normal and short-term (3 days) diabetic rats. Methoxamine increased the tension of both normal and diabetic ventricles, but in diabetic ones, the dose-response curve to methoxamine was shifted to the left and the efficacy of the alpha-agonist was enhanced. This phenomenon was accompanied by an increase in receptor affinity, while the number of alpha-adrenoceptor sites decreased. Inhibitors of alpha 1-adrenoceptors blocked, in a competitive manner, the positive inotropic effect of methoxamine in both types of ventricles. Inhibition of phospholipase C blocked the ventricular response to the methoxamine in nondiabetic as well as in diabetic hearts. Synthetic diacylglyceride (DAG) potentiated the inotropic action of the alpha-agonist in normal ventricles and increased the affinity with a decreased number of alpha-adrenoceptor sites in normal ventricles, producing values of Kd and Bmax similar to those of the acute diabetic heart. Inhibitors of protein kinase C partially reduced the supersensitivity to alpha-agonists in diabetic ventricles and prevented the stimulatory action of DAG upon the positive inotropic effect of methoxamine in normal ventricles. These results suggest that alpha-adrenergic inotropic stimulation is secondary to receptor-mediated hydrolysis of phosphoinositides, generating some oxidative metabolites (DAG) which, in turn, may be responsible for the inotropic effect. In the acute diabetic state, the supersensitivity to alpha-agonist could be due to high activity of phospholipase C (with an increase in DAG production) which induces alteration in the membrane alpha-adrenergic receptors.


Structural host-microbiota interaction networks.
Hundreds of different species colonize multicellular organisms making them "metaorganisms". A growing body of data supports the role of microbiota in health and in disease. Grasping the principles of host-microbiota interactions (HMIs) at the molecular level is important since it may provide insights into the mechanisms of infections. The crosstalk between the host and the microbiota may help resolve puzzling questions such as how a microorganism can contribute to both health and disease. Integrated superorganism networks that consider host and microbiota as a whole-may uncover their code, clarifying perhaps the most fundamental question: how they modulate immune surveillance. Within this framework, structural HMI networks can uniquely identify potential microbial effectors that target distinct host nodes or interfere with endogenous host interactions, as well as how mutations on either host or microbial proteins affect the interaction. Furthermore, structural HMIs can help identify master host cell regulator nodes and modules whose tweaking by the microbes promote aberrant activity. Collectively, these data can delineate pathogenic mechanisms and thereby help maximize beneficial therapeutics. To date, challenges in experimental techniques limit large-scale characterization of HMIs. Here we highlight an area in its infancy which we believe will increasingly engage the computational community: predicting interactions across kingdoms, and mapping these on the host cellular networks to figure out how commensal and pathogenic microbiota modulate the host signaling and broadly cross-species consequences.


TLR4 down-regulation identifies high risk HPV infection and integration in head and neck squamous cell carcinomas.
TLRs are main actors of the innate immune response against HPV. There are very few studies on the role of TLRs mediated HPV clearance in Head and Neck oncology. Our aim was to evaluate whether TLR4 expression identifies HPV infection and/or HR-HPV integration status in oral and oropharyngeal cancers. By immunohistochemistry we assessed TLR4 levels in OSCC/OPSCC. To detect viral integration or episomic status In situ hybridization for HPV-DNA and Pyro-sequencing techniques have been performed. The relationship between TLR4 expression with HPV infection status has been investigated. ISH HPV positive samples have reported lower levels of TLR4 intensity than negative samples (p = .002). There was no statistical correlation between TLR4 intensity and PCR HPV results (p more than 0.0.5). Point-biserial correlation coefficient revealed significant association between TLR4 expression and HR-HPV integration status (p = .0001) and between TLR4 expression index and HR-HPV infection (p = .001). These data have shown that TLR4 down-regulation is strongly associated to both HPV-16 infection and its integration into the host DNA.


The catalytic mechanism of intercalated chlorine anions as active basic sites in MgAl-layered double hydroxide for carbonyl sulfide hydrolysis.
In order to make clear the role of intercalated anions in layered double hydroxides (LDHs) for catalytic hydrolysis of carbonyl sulfide (COS), the adsorption and reaction characteristics of COS over the simple Mg2Al-Cl-LDH model catalyst were studied by both theoretical and experimental methods. Density functional theory (DFT) calculations by CASTEP found that the chloride ions in LDH function as the key Brønsted base sites to activate the adsorbed H2O with enlarged bond length and angle, facilitate the dissociative adsorption of intermediates including mono-thiocarbonic acid (MTA) and hydrogen thiocarbonic acid (HTA), and participate in the formation of transient states and subsequent hydrogen transfer process with decreased energy barriers during COS hydrolysis. COS hydrolysis will preferentially go through the dissociated intermediates of mono-thiocarbonates (MT) and hydrogen thiocarbonates (HT) with dramatically decreased energy barriers, and the rate-determining step of COS hydrolysis over Mg2Al-Cl-LDH will be the nucleophilic addition of C=O in COS by H2O (Ea = 1.10 eV). The experimental results further revealed that the apparent activation energy (0.89 eV) of COS hydrolysis over Mg2Al-Cl-LDH is close to theoretical value (1.10 eV), and the accumulated intermediates of MT, HT, or carbonate were also observed by FT-IR around 1363 cm-1 on the used Mg2Al-Cl-LDH, which are well in accordance with the theoretical prediction. The demonstrated participation of intercalated chlorine anions in the evolution of intermediates and transient states as Brønsted base sites during COS hydrolysis will give new insight into the basic sites in LDH materials.


International cooperation in healthcare: model of IRCCS Policlinico San Donato and Bambini Cardiopatici nel Mondo Association for congenital heart diseases.
Cooperation activity in training programmes promoted by IRCCS Policlinico San Donato and Bambini Cardiopatici nel Mondo Association is a model of cooperation between people as an alternative intervention in promoting the right to healthcare, especially offering programmes of training and medical care on cardiovascular and congenital heart disease. This new strategy, implemented in several developing countries, has absolutely contributed to the improvement of the medical services concerning the diagnostic and surgical approach in the treatment of paediatric and adult cardiovascular disease. To strengthen this kind of activity, both IRCCS Policlinico San Donato and Bambini Cardiopatici nel Mondo have introduced a global perspective aiming at the realization of surgical missions 'in situ', building new cardiac surgery units in collaboration with the local partners, which are mainly university hospitals. They, furthermore, support financially the scholarship and accommodation in favour of medical and paramedical staff.


Finishing and polishing procedures of composite restorations by Saudi dentists: a cross-sectional study.
The purpose of this study was to assess the knowledge and practices of Saudi dentists in finishing and polishing composite restorations. A cross-sectional questionnaire-based study was conducted among 306 Saudi dentists from March to April 2012. The collected data were analyzed using Microsoft Excel 2010 program and descriptive statistics were obtained. Completed questionnaires were returned by 191 participants, giving a response rate of 62.4%. 115 (65.7%) respondents are using fine diamond finishing burs for finishing occlusal surfaces, 82 (48%) used fine aluminum oxide finishing discs for finishing facial surfaces, 130 (76%) used diamond finishing strips for finishing interproximal surfaces.121 (63.4%) respondents were of the view that the type of filler content has a major influence in providing color stability to the composite restoration and 137 (72.1%) believed nano-composites provided enhanced color stability. Dentists in Saudi Arabia are aware of the benefits of proper finishing and polishing of composite restorations. They however need to use finishing and polishing burs, disks, strips and pastes in a sequential series. Usage of composite polishing pastes and composite surface sealants should be emphasized in undergraduate curriculum.


Cyanine Dye Conjugation Enhances Crizotinib Localization to Intracranial Tumors, Attenuating NF-κB-Inducing Kinase Activity and Glioma Progression.
Glioblastoma (GBM) is a highly aggressive form of brain cancer with a poor prognosis and limited treatment options. The ALK and c-MET inhibitor Crizotinib has demonstrated preclinical therapeutic potential for newly diagnosed GBM, although its efficacy is limited by poor penetration of the blood brain barrier. Here, we identify Crizotinib as a novel inhibitor of nuclear factor-κB (NF-κB)-inducing kinase, which is a key regulator of GBM growth and proliferation. We further show that the conjugation of Crizotinib to a heptamethine cyanine dye, or a near-infrared dye (IR-Crizotinib), attenuated glioma cell proliferation and survival in vitro to a greater extent than unconjugated Crizotinib. Moreover, we observed increased IR-Crizotinib localization to orthotopic mouse xenograft GBM tumors, which resulted in impaired tumor growth in vivo. Overall, IR-Crizotinib exhibited improved intracranial chemotherapeutic delivery and tumor localization with concurrent inhibition of NIK and noncanonical NF-κB signaling, thereby reducing glioma growth in vitro, as well as in vivo, and increasing survival in a preclinical rodent model.


Frequency Band Analysis of Electrocardiogram (ECG) Signals for Human Emotional State Classification Using Discrete Wavelet Transform (DWT).
[Purpose] Intelligent emotion assessment systems have been highly successful in a variety of applications, such as e-learning, psychology, and psycho-physiology. This study aimed to assess five different human emotions (happiness, disgust, fear, sadness, and neutral) using heart rate variability (HRV) signals derived from an electrocardiogram (ECG). [Subjects] Twenty healthy university students (10 males and 10 females) with a mean age of 23 years participated in this experiment. [Methods] All five emotions were induced by audio-visual stimuli (video clips). ECG signals were acquired using 3 electrodes and were preprocessed using a Butterworth 3rd order filter to remove noise and baseline wander. The Pan-Tompkins algorithm was used to derive the HRV signals from ECG. Discrete wavelet transform (DWT) was used to extract statistical features from the HRV signals using four wavelet functions: Daubechies6 (db6), Daubechies7 (db7), Symmlet8 (sym8), and Coiflet5 (coif5). The k-nearest neighbor (KNN) and linear discriminant analysis (LDA) were used to map the statistical features into corresponding emotions. [Results] KNN provided the maximum average emotion classification rate compared to LDA for five emotions (sadness - 50.28%; happiness - 79.03%; fear - 77.78%; disgust - 88.69%; and neutral - 78.34%). [Conclusion] The results of this study indicate that HRV may be a reliable indicator of changes in the emotional state of subjects and provides an approach to the development of a real-time emotion assessment system with a higher reliability than other systems.


Segmental variability of glucocorticoid induced electrolyte transport in rat colon.
Recent studies suggest that the ability of glucocorticoids to reduce diarrhoea in active colitis may reflect their direct effects on distal colonic electrogenic Na+ transport and water absorption, as well as their anti-inflammatory action. To determine whether glucocorticoids induce similar changes in proximal colon, specific Na+ and K+ channel blockers (amiloride and tetraethylammonium chloride (TEA) respectively) were used to evaluate the cation transport properties of rat proximal and distal colon in vitro after three days treatment with the glucocorticoid agonist dexamethasone (600 micrograms/100 g/day). In the proximal colon, dexamethasone increased short circuit current (Isc) 2.3 fold (p less than 0.025) and total conductance (Gt) by 87% (p less than 0.015), but had negligible effects on the maximum activity of the basolateral membrane Na(+)-K+ pump and the baseline Na+ and K+ conductive properties of the apical membrane. Additional studies with diphenylamine-2-carboxylic acid (a Cl- channel blocker) suggested that the dexamethasone induced increases in Isc and Gt in proximal colon reflected stimulation of an electrogenic Cl- secretory process. In contrast, in the distal colon dexamethasone increased Isc 10 fold (p less than 0.025), Gt by 100% (p less than 0.015), and the maximum activity of the basolateral Na(+)-K+ pump by 200% (p less than 0.05), and induced substantial Na+ and K+ conductances in the apical membrane. These results indicate that dexamethasone stimulates electrogenic Na+ transport and water absorption to a significant degree only in the distal segment of rat colon. Thus in patients with active colitis, that part of the antidiarrhoeal action of glucocorticoids that reflects stimulation of electrogenic Na+ transport (and hence water absorption) may be restricted to the descending colon and rectum.


[Penetration of thiamine pyrophosphate into rat hepatocytes].
Thiamin pyrophosphate transport into rat hepatocytes has been studied using TPP-beta-33P and 14C-TPP-beta-33P synthesized in the thiamin pyrophosphokinase reaction. Thiamin pyrophosphate (cocarboxylase) did not penetrate across cytoplasmic membrane.


Sequence representation as an early step in the evolution of language.
Human language is unique in its compositional, open-ended, and sequential form, and its evolution is often solely explained by advantages of communication. However, it has proven challenging to identify an evolutionary trajectory from a world without language to a world with language, especially while at the same time explaining why such an advantageous phenomenon has not evolved in other animals. Decoding sequential information is necessary for language, making domain-general sequence representation a tentative basic requirement for the evolution of language and other uniquely human phenomena. Here, using formal evolutionary analyses of the utility of sequence representation we show that sequence representation is exceedingly costly and that current memory systems found in animals may prevent abilities necessary for language to emerge. For sequence representation to evolve, flexibility allowing for ignoring irrelevant information is necessary. Furthermore, an abundance of useful sequential information and extensive learning opportunities are required, two conditions that were likely fulfilled early in human evolution. Our results provide a novel, logically plausible trajectory for the evolution of uniquely human cognition and language, and support the hypothesis that human culture is rooted in sequential representational and processing abilities.


[30 years of successful mycobacteriology research, The AHRI in Addis Abeba--a unique research environment in a developing country].
The Armauer Hansen Research Institute (AHRI) in Addis Abeba, Ethiopia, was established by the Swedish and Norwegian Save the Children organisations in collaboration with the University of Bergen, with the principal objective of pursuing basic research in leprosy. The institute has a commendable record of achievement, and has made significant contributions to our understanding of leprosy and its control, and to the training of scientists from Ethiopia and other African countries. Recently, the Ethiopian, Swedish and Norwegian governments agreed to continue supporting the AHRI as an autonomous research centre. Its main objectives will be to conduct research in mycobacterial diseases, particularly tuberculosis, and to promote the enhancement of human resources in health research through instruction, supervision, and scientific collaboration.


Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology.
Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen major cancer types, we compared heterogeneities at the levels of mutations and gene expression with the repertoires of targeted therapeutics and their molecular targets accepted by the current guidelines in oncology. Totally, 85 drugs were investigated, collectively covering 82 individual molecular targets. For the first time, we showed that the repertoires of molecular targets of accepted drugs did not correlate with molecular heterogeneities of different cancer types. On the other hand, we found that the clinical recommendations for the available cancer drugs were strongly congruent with the gene expression but not gene mutation patterns. We detected the best match among the drugs usage recommendations and molecular patterns for the kidney, stomach, bladder, ovarian and endometrial cancers. In contrast, brain tumors, prostate and colorectal cancers showed the lowest match. These findings provide a theoretical basis for reconsidering usage of targeted therapeutics and intensifying drug repurposing efforts.


Impulsivity, defensive functioning, and borderline personality disorder.
To replicate previous research suggesting that impulsivity highly predicts current DIB(R) score and social functioning, with the additional inclusion of other measures, including defensive functioning. Correlational analyses between impulsivity and other measures, and regression analyses with DIB(R) and SAS-SR as outcome measures, and impulsivity and other measures as predictor variables, were performed on data derived from n = 57 initially borderline personality disorder (BPD) subjects recruited as part of a 7-year follow-up study of BPD. Data showed strong correlations between the elements of impulsivity described previously and defensive functioning. The initial study results were repeated, and only a minor contribution from defensive functioning additionally contributed to the regression models. No other variables entered the model, unless anger was dropped from the variables entered into the analysis. The results may contribute to a better definition of the term "impulsivity" as related to BPD, and may lead to further, improved research into the cause, treatment, and prognosis of BPD.


[The use of a silver staining method in the diagnosis of the late skin lesions in ixodid tick-borne borreliosis in man].
The borreliosis etiology was verified in 60% cases of the morphea, 100% cases of the atrophoderma of Pasini-Pierini and 100% cases of anetoderma by means of IFA with Ip-21 antigen (B. afzelii) and silver staining after Levadity. Borreliae were located near the capillaries, muscular and areolar tissue fibers of the derm and near the granulated cells of epidermis.


Deciphering the distinct transcriptomic and gene regulatory map in adult macaque basal ganglia cells.
The basal ganglia are a complex of interconnected subcortical structures located beneath the mammalian cerebral cortex. The degeneration of dopaminergic neurons in the basal ganglia is the primary pathological feature of Parkinson's disease. Due to a lack of integrated analysis of multiomics datasets across multiple basal ganglia brain regions, very little is known about the regulatory mechanisms of this area. We utilized high-throughput transcriptomic and epigenomic analysis to profile over 270,000 single-nucleus cells to create a cellular atlas of the basal ganglia, characterizing the cellular composition of 4 regions of basal ganglia in adult macaque brain, including the striatum, substantia nigra (SN), globus pallidum, and amygdala. We found a distinct epigenetic regulation on gene expression of neuronal and nonneuronal cells across regions in basal ganglia. We identified a cluster of SN-specific astrocytes associated with neurodegenerative diseases and further explored the conserved and primate-specific transcriptomics in SN cell types across human, macaque, and mouse. Finally, we integrated our epigenetic landscape of basal ganglia cells with human disease heritability and identified a regulatory module consisting of candidate cis-regulatory elements that are specific to medium spiny neurons and associated with schizophrenia. In general, our macaque basal ganglia atlas provides valuable insights into the comprehensive transcriptome and epigenome of the most important and populous cell populations in the macaque basal ganglia. We have identified 49 cell types based on transcriptomic profiles and 47 cell types based on epigenomic profiles, some of which exhibit region specificity, and characterized the molecular relationships underlying these brain regions.


Project Shikamana: Community Empowerment-Based Combination HIV Prevention Significantly Impacts HIV Incidence and Care Continuum Outcomes Among Female Sex Workers in Iringa, Tanzania.
To determine the impact of a community empowerment model of combination HIV prevention (Project Shikamana) among female sex workers (FSW) in Iringa, Tanzania. We conducted a 2-community randomized trial. Intervention elements included the following: (1) Community-led drop-in center and mobilization activities; (2) venue-based peer education, condom distribution, and HIV testing; (3) peer service navigation; (4) provider sensitivity trainings; and (5) SMS reminders. We used time-location sampling to enroll 496 FSW and conducted a survey and blood draws to screen for HIV and assess viral load at 0 and 18 months. We conducted an intent-to-treat analysis using logistic and Poisson regression and inverse probability weighting for primary outcomes. The analysis included 171 HIV-positive and 216 HIV-negative FSW who completed baseline and 18-month study visits. Participants in the intervention were significantly less likely to become infected with HIV at 18-month follow-up (RR 0.38; P = 0.047), with an HIV incidence of 5.0% in the intervention vs. 10.4% control. Decreases in inconsistent condom use over time were significantly greater in the intervention (72.0%-43.6%) vs. control (68.8%-54.0%; RR 0.81, P = 0.042). At follow-up, we observed significant differences in behavioral HIV care continuum outcomes, and positive, but nonsignificant, increases in viral suppression (40.0%-50.6%) in the intervention vs. control (35.9%-47.4%). There was a strong association of between higher intervention exposure and HIV outcomes including viral suppression. Project Shikamana is the first trial of community empowerment-based combination prevention among FSW in Africa to show a significant reduction in HIV incidence warranting its broader implementation and evaluation.


An Approach to Assessing the Influence of Environmental and Occupational Cancer Hazard Identification on Policy Decision-Making.
Cancer hazard identification is critical to informing decisions on preventive actions. However, the influence of cancer hazard assessments on the creation of health-protective regulations is poorly understood. Although prior studies have measured the health and economic benefits of regulatory actions in general, we are not aware of efforts to explicitly study the influence of cancer hazard identification on policy decisions in the United States. In this commentary, we present an approach to examine whether formal identification of a substance as a human carcinogen may prompt a regulatory action to reduce exposure to carcinogens and enhance public health. Further, we discuss the broader implications of cancer hazard identification on policy decision-making, including identifying gaps and providing recommendations. Using the Report on Carcinogens (RoC) as a test case, we systematically searched U.S. federal and state databases for notices of regulations mentioning the RoC from 1995 to 2023. For each regulation, we extracted information on the carcinogen(s) regulated, the regulatory agency, the regulatory purpose, the economic sector exposure sources, and the analyzed public health benefits and costs. We created a publicly available, web-based interactive tool to visualize the data. U.S. regulatory agencies have been using cancer hazard evaluations, such as the RoC, for decades to inform public health policy actions to prevent or mitigate cancer risks. Specifically, nonregulatory cancer hazard assessments have been used to prioritize chemical evaluations, support regulatory-based assessments, and trigger regulatory action. Our approach showed that assessing the influence of cancer hazard identification on science-based public health policies is feasible, informative, and needed, and our study is a first step in this direction. We recommend expanding this approach to other cancer and noncancer hazard assessments to ultimately inform our understanding of the influence of hazard classifications on policymaking. https://doi.org/10.1289/EHP12681.


Open source marketing: Camel cigarette brand marketing in the "Web 2.0" world.
The international trend towards comprehensive bans on tobacco advertising has seen the tobacco industry become increasingly innovative in its approach to marketing. Further fuelling this innovation is the rapid evolution and accessibility of web-based technology. The internet, as a relatively unregulated marketing environment, provides many opportunities for tobacco companies to pursue their promotional ambitions. In this paper, "open source marketing" is considered as a vehicle that has been appropriated by the tobacco industry, through a case study of efforts to design the packaging for the Camel Signature Blends range of cigarettes. Four sources are used to explore this case study including a marketing literature search, a web-based content search via the Google search engine, interviews with advertising trade informants and an analysis of the Camel brand website. RJ Reynolds (RJR) has proven to be particularly innovative in designing cigarette packaging. RJR engaged with thousands of consumers through their Camel brand website to design four new cigarette flavours and packages. While the Camel Signature Blends packaging designs were subsequently modified for the retail market due to problems arising with their cartoon-like imagery, important lessons arise on how the internet blurs the line between marketing and market research. Open source marketing has the potential to exploit advertising ban loopholes and stretch legal definitions in order to generate positive word of mouth about tobacco products. There are also lessons in the open source marketing movement for more effective tobacco control measures including interactive social marketing campaigns and requiring plain packaging of tobacco products.


[Continuous cultivation of hydrogen bacteria with multiple use of the medium].
The possibility of continuous cultivation of hydrogen bacteria was studied in the conditions of recirculation of the medium. The hydrogen bacteria accumulated proteins, carbohydrates, lipids, organic and amino acids in the medium during its multiple reutilization, which however had no effect on the specific growth rate and the ability of the bactetia to oxidize molecular hydrogen.


[Evaluation of In Vitro Efficacy of Ceftazidime-Avibactam, Meropenem, and Colistin Single and Binary Combinations Against Carbapenem Resistant Klebsiella pneumoniae Strains Isolated from Various Clinical Specimens].
It has been reported that many antibiotics used today, including the carbapenem group, fail to treat Klebsiella pneumoniae infections effectively. Despite many studies in recent years, the definitive treatment for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is still uncertain. In this study, it was aimed to investigate in vitro activities of colistin (COL) and meropenem (MEM), which are frequently used in the treatment of CRKP infections, and ceftazidime-avibactam (CZA), which is recently used in our country, alone or in combination against different CRKP isolates having different carbapenem resistance mechanisms andto analyze whether the presence of colistin resistance, which is an important problem in CRKP strains, influences the drug interaction results. This study was carried out in 42 K.pneumoniae isolates, which were isolated from various clinical samples as an infectious agent in Süleyman Demirel University Faculty of Medicine, Department of Medical Microbiology, Bacteriology Laboratory and whose carbapenem resistance was confirmed by carbapenemase inactivation test. The carbapenemase genes of the isolates were determined by the polymerase chain reaction (PCR) method. Antimicrobial susceptibilities of CRKP strains to CZA, MEM, and COL were determined by the broth microdilution method and in vitro synergy activities of dual combinations of these drugs were evaluated by checkerboard and time-kill methods. Statistical evaluation of categorical data was performed using Fisher's exact test, and p-value of less than 0.05 was considered statistically significant in terms of difference between the groups. Of the 42 CRKP isolates 34 (81%) were only OXA-48 positive, 5 (11.9%) were OXA-48+NDM and 3 (7.1%) were OXA-48+KPC positive. In the checkerboard test, synergy was detected against 97.6% of the isolates both with CZA+MEM and CZA+COL combinations, whereas this rate was 50% with MEM+COL. In the time-kill test, synergy was detected with CZA+MEM and CZA+COL combinations in the OXA-48 positive isolate and OXA-48+KPC positive isolate, while synergy was detected with CZA+COL and MEM+COL combinations in the OXA-48+NDM positive isolate. There was no significant relationship between whether the isolates were resistant to colistin or not and the checkerboard test results of antibiotic combinations (pCZA+MEM= 0.33, pCZA+COL= 0.11, pMEM+COL= 0.61). Results of our study revealed that the most common carbapenemase type in CRKP isolates was OXA-48 in our hospital, and the combinations of CZA with MEM and COL had high potential for synergism against these isolates.


Performance evaluation of medical records departments by analytical hierarchy process (AHP) approach in the selected hospitals in Isfahan : medical records dep. & AHP.
Medical Records Department (MRD) is an important unit for evaluating and planning of care services. The goal of this study is evaluating the performance of the Medical Records Departments (MRDs) of the selected hospitals in Isfahan, Iran by using Analytical Hierarchy Process (AHP). This was an analytic of cross-sectional study that was done in spring 2008 in Isfahan, Iran. The statistical population consisted of MRDs of Alzahra, Kashani and Khorshid Hospitals in Isfahan. Data were collected by forms and through brainstorm technique. To analyze and perform AHP, Expert Choice software was used by researchers. Results were showed archiving unit has received the largest importance weight with respect to information management. However, on customer aspect admission unit has received the largest weight. Ordering weights of Medical Records Departments' Alzahra, Kashani and Khorshid Hospitals in Isfahan were with 0.394, 0.342 and 0.264 respectively. It is useful for managers to allocate and prioritize resources according to AHP technique for ranking at the Medical Records Departments.


Generation and migration of light hydrocarbons.
Light hydrocarbons (containing from 1 to 14 carbon atoms) are formed from disseminated organic matter in sediments at the parts-per-billion level by biological and low-temperature (< 50 degrees C) chemical reactions and at the parts-permillion level by high-temperature (> 50 degrees C) cracking reactions. The cooler reactions produce mainly branched hydrocarbons, whereas the hotter reactions yield more straight chains. Hydrocarbon generation zones in the subsurface can be recognized on the basis of hydrocarbon distribution patterns. Hydrocarbons with tertiary carbon atoms form at lower temperatures than those with quaternary carbons. Methane and ethane migrate vertically through fine-grained shales by diffusion and solution, whereas many of the C(3+) hydrocarbons show little or no vertical migration. Concentrations of light hydrocarbons, including methane, in fine-grained source rocks decrease to low values in deep, high-temperature (>200 degrees C) sediments. This decrease may be one reason why no economic accumulation of gas has been found to date deeper than 8.2 kilometers (27,000 feet).


Reduced O2 and elevated ROS in sea urchin embryos leads to defects in ectoderm differentiation.
The sea urchin oral-aboral (OA) axis is established in part by Nodal signaling. The OA axis is also influenced by treatments affecting respiration and Nodal transcription is influenced by redox-dependent transcription factors. This suggests that intracellular redox state plays a role in OA axis specification. Since cellular redox state can be altered by the formation of excess reactive oxygen species (ROS), and hypoxia and paraquat generate ROS in cells, we asked whether these treatments affected specification of the OA axis and Nodal expression. Embryos cultured under conditions that elevate ROS, demonstrate perturbed ectoderm specification, but other territories are not affected. Immunohistochemical and Q-RT-PCR analyses revealed that both oral and aboral ectoderm genes are downregulated. Our results argue that elevating ROS in sea urchin embryos by these treatments blocks early steps in ectoderm differentiation preceding the polarization of the ectoderm into oral and aboral territories.


Quality assessment of cross-species hybridization of CHO transcriptome on a mouse DNA oligo microarray.
DNA microarray technology has been widely utilized for species with extensive genome sequence information available. Given the limited genomic information pertaining to Chinese hamster ovary (CHO) cell line, cross-species hybridization using mouse microarrays provides a viable alternative. In this study, the utility of mouse Affymetrix microarrays for transcriptome profiling in CHO cells was assessed by hybridizing identical sets of cRNA samples from CHO cells on both mouse and CHO Affymetrix microarrays. Expression level measured by probe sets for orthologous transcripts on the two microarrays was compared. Only a fraction of the orthologous probes which detected expression calls in same species hybridization were similarly called present in cross species hybridization. In further analysis at the 25-mer probe level, it was revealed that specific hybridization signals were detectable by the subset of mouse probes that have a high degree of homology to the corresponding CHO sequences. The feasibility of cross species hybridization for quantifying the extent of differential expression was assessed by comparing transcript levels of CHO cells cultivated with and without sodium butyrate. While same species hybridization gave consistent degree of differential expression calls in replicated runs, a much inferior ability in quantifying differential expression was seen with cross species hybridization. Our results demonstrate that through detailed analysis of homology at the probe pair level, a subset of probes on existing mouse Affymetrix oligo-array can be used successfully for transcriptome profiling of CHO cells.


Evaluation of T-Cell Responses Against Shared Melanoma Associated Antigens and Predicted Neoantigens in Cutaneous Melanoma Patients Treated With the CSF-470 Allogeneic Cell Vaccine Plus BCG and GM-CSF.
The CSF-470 vaccine consists of lethally-irradiated allogeneic cells derived from four cutaneous melanoma cell lines administered plus BCG and GM-CSF as adjuvants. In an adjuvant phase II study vs. IFN-α2b, the vaccine significantly prolonged the distant metastasis-free survival (DMFS) of stages IIB-IIC-III melanoma patients with evidence of the induction of immune responses against vaccine cells. Purpose: The aim of this study was to analyze the antigens against which the immune response was induced, as well as the T-helper profile and lytic ability of immune cells after CSF-470 treatment. Methods: HLA-restricted peptides from tumor-associated antigens (TAAs) were selected from TANTIGEN database for 13 evaluable vaccinated patients. In addition, for patient #006 (pt#006), tumor somatic variants were identified by NGS and candidate neoAgs were selected by predicted HLA binding affinity and similarity between wild type (wt) and mutant peptides. The patient's PBMC reactivity against selected peptides was detected by IFNγ-ELISPOT. T-helper transcriptional profile was determined by quantifying GATA-3, T-bet, and FOXP3 mRNA by RT-PCR, and intracellular cytokines were analyzed by flow cytometry. Autologous tumor cell lysis by PBMC was assessed in an in vitro calcein release assay. Results: Vaccinated patient's PBMC reactivity against selected TAAs derived peptides showed a progressive increase in the number of IFNγ-producing cells throughout the 2-yr vaccination protocol. ELISPOT response correlated with delayed type hypersensitivity (DTH) reaction to CSF-470 vaccine cells. Early upregulation of GATA-3 and Foxp3 mRNA, as well as an increase in CD4+IL4+cells, was associated with a low DMFS. Also, IFNγ response against 9/73 predicted neoAgs was evidenced in the case of pt#006; 7/9 emerged after vaccination. We verified in pt# 006 that post-vaccination PBMC boosted in vitro with the vaccine lysate were able to lyse autologous tumor cells. Conclusions: A progressive increase in the immune response against TAAs expressed in the vaccine and in the patient's tumor was induced by CSF-470 vaccination. In pt#006, we demonstrated immune recognition of patient's specific neoAgs, which emerged after vaccination. These results suggest that an initial response against shared TAAs could further stimulate an immune response against autologous tumor neoAgs.


Anti-malarial activity and HS-SPME-GC-MS chemical profiling of Plinia cerrocampanensis leaf essential oil.
Plinia cerrocampanensis is an endemic plant of Panama. The leaf essential oil of this plant has shown antibacterial activity. However, anti-malarial activity and chemical profiling by HS-SPME-GC-MS of this essential oil have not been reported before. Anti-malarial activity of the essential oil (EO) was evaluated in vitro against chloroquine-sensitive HB3 and chloroquine-resistant W2 strains of Plasmodium falciparum. Synergistic effect of chloroquine and the EO on parasite growth was evaluated by calculating the combination index. A methodology involving headspace solid phase microextraction and gas chromatography-mass spectrometry (HS-SPME-GC-MS) was developed to investigate the composition of Plinia cerrocampanensis EO. Plinia cerrocampanensis EO showed a high anti-malarial activity and a synergistic interaction with chloroquine. The Plinia cerrocampanensis EO inhibited P. falciparum growth in vitro at an IC50 of 7.3 μg/mL. Chloroquine together with the EO decreased the IC50 of chloroquine from 0.1 μg/mL to 0.05 μg/mL, and of the EO from 7.3 μg/mL to 1.1 μg/mL. The measured combination index was 0.58, which clearly indicates that the EO acts synergistically with chloroquine. Since the EO maintained its inhibitory activity on the chloroquine-sensitive strain of the parasite, it could be acting by a different mechanism of action than chloroquine. The best HS-SPME-GC-MS analytical conditions were obtained when the temperature of extraction was 49°C, incubation time 14 min, and the time of extraction 10 min. This method allowed for the identification of 53 volatile constituents in the EO, including new compounds not reported earlier. The anti-malarial activity exhibited by the Plinia cerrocampanensis EO may lend support for its possible use as an alternative for anti-malarial therapy.


Estimation of dissolution rate from in vivo studies of synthetic vitreous fibers.
Although the dissolution rate of a fiber was originally defined by a measurement of dissolution in simulated lung fluid in vitro, it is feasible to determine it from animal studies as well. The dissolution rate constant for a fiber may be extracted from the decrease in long fiber diameter observed in certain intratracheal instillation experiments or from the observed long fiber retention in short-term biopersistence studies. These in vivo dissolution rates agree well with those measured in vitro for the same fibers. For those special types of fibers, the high-alumina rock wool fibers that could not be measured in vitro, the method provides a way of obtaining a chemical dissolution rate constant from an animal study. The inverse of the in vivo dissolution rate, the fiber dissolution time, correlates well with the weighted half life of long fibers in a biopersistence study, and the in vivo dissolution rate may be estimated accurately from this weighted half-life.


Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases.
Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.


Cranioplasty complications following wartime decompressive craniectomy.
In support of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom-Afghanistan (OEF-A), military neurosurgeons in the combat theater are faced with the daunting task of stabilizing patients in such a way as to prevent irreversible neurological injury from cerebral edema while simultaneously allowing for prolonged transport stateside (5000-7000 miles). It is in this setting that decompressive craniectomy has become a mainstay of far-forward neurosurgical management of traumatic brain injury (TBI). As such, institutional experience with cranioplasty at the Walter Reed Army Medical Center (WRAMC) and the National Naval Medical Center (NNMC) has expanded concomitantly. Battlefield blast explosions create cavitary injury zones that often extend beyond the border of the exposed surface wound, and this situation has created unique reconstruction challenges not often seen in civilian TBI. The loss of both soft-tissue and skull base support along with the need for cranial vault reconstruction requires a multidisciplinary approach involving neurosurgery, plastics, oral-maxillofacial surgery, and ophthalmology. With this situation in mind, the authors of this paper endeavored to review the cranial reconstruction complications encountered in these combat-related injuries. A retrospective database review was conducted for all soldiers injured in OIF and OEF-A who had undergone decompressive craniectomy with subsequent cranioplasty between April 2002 and October 2008 at the WRAMC and NNMC. During this time, both facilities received a total of 408 OIF/OEF-A patients with severe head injuries; 188 of these patients underwent decompressive craniectomies in the theater before transfer to the US. Criteria for inclusion in this study consisted of either a closed or a penetrating head injury sustained in combat operations, resulting in the performance of a decompressive craniectomy and subsequent cranioplasty at either the WRAMC or NNMC. Excluded from the study were patients for whom primary demographic data could not be verified. Demographic data, indications for craniectomy, as well as preoperative, intraoperative, and postoperative parameters following cranioplasty, were recorded. Perioperative and postoperative complications were also recorded. One hundred eight patients (male/female ratio 107:1) met the inclusion criteria for this study, 93 with a penetrating head injury and 15 with a closed head injury. Explosive blast injury was the predominant mechanism of injury, occurring in 72 patients (67%). The average time that elapsed between injury and cranioplasty was 190 days (range 7-546 days). An overall complication rate of 24% was identified. The prevalence of perioperative infection (12%), seizure (7.4%), and extraaxial hematoma formation (7.4%) was noted. Twelve patients (11%) required prosthetic removal because of either extraaxial hematoma formation or infection. Eight of the 13 cases of infection involved cranioplasties performed between 90 and 270 days from the date of injury (p = 0.06). This study represents the largest to date in which cranioplasty and its complications have been evaluated in a trauma population that underwent decompressive craniectomy. The overall complication rate of 24% is consistent with rates reported in the literature (16-34%); however, the perioperative infection rate of 12% is higher than the rates reported in other studies. This difference is likely related to aspects of the initial injury pattern-such as skull base injury, orbitofacial fractures, sinus injuries, persistent fluid collection, and CSF leakage-which can predispose these patients to infection.


Effects of continuous renal replacement therapy on intestinal mucosal barrier function during extracorporeal membrane oxygenation in a porcine model.
Extracorporeal membrane oxygenation (ECMO) has been recommended for treatment of acute, potentially reversible, life-threatening respiratory failure unresponsive to conventional therapy. Intestinal mucosal barrier dysfunction is one of the most critical pathophysiological disorders during ECMO. This study aimed to determine whether combination with CRRT could alleviate damage of intestinal mucosal barrier function during VV ECMO in a porcine model. Twenty-four piglets were randomly divided into control(C), sham(S), ECMO(E) and ECMO + CRRT(EC) group. The animals were treated with ECMO or ECMO + CRRT for 24 hours. After the experiments, piglets were sacrificed. Jejunum, ileum and colon were harvested for morphologic examination of mucosal injury and ultrastructural distortion. Histological scoring was assessed according to Chiu's scoring standard. Blood samples were taken from the animals at -1, 2, 6, 12 and 24 h during experiment. Blood, liver, spleen, kidney and mesenteric lymphnode were collected for bacterial culture. Serum concentrations of diamine oxidase (DAO) and intestinal fatty acid binding protein (I-FABP) were tested as markers to assess intestinal epithelial function and permeability. DAO levels were determined by spectrophotometry and I-FABP levels by enzyme linked immunosorbent assay. Microscopy findings showed that ECMO-induced intestinal microvillus shedding and edema, morphological distortion of tight junction between intestinal mucous epithelium and loose cell-cell junctions were significantly improved with combination of CRRT. No significance was detected on positive rate of serum bacterial culture. The elevated colonies of bacterial culture in liver and mesenteric lymphnode in E group reduced significantly in EC group (p < 0.05). Compared with E group, EC group showed significantly decreased level of serum DAO and I-FABP (p < 0.05). CRRT can alleviate the intestinal mucosal dysfunction and bacterial translocation during VV ECMO, which may extenuate the ECMO-associated SIRS and raise the clinical effect and safety.


Cell-mediated immunity to hepatitis B surface antigen in blood donors with persistent antigenaemia.
Cellular immunity to the hepatitis B surface antigen (HBsAg) and a liver-specific lipoprotein was studied, using the leucocyte migration test, in 38 asymptomatic blood donors found to have HBsAg in the serum. Sensitization to HBsAg was found in 26% and was related to the presence of liver damage, being detected in 47% of those with elevated serum aspartate aminotransferase but in only 13% with normal enzyme levels. The frequency of sensitization to this antigen in those with chronic persistent or chronic aggressive hepatitis on biopsy was also higher than in those with unrelated or minimal changes. The findings using the liver-specific lipoprotein as antigen were similar and there was a correlation between the results obtained with this and the hapatitis B surface antigen. This study supports the hypothesis that a T-lymphocyte response to hepatitis B virus antigen can initiate an autoimmune reaction to antigens such as liver-specific lipoprotein on the hepatocyte surface, and that this reaction may be of importance in the production of chronic liver damage. In the absence of the T-cell response, the autoimmune reaction cannot occur and the virus is able to establish a harmless symbiotic union with the host.


Functional characterization of transcription factor motifs using cross-species comparison across large evolutionary distances.
We address the problem of finding statistically significant associations between cis-regulatory motifs and functional gene sets, in order to understand the biological roles of transcription factors. We develop a computational framework for this task, whose features include a new statistical score for motif scanning, the use of different scores for predicting targets of different motifs, and new ways to deal with redundancies among significant motif-function associations. This framework is applied to the recently sequenced genome of the jewel wasp, Nasonia vitripennis, making use of the existing knowledge of motifs and gene annotations in another insect genome, that of the fruitfly. The framework uses cross-species comparison to improve the specificity of its predictions, and does so without relying upon non-coding sequence alignment. It is therefore well suited for comparative genomics across large evolutionary divergences, where existing alignment-based methods are not applicable. We also apply the framework to find motifs associated with socially regulated gene sets in the honeybee, Apis mellifera, using comparisons with Nasonia, a solitary species, to identify honeybee-specific associations.


[Role of immune inflammatory activity in chronic heart failure progress].
Significant role of immune inflammatory reactions along with activation of the RAAS (rennin-angiotensin-aldosterone system) and the sympatho-adrenal system in CHF (chronic heart failure) pathogenesis is considered in the present survey article. Together with haemodynamic disorders activation of inflammatory reactions, which involve anti-inflammatory cytokines, is shown to be one of the main factors affecting CHF course and prognosis. Alteration of cytokine level is associated with injury level, gravity of the disease course and its clinical outcome. Prognostic value of determination of inflammation mediators as predictors of cardiovascular diseases and clinical outcomes is evaluated. Urgency of search for new medication in addition to "traditional preparations" used for the treatment of CHF is shown.


Changes in muscle responses to stimulation of the motor cortex induced by peripheral nerve stimulation in human subjects.
The aim of this study was to determine whether prolonged, repetitive mixed nerve stimulation (duty cycle 1 s, 500 ms on-500 ms off, 10 Hz) of the ulnar nerve leads to a change in excitability of primary motor cortex in normal human subjects. Motor-evoked potentials (MEPs) generated in three intrinsic hand muscles [abductor digiti minimi (ADM), first dorsal interosseous (FDI) and abductor pollicis brevis (APB)] by focal transcranial magnetic stimulation were recorded during complete relaxation before and after a period of prolonged repetitive ulnar nerve stimulation at the wrist. Transcranial magnetic stimuli were applied at seven scalp sites separated by 1 cm: the optimal scalp site for eliciting MEPs in the target muscle (FDI), three sites medial to the optimal site and three sites lateral to the optimal stimulation site. The area of the MEPs evoked in the ulnar-(FDI, ADM) but not the median-innervated (APB) muscles was increased after prolonged ulnar nerve stimulation. Centre of gravity measures demonstrated that there was no significant difference in the distribution of cortical excitability after the peripheral stimulation. F-wave responses in the intrinsic hand muscles were not altered after prolonged ulnar nerve stimulation, suggesting that the changes in MEP areas were not the result of stimulus-induced increases in the excitability of spinal motoneurones. Control experiments employing transcranial electric stimulation provided no evidence for a spinal origin for the excitability changes. These results demonstrate that in normal human subjects the excitability of the cortical projection to hand muscles can be altered in a manner determined by the peripheral stimulus applied.


Mouse genomic representational oligonucleotide microarray analysis: detection of copy number variations in normal and tumor specimens.
Genomic amplifications and deletions, the consequence of somatic variation, are a hallmark of human cancer. Such variation has also been observed between "normal" individuals, as well as in individuals with congenital disorders. Thus, copy number measurement is likely to be an important tool for the analysis of genetic variation, genetic disease, and cancer. We developed representational oligonucleotide microarray analysis, a high-resolution comparative genomic hybridization methodology, with this aim in mind, and reported its use in the study of humans. Here we report the development of a representational oligonucleotide microarray analysis microarray for the genomic analysis of the mouse, an important model system for many genetic diseases and cancer. This microarray was designed based on the sequence assembly MM3, and contains approximately 84,000 probes randomly distributed throughout the mouse genome. We demonstrate the use of this array to identify copy number changes in mouse cancers, as well to determine copy number variation between inbred strains of mice. Because restriction endonuclease digestion of genomic DNA is an integral component of our method, differences due to polymorphisms at the restriction enzyme cleavage sites are also observed between strains, and these can be useful to follow the inheritance of loci between crosses of different strains.


Pyrethroid insecticide evaluation on different house structures in a Chagas disease endemic area of the Paraguayan Chaco.
Insecticide effects of deltamethrin 2.5% SC (flowable solution) on different substrates and triatomine infestation rates in two indigenous villages (Estancia Salzar and Nueva Promesa) of the Paraguayan Chaco are reported. This field study was carried out to determine the extent to which variability in spray penetration may affect residual action of the insecticide. A total of 117 houses in the two villages were sprayed. Filter papers discs were placed on aluminium foil pinned to walls and roofs in selected houses and the applied insecticide concentration was determined by high pressure liquid chromatography (HPLC). The target dose rate was 25 mg a.i./m2. The mean actual applied dose in Estancia Salazar was 11.2 +/- 3.1 mg a.i./m2 in walls and 11.9 +/- 5.6 mg a.i./m2 in roofs while in Nueva Promesa, where duplicates were carried out, the mean values were 19.9 +/- 6.9 mg a.i./m2 and 34.7 +/- 10.4 mg a.i./m2 in walls and 28.8 +/- 19.2 mg a.i./m2 and 24.9 +/- 21.8 mg a.i./m2 in roofs. This shows the unevenness and variability of applied doses during spraying campaigns, and also the reduced coverage over roof surfaces. However, wall bioassays with Triatoma infestans nymphs in a 72 h exposure test showed that deposits of deltamethrin persisted in quantities sufficient to kill triatomines until three months post spraying. Knockdown by deltamethrin on both types of surfaces resulted in 100% final mortality. A lower insecticidal effect was observed on mud walls. However, three months after treatment, sprayed lime-coated mud surfaces displayed a twofold greater capacity (57.5%) to kill triatomines than mud sprayed surfaces (25%). Re-infestation was detected by manual capture only in one locality, six months after spraying.


Improved survivorship of hybrid metal-on-metal hip resurfacing with second-generation techniques for Crowe-I and II developmental dysplasia of the hip.
The purpose of this study was to determine the influence of improved femoral fixation techniques on the survivorship of metal-on-metal total hip resurfacing prostheses in patients with developmental dysplasia of the hip and to report the long-term results of our patients managed earlier with first-generation fixation techniques. One hundred and three hips (ninety patients) were resurfaced for osteoarthritis secondary to developmental dysplasia. The mean age of the patients was forty-seven years, and 77% were women. Most hips (94%) were Crowe class I, but 43% had femoral head defects of >1 cm in size. The clinical results of these hips were compared with those of a group of patients with other etiologies, largely dominated by idiopathic osteoarthritis (78%). All clinical scores improved significantly (p < 0.0001) and were comparable with those of patients with other etiologies except for the postoperative activity scores, which were lower (7.0 compared with 7.5). Range of motion was greater for the patients with dysplasia than for the patients with other etiologies. Seven hips that were resurfaced with the first-generation femoral fixation techniques and one hip that was resurfaced with the second and third-generation techniques had conversion to total hip arthroplasty. This difference was found to be significant (p = 0.032) in a multivariate, time-dependent analysis after adjustment for other covariates known to affect prosthetic survival. There was no loosening of the acetabular component in this series. The current improvements in the short-term to midterm results after resurfacing in patients with developmental dysplasia of the hip in whom more current techniques were used are encouraging and allow for greater expectations regarding the elimination of short-term failures and improved long-term durability of resurfacing in this population.


Interspecific interactions between acanthocephalan species in the intestine of stone loach and minnow.
Interspecific interactions between parasites sharing the same host are often antagonistic; the presence of one species decreases the number of individuals or negatively affects both the distribution and reproduction of the other species. Antagonistic interactions between co-infecting parasites may translate into direct competition or interactive segregation, but elements of both may be present. Potential interactions between two acanthocephalan species, Pomphorhynchus laevis and Acanthocephalus anguillae, were studied in the field in two of their natural fish definitive hosts. There was no evidence for competitive exclusion between P. laevis and A. anguillae. However, a negative interaction was found for the first time in the field between these two species. Based on the analysis of parasite abundance and total biomass using a static regression approach, I found that the abundance and total biomass of parasite was also limited by host characteristics. These results are consistent with previous laboratory studies on competition between P. laevis and A. anguillae.


Role of the Vi antigen of Salmonella typhi in resistance to host defense in vitro.
The virulence of Salmonella typhi is associated with the presence of the Vi antigen. Mechanisms of Vi antigen virulence were examined in vitro. The Vi antigen-containing strain Quailes was significantly (P less than 0.025) more resistant to lysis by nonimmune serum than S. typhi 0901, which does not have the Vi antigen, and resulted in less activation of complement by the alternative pathway (P less than 0.05). Human polymorphonuclear leukocytes (PMNs) ingested strain Quailes significantly (P less than 0.01) more slowly and less completely than strain 0901 as assessed by three measures of phagocytic rate. In contrast to prior reports, the Vi antigen did not prevent an oxidative burst, measured by O2- production, chemiluminescence, and O2 consumption. The extent of the oxidative burst correlated directly and closely with the rate of phagocytosis. When the rate of PMN phagocytosis for both strains was equalized by opsonizing strain 0901 with 1% and strain Quailes with a 3% concentration of serum, the PMN oxidative burst was equal. C3 binding to strain Quailes was significantly (P less than 0.005) less than to strain 0901. Hence the Vi antigen inhibited phagocytosis by preventing C3b binding and solely as a consequence of this induced a lesser PMN oxidative burst. Furthermore, strain Quailes was significantly (P less than 0.025) less susceptible to killing by H2O2 than strain 0901. To ensure that these observations were a consequence of the Vi antigen and not other strain differences, another pair of S. typhi with and without the Vi antigen were similarly compared, and the results were the same as with strains Quailes and 0901. Strains 0901 and Quailes were killed by PMNs from a patient with chronic granulomatous disease but more slowly than by normal PMNs, indicating that S. typhi is susceptible to nonoxidative killing.


Prolonged activation of mitochondrial conductances during synaptic transmission.
Although ion channels have been detected in mitochondria, scientists have not been able to record ion transport in mitochondria of intact cells. A variation of the patch clamp technique was used to record ion channel activity from intracellular organelles in the presynaptic terminal of the squid. Electron microscopy indicated that mitochondria are numerous in this terminal and are the only organelles compatible with the tips of the pipettes. Before synaptic stimulation, channel activity was infrequent and its conductance was small, although large conductances ( approximately 0.5 to 2.5 nanosiemens) could be detected occasionally. During a train of action potentials, the conductance of the mitochondrial membrane increased up to 60-fold. The conductance increased after a delay of several hundred milliseconds and continued to increase after stimulation had stopped. Recovery occurred over tens of seconds.


[Pathogenesis of abdominal actinomycosis].
According to the author's findings in 80 of 125 patients under observation the development of abdominal actinomycosis was related with inflammation in the appendicular process, in 65 patients the former starting after appendectomy. In examination of 100 patients with diagnosis of acute appendicitis actinomycosis of the ileocecal region was diagnosed in 5 patients. Actinomycosis was spreading from the ileocecal region by contact in retroperitoneal cellular tissue in 23 cases, in the left iliac region--in 12, in the lesser pelvis--in 8.


Profile of Circulatory Metabolites in a Relapsing-remitting Animal Model of Multiple Sclerosis using Global Metabolomics.
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Although, MS is well characterized in terms of the role played by immune cells, cytokines and CNS pathology, nothing is known about the metabolic alterations that occur during the disease process in circulation. Recently, metabolic aberrations have been defined in various disease processes either as contributing to the disease, as potential biomarkers, or as therapeutic targets. Thus in an attempt to define the metabolic alterations that may be associated with MS disease progression, we profiled the plasma metabolites at the chronic phase of disease utilizing relapsing remitting-experimental autoimmune encephalomyelitis (RR-EAE) model in SJL mice. At the chronic phase of the disease (day 45), untargeted global metabolomic profiling of plasma collected from EAE diseased SJL and healthy mice was performed, using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry. A total of 282 metabolites were identified, with significant changes observed in 44 metabolites (32 up-regulated and 12 down-regulated), that mapped to lipid, amino acid, nucleotide and xenobiotic metabolism and distinguished EAE from healthy group (p<0.05, false discovery rate (FDR)<0.23). Mapping the differential metabolite signature to their respective biochemical pathways using the Kyoto Encyclopedia of Genes and Genomics (KEGG) database, we found six major pathways that were significantly altered (containing concerted alterations) or impacted (containing alteration in key junctions). These included bile acid biosynthesis, taurine metabolism, tryptophan and histidine metabolism, linoleic acid and D-arginine metabolism pathways. Overall, this study identified a 44 metabolite signature drawn from various metabolic pathways which correlated well with severity of the EAE disease, suggesting that these metabolic changes could be exploited as (1) biomarkers for EAE/MS progression and (2) to design new treatment paradigms where metabolic interventions could be combined with present and experimental therapeutics to achieve better treatment of MS.


Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer.
Squamous cell cancers account for more than half of all human cancers, and esophageal cancer is the sixth leading cause of cancer death worldwide. The majority of esophageal squamous cell carcinomas have identifiable p53 mutations, yet the same p53 mutations are found at comparable frequencies in precancerous dysplasia, indicating that transformation requires additional somatic changes yet to be defined. Here, we show that the zinc finger transcription factor Krüppel-like factor 5 (KLF5) transactivates NOTCH1 in the context of p53 mutation or loss. KLF5 loss limited NOTCH1 activity and was sufficient on its own to transform primary human keratinocytes harboring mutant p53, leading to the formation of invasive tumors. Restoration of NOTCH1 blocked transformation of KLF5-deficient and p53-mutant keratinocytes. Although human dysplastic epithelia accumulated KLF5, KLF5 expression was lost concurrently with NOTCH1 in squamous cell cancers. Taken together, these results define KLF5 loss as a critical event in squamous cell transformation and invasion. Our findings suggest that KLF5 may be a useful diagnostic and therapeutic target in esophageal squamous carcinomas and possibly more generally in other cancers associated with p53 loss of function.


Case 298.
History A 37-year-old man from the United States presented with a 1-year history of neck pain and stiffness that had been unsuccessfully treated with manipulative therapy by a chiropractor at another institution. Past medical history was remarkable only for marijuana and air duster abuse. He denied use of any prescription medications. Physical examination was notable for markedly reduced range of motion of the cervical spine. Laboratory work-up revealed an elevated alkaline phosphatase level (302 U/L [5.0 μkat/L]; normal range, 40-100 U/L [0.7-1.67 μkat/L]), but all other laboratory findings, including complete blood count, renal function, liver function, vitamin A level, serum protein electrophoresis, and hepatitis C antibodies were within normal limits. Cervical spine radiography was performed (Fig 1), followed by MRI (Fig 2). Subsequently, a full skeletal survey was ordered. Included are representative radiographs of the pelvis (Fig 3), left forearm (Fig 4), and distal right leg with ankle (Fig 5).


Parasympathetic reflex vasodilatation in rat submandibular gland.
The present study was designed to investigate 1) whether parasympathetic reflex vasodilatation occurs in the submandibular gland (SMG) in deeply urethan-anesthetized, cervically vagotomized, and sympathectomized rats when the central cut end of the lingual nerve (LN) is electrically stimulated and 2) to what extent the neural mechanisms underlying such responses are the same as those involved in the response to direct stimulation of the chorda-LN (CLN). Stimulation of each nerve separately elicited a marked blood flow increase in SMG. Section of the chorda tympani abolished the SMG blood flow response but had no effect on the lip blood flow increase evoked by LN stimulation. Section of the CLN abolished the SMG blood flow increases evoked by stimulation of either nerve. The SMG blood flow increases (regardless of whether they were evoked by LN or CLN stimulation) were markedly reduced by the autonomic cholinergic ganglion blocker hexamethonium. The present study demonstrates that a parasympathetic reflex vasodilator mechanism is present in the rat SMG and that it can express its effects under deep general anesthesia.


Intracellular selection of peptide inhibitors that target disulphide-bridged Aβ42 oligomers.
The β-amyloid (Aβ) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility, many have inadvertently raised the concentration of these soluble neurotoxic species. Sandberg et al. previously reported a β-hairpin stabilized variant of Aβ42 that results from an intramolecular disulphide bridge (A21C/A31C; Aβ42cc), which generates highly toxic oligomeric species incapable of converting into mature fibrils. Using an intracellular protein-fragment complementation (PCA) approach, we have screened peptide libraries using E. coli that harbor an oxidizing environment to permit cytoplasmic disulphide bond formation. Peptides designed to target either the first or second β-strand have been demonstrated to bind to Aβ42cc, lower amyloid cytotoxicity, and confer bacterial cell survival. Peptides have consequently been tested using wild-type Aβ42 via ThT binding assays, circular dichroism, MTT cytotoxicity assays, fluorescence microscopy, and atomic force microscopy. Results demonstrate that amyloid-PCA selected peptides function by both removing amyloid oligomers as well as inhibiting their formation. These data further support the use of semirational design combined with intracellular PCA methodology to develop Aβ antagonists as candidates for modification into drugs capable of slowing or even preventing the onset of AD.


Role of dipole-dipole interaction on enhancing Brownian coagulation of charge-neutral nanoparticles in the free molecular regime.
In contrast to van der Waals (vdW) forces, Coulombic dipolar forces may play a significant role in the coagulation of nanoparticles (NPs) but has received little or no attention. In this work, the effect of dipole-dipole interaction on the enhancement of the coagulation of two spherically shaped charge-neutral TiO(2) NPs, in the free molecular regime, is studied using classical molecular dynamics (MD) simulation. The enhancement factor is evaluated by determining the critical capture radius of two approaching NPs for different cases of initial dipole direction with respect to path (parallel∕perpendicular) and orientation with respect to each other (co-orientated∕counterorientated). As particle diameter decreases, the enhancement of coagulation is augmented as the ratio of dipole-dipole force to vdW force becomes larger. For 2-nm TiO(2) NPs at 273 K, the MD simulation predicts an average enhancement factor of about 8.59, which is much greater than the value of 3.78 when only the vdW force is considered. Nevertheless, as temperature increases, the enhancement factor due to dipole-dipole interaction drops quickly because the time-averaged dipole moment becomes small due to increased thermal fluctuations (in both magnitude and direction) of the instantaneous dipole moment.


Upper airway resistance syndrome. Central electroencephalographic power and changes in breathing effort.
Upper airway resistance syndrome (UARS) is defined by excessive daytime sleepiness and tiredness, and is associated with increased breathing effort. Its polygraphic features involve progressive increases in esophageal pressure (Pes), terminated by arousal (AR) as defined by the American Sleep Disorders Association (ASDA). With the arousal there is an abrupt decrease in Pes, called Pes reversal. However, Pes reversal can be seen without the presence of an AR. We performed spectral analysis on electroencephalographic data from a central lead for both AR and nonarousal (N-AR) events obtained from 15 UARS patients (eight men and seven women). Delta band activity was increased before and surrounding Pes reversal regardless of the presence or absence of AR. In the period after Pes reversal, alpha, sigma, and beta activity showed a greater increase in AR events than in N-AR events. The Pes measures were identical leading up to the point of reversal, but showed a longer-lasting and significantly greater decrease in respiratory effort after an AR. The data indicate that substantial electroencephalographic changes can be identified in association with Pes events, even when ARs cannot be detected according to standard criteria; however, visually identifiable electroencephalographic arousals clearly have a greater impact on ongoing inspiratory effort.


[Immunology of dental caries].
Dental carie is the most common infectious disease in humans. In the past decades, it has been described as a multifactorial condition, where diet and the immune response are main factors for the establishment of the disease. The authors approach the formation of the bacterian biofilm, the host's immune response, according to its maturation and deficiencies, and the current research to find a preventive intervention for this disease.


[Lympho- and hemosorption in the surgical treatment of hepatic insufficiency].
Results of the examination of 133 patients show sorption methods of detoxication to be effective means in the complex treatment of hepatic insufficiency. In hepatocerebral insufficiency however resulting from portal cirrhosis better results were obtained after lymphosorption. Hemosorption is indicated in cholemic intoxications as well as after liquidation of the obstruction of the common bile duct.


The mixed-ligand strategy to assemble a microporous anionic metal-organic framework: Ln3+ post-functionalization, sensors and selective adsorption of dyes.
A unique microporous anionic metal-organic framework, namely [Zn2(btb)2(bbis)](Me2NH2)2·6DMF (1), has been synthesized and structurally characterized [bbis = bis(4-benzylimidazol-ylphenyl)sulfone and H3btb = 4,4',4''-benzene-1,3,5-triyltribenzoic acid]. This compound exhibits a 4-fold interpenetrated anionic framework with ins topology. The post-synthetic cation exchange of 1 with Eu3+, Tb3+, Dy3+ and Sm3+ afforded lanthanide(iii)-loaded materials. Eu3+@1 and Tb3+@1 can be used as the potential luminescent probes in nitrobenzene. The adsorption behavior of 1 towards organic dyes was investigated, revealing rapid and selective separation of methylene blue.


Mycobacterium tuberculosis infection in patients with cancer, the role of 18-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring treatment response.
Active tuberculosis (TB) infection including asymptomatic and extrapulmonary disease may be detected with 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). This report highlights the promising role of FDG-PET/CT for evaluation of TB in high-risk, immunocompromised patients with cancer. PET/CT performed for cancer evaluation may detect asymptomatic infection and guide definitive diagnosis. It may also be a useful tool in the assessment of latent TB, to exclude active disease prior to treatment. PET/CT has potential for monitoring response to anti-tuberculosis treatment. Metabolic response may indicate clinical response and guide duration of anti-microbial therapy.


A facile one-pot synthesis of microgels and nanogels of laminarin for biomedical applications.
Laminarin (LAM) as a nontoxic, biodegradable, and biocompatible marine polysaccharide, has been reported for its ingenious bioactivities such as antioxidant, antitumor antiapoptotic anti-inflammatory, immunomodulatory and dietary fiber activities, and distinct physicochemical structure possess a remarkably promising potential in biomaterial science. Synthesis of LAM-based microgels and bulk hydrogels have been reported in two stages: modification of LAM polysaccharide with polymerizable functional groups and subsequent crosslinking reaction. Therefore, here an easier and more effortless methods to prepare poly(laminarin) (p(LAM)) particles were tackled. A direct and facile single step fabrication of micro/nanogels of p(LAM) for the first time by means of reverse micelle microemulsion system were illustrated. Preparation of p(LAM) particles were achieved by the well-known Oxa-Michael addition reaction mechanism using divinyl sulfone as the crosslinker. P(LAM) particles in 0.3-10 µm size range in spherical morphologies were prepared with 93 ± 7% yield and functionalized with chlorosulfonic acid (CSA) demonstrating their chemical modifiability for variety of agents e.g., targeting ligands. The bare and modified p(LAM) particles showed excellent blood compatibility with hemolytic indices of <1% and blood clotting indices higher than 90%. The reported p(LAM) particles hold great promise as natural alternative surrogates in biomedical applications including drug delivery.


Fibrosarcoma-like lipomatous neoplasm: a reappraisal of so-called spindle cell liposarcoma defining a unique lipomatous tumor unrelated to other liposarcomas.
The term "spindle cell liposarcoma" has been applied to liposarcomas (LPSs) composed predominantly or exclusively of spindled cells. These tumors have been considered variants of well-differentiated LPS (WDL), myxoid LPS, and spindle cell lipoma, suggesting that this is a heterogenous group of lesions. Using strict morphologic criteria and molecular and immunohistochemical analyses, we have identified a homogenous group of spindle cell lipomatous tumors, histologically and genetically distinct from other forms of LPS, which we have called "fibrosarcoma-like lipomatous neoplasm." Cases classified as "spindle cell LPS" or "low-grade LPS with spindle cell features" were reviewed. Final selection criteria included: (1) an exclusive low-grade spindle cell component resembling fibrosarcoma; (2) a mixture of bland fibroblastic cells resembling the preadipocyte and early-adipocyte stage of embryonic fat; and (3) molecular-genetic analysis that excluded other forms of lipomatous tumors. Of the initial 25 cases identified, comparative genomic hybridization (CGH) was uninformative in 2 cases; 5 were reclassified as WDL on the basis of molecular data (MDM2 amplification) and 6 as spindle cell lipoma (CGH profiles with a few gains and losses including a constant loss of chromosome 13 and frequent losses of chromosomes 16 and 6). The 12 remaining cases showed flat CGH profiles; of these cases, 11 were negative for DDIT3 gene rearrangements, and 1 result was uninterpretable. Patients ranged in age from 15 to 82 years (mean 50 y); male patients were affected slightly more often (7:5). Tumors arose in the deep (6) and superficial (3) soft tissue of the groin (4), buttock (3), thigh (2), flank (1), shoulder (1), and paratesticular tissue (1) and ranged in size from 2 to 20 cm (mean 7.5 cm). Clinical follow-up in 11 patients (9 mo to 20 y; mean 68 mo) showed no recurrences or metastases. As defined above, "fibrosarcoma-like lipomatous neoplasm" is a unique lipomatous tumor that should be distinguished from WDL/(low-grade) dedifferentiated LPS and myxoid LPS on combined histologic/molecular features because of its better prognosis.


Risk factors for infection following total joint arthroplasty in rheumatoid arthritis.
Determine risk factors for infection following hip or knee total joint arthroplasty in patients with rheumatoid arthritis. All rheumatoid arthritis patients with a hip or knee arthroplasty between years 2000 and 2010 were identified from population-based administrative data from the Calgary Zone of Alberta Health Services. Clinical data from patient charts during the hospital admission and during a one year follow-up period were extracted to identify incident infections. We identified 381 eligible procedures performed in 259 patients (72.2% female, mean age 63.3 years, mean body mass index 27.6 kg/m2). Patient comorbidities were hypertension (43.2%), diabetes (10.4%), coronary artery disease (13.9%), smoking (10.8%) and obesity (32%). Few infectious complications occurred: surgical site infections occurred within the first year after 5 procedures (2 joint space infections, 3 deep incisional infections). Infections of non-surgical sites (urinary tract, skin or respiratory, n=4) complicated the hospital admission. The odds ratio for any post-arthroplasty infection was increased in patients using prednisone doses exceeding 15 mg/day (OR 21.0, 95%CI 3.5-127.2, p=<0.001), underweight patients (OR 6.0, 95%CI 1.2-30.9, p=0.033) and those with known coronary artery disease (OR 5.1, 95%CI 1.3-19.8, p=0.017). Types of disease-modifying therapy, age, sex, and other comorbidities were not associated with an increased risk for infection. Steroid doses over 15 mg/day, being underweight and having coronary artery disease were associated with significant increases in the risk of post-arthroplasty infection in rheumatoid arthritis. Maximal tapering of prednisone and comorbidity risk reduction must be addressed in the peri-operative management strategy.


Risk stratification for patients with community-acquired pneumonia.
Community-acquired pneumonia (CAP) is a common medical illness with a prognosis that ranges from rapid complete recovery to severe medical complications and death. Approximately 4 million adults are diagnosed with CAP in the US each year; with more than 600,000 (15%) hospitalised. An estimated $4 billion is expended annually on patients with CAP, with inpatient therapy costing as much as 20 times that of outpatient antimicrobial therapy. Determining severity of illness and using this information to risk-stratify patients with CAP is important from several perspectives. Clinically, understanding prognosis can assist physicians in the initial site of treatment decision (home versus hospital) and can be used to communicate expected outcomes to patients. From a research perspective, risk stratification can be used to select appropriate patient subgroups for clinical trials and to provide severity-adjusted outcomes comparisons. From a policy perspective, severity-adjusted outcomes can be used as a proxy for quality of medical care.


Impact of Different KDIGO Criteria on Clinical Outcomes for Early Identification of Acute Kidney Injury after Non-Cardiac Surgery.
The Kidney Disease Improving Global Outcomes (KDIGO) guidelines are currently used in acute kidney injury (AKI) diagnosis and include both serum creatinine (SCR) and urine output (UO) criteria. Currently, many AKI-related studies have inconsistently defined AKI, which possibly affects the comparison of their results. Therefore, we hypothesized that the different criteria in the KDIGO guidelines vary in measuring the incidence of AKI and its association with clinical outcomes. We retrospectively analyzed that data of patients admitted to the intensive care unit after non-cardiac surgery in 2019. Three different criteria used to define AKI were included: UOmean, mean UO < 0.5 mL/kg/h over time; UOcont, hourly UO < 0.5 mL/kg/h over time; or SCR, KDIGO guidelines SCR criteria. A total of 777 patients were included, and the incidence of UOmean-AKI was 33.1%, the incidence of UOcont-AKI was 7.9%, and the incidence of SCR-AKI was 2.0%. There were differences in the length of ICU stay and hospital stay between AKI and non-AKI patients under different criteria. We found differences in the incidence and clinical outcomes of AKI after non-cardiac surgery when using different KDIGO criteria.