Ebola, jobs and economic activity in Liberia.
The 2014 Ebola virus disease (EVD) outbreak in the neighbouring West African countries of Guinea, Liberia and Sierra Leone represents the most significant setback to the region's development in over a decade. This study provides evidence on the extent to which economic activity declined and jobs disappeared in Liberia during the outbreak. To estimate how the level of activity and number of jobs in a given set of firms changed during the outbreak, we use a unique panel data set of registered firms surveyed by the business-development non-profit organisation, Building Markets. We also compare the change in economic activity during the outbreak, across regions of the country that had more versus fewer Ebola cases in a difference-in-differences approach. We find a large decrease in economic activity and jobs in all of Liberia during the Ebola outbreak, and an especially large decline in Monrovia. Outside of Monrovia, the restaurants, and food and beverages sectors have suffered the most among the surveyed sectors, and in Monrovia, the construction and restaurant sectors have shed the most employees, while the food and beverages sectors experienced the largest drop in new contracts. We find little association between the incidence of Ebola cases and declines in economic activity outside of Monrovia. If the large decline in economic activity that occurred during the Ebola outbreak persists, a focus on economic recovery may need to be added to the efforts to rebuild and support the healthcare system in order for Liberia to regain its footing.


Management of group A streptococcus pharyngitis with a second-generation rapid strep screen: Strep A OIA.
Empirical therapy of presumed group A streptococcus (GAS) pharyngitis leads to unnecessary and inappropriate use of antibiotics and pressure for emergence of resistant strains of common bacteria. Immunoassay technology has produced several rapid tests for GAS. The wide variations in diagnosis and treatment of acute pharyngitis are reviewed including the impact of rapid strep tests. Published studies comparing Strep A OIA to routine agar culture and other rapid strep screens are presented to assess the reliability and applicability of this novel assay. These data suggest that Strep A OIA may be superior to the "gold standard" throat culture and other rapid streptococcal antigen detection assays. Judicious use of Strep A OIA can result in rapid, precise diagnoses and eliminate unnecessary and inappropriate use of antibiotics. Careful antibiotic selection can reduce the pressure for emergence of resistant bacteria. This innovative, effective assay can contribute to a lessening of this serious clinical challenge.


Dendritic cell vaccination in pediatric gliomas: lessons learnt and future perspectives.
Immunotherapy of malignant gliomas with autologous dendritic cells (DCs) in addition to surgery and radiochemotherapy has been a focus of intense research during the past decade. Since both children and adults are affected by this highly aggressive brain tumor, 10-15% of the several hundred vaccinated patients represent children, making pediatric glioma patients the largest uniform pediatric vaccination cohort so far. In general, DC vaccination in malignant gliomas has been shown to be safe and several studies with a non-vaccinated control group could clearly demonstrate a survival benefit for the vaccinated patients. Interestingly, children and adolescents below 21 years of age seem to benefit even more than adult patients. This review summarizes the findings of the 25 clinical trials published so far and gives a perspective how DC vaccination could be implemented as part of multimodal therapeutic strategies in the near future.


Immunoelectron microscopic localisation of transforming growth factor alpha in rat colon.
Transforming growth factor alpha (TGF alpha) is a polypeptide, which binds to the epidermal growth factor receptor to carry out its function related to cell proliferation and differentiation. The ultrastructural localisation of TGF alpha was studied in both the proximal and the distal colon. The columnar cells, lining the surface epithelium of the proximal colon, showed a strong immunoreactivity in the polyribosomes and in the interdigitations of the lateral membrane. The columnar cells of the crypts and the goblet cells in both the proximal and the distal colon showed the immunostaining in the cis and trans cisternae of the Golgi apparatus. TGF alpha seems to be processed differently in the surface columnar cells and in the crypt columnar cells and goblet cells. Moreover, it probably has different roles in proliferation and differentiation.


Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo.
Metastasis is a leading cause of breast cancer mortality. The induction of epithelial-to-mesenchymal transition (EMT) and complex oncogenic signaling is a vital step in the evolution of highly metastatic and therapeutically-intractable breast cancer; necessitating novel target discovery or development of therapeutics that target metastatic breast cells (MBCs). To achieve this, this study employs a combination of in silico bioinformatics analyses, protein and transcript analyses, drug sensitivity assays, functional assays and animal studies. The present study identified CDH11 as an inductor and/or facilitator of metastatic signaling, and biomarker of poor prognosis in MBCs. Furthermore, we showed that in the presence of CDH11-rich cancer-associated fibroblasts (CAFs), MCF7 and MDA-MB-231 MBC cell lines acquired enhanced metastatic phenotype with increased CDH11, β-catenin, vimentin, and fibronectin (FN) expression. We also demonstrated, for the first time to the best of our knowledge that exposure to anti-CDH11 antibody suppresses metastasis, reduces CDH11, FN and β-catenin expression, and abrogate the cancer stem cell (CSC)-like traits of MBC cells. Interestingly, ectopic expression of miR-335 suppressed CDH11, β-catenin and vimentin expression, in concert with attenuated metastatic and CSC potentials of the MBC cells; conversely, inhibition of miR-335 resulted in increased metastatic potential. Finally, corroborating the in silica and in vitro findings, in vivo assays showed that the administration of anti-CDH11 antibody or miR-335 mimic suppressed tumorigenesis and inhibited cancer metastasis. These findings validate our hypotheses that miR-335 mediates anti-CDH11 antibody therapy response and that an enhanced miR-335/CDH11 ratio elicits marked suppression of the MBC CSC-like and metastatic phenotypes, thus revealing a therapeutically-exploitable inverse correlation between CDH11-enhanced CSC-like and metastatic phenotype and miR-335 expression in MBCs. Thus, we highlight the therapeutic promise of humanized anti-CDH11 antibodies or miR-335-mimic, making a case for their clinical application as efficacious therapeutic option in patients with MBC.


Photoacoustic probing of fluorophore excited state lifetime with application to oxygen sensing.
A new method is developed to perform local measurements of fluorophore excited state lifetimes in turbid media without collecting the fluorescence emission. The method is based on a pump-probe approach where a first laser pulse excites the dye and then a second laser pulse is used for photoacoustic probing of the transient absorption. The photoacoustic response generated by the probe pulse is recorded by an ultrasound receiver. Repeating the measurement for increasing pump-probe time delays yields a series of photoacoustic signals that are used to extract the lifetime of the excited state. The method is validated by measuring the lifetime of an oxygen sensitive dye solution at different concentrations of dissolved oxygen. The dye is pumped with a 532-nm pulsed laser and the transient absorption at 740 nm is probed using a second pulsed laser system. The photoacoustic-based results are in close agreement with those obtained from time-dependent fluorescent measurements. The method can be extended to photoacoustic lifetime imaging by using a receiver array instead of a single receiver. Potential applications of this method include tissue oxygen imaging for cancer diagnostics and mapping molecular events such as resonant energy transfer and ion collisions in a biological environment.


Ammonium dodecyl sulfate as an alternative to sodium dodecyl sulfate for protein sample preparation with improved performance in MALDI mass spectrometry.
Sodium dodecyl sulfate (SDS) is a strong surfactant that is widely used in protein sample preparation. While protein and peptide samples containing up to approximately 1% SDS can be analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) using a two-layer matrix/sample deposition method, the presence of SDS in a protein sample generally degrades mass resolution and mass measurement accuracy. This degradation in performance is found to be related to the formation of sodium-protein adducts in the MALDI process. If the instrument resolving power is insufficient to separate these adduct peaks from the protonated molecular ion peak, peak broadening is observed in the protein molecular ion region, and as a result, the peak centroid shifts to a higher mass. In this work, we present a method using ammonium dodecyl sulfate as a viable alternative to SDS for protein sample preparation with much improved MALDI MS performance. Three non-sodium-based dodecyl sulfate surfactants, ammonium dodecyl sulfate (ADS), hydrogen dodecyl sulfate, and tris(hydroxymethyl)aminomethane dodecyl sulfate were investigated. Of the three surfactants tested, it is found that ADS gives the best performance in MALDI. For proteins with moderate molecular masses (i.e., up to approximately 25 kDa), the presence of ADS in a protein sample does not result in significant degradation in mass resolution and accuracy, and the protonated molecular ion peak is the dominant peak in the MALDI spectrum. The ammonium adduct ions dominate the MALDI spectra when the protein mass exceeds approximately 25 kDa; however, ADS still gives better results than SDS. The behavior of ADS in gel electrophoresis was also investigated. It is shown that cell extracts dissolved in ADS can be separated by normal SDS-polyacrylamide gel electrophoresis by simply mixing them with the SDS sample buffer. The application of ADS as the surfactant for protein solubilization with improved performance in MALDI analysis is demonstrated in the study of a detergent insoluble fraction from a Raji/CD9 B-cell lymphocyte lysate.


Inosine 5'-monophosphate dehydrogenase inhibitors for the treatment of autoimmune diseases.
Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo biosynthesis of guanine nucleotides. Proliferation of T- and B-lymphocytes, a hallmark of many autoimnunne diseases, is heavily dependent on access to a large pool of guanine nucleotides. To support this activity IMPDH is upregulated. The clinical benefit observed with mnycophenolic acid, a potent IMPDH inhibitor, in a number of autoimmune diseases, including those associated with organ transplantation, rheumatoid arthritis, psoriasis, systemic lupus erythenmatosus and inflammatory bowel disease, has validated IMPDH as an immunosuppressive target, and triggered the search from the pharmaceutical industry for IMPDH inhibitors with best-in-class status. This review will highlight recent advances in the IMPDH field, with a focus on the discovery and development of non-nucleoside IMPDH inhibitors.


Runtime Safety Monitoring of Neural-Network-Enabled Dynamical Systems.
Complex dynamical systems rely on the correct deployment and operation of numerous components, with state-of-the-art methods relying on learning-enabled components in various stages of modeling, sensing, and control at both offline and online levels. This article addresses the runtime safety monitoring problem of dynamical systems embedded with neural-network components. A runtime safety state estimator in the form of an interval observer is developed to construct the lower bound and upper bound of system state trajectories in runtime. The developed runtime safety state estimator consists of two auxiliary neural networks derived from the neural network embedded in dynamical systems, and observer gains to ensure the positivity, namely, the ability of the estimator to bound the system state in runtime, and the convergence of the corresponding error dynamics. The design procedure is formulated in terms of a family of linear programming feasibility problems. The developed method is illustrated by a numerical example and is validated with evaluations on an adaptive cruise control system.


Nerve transcriptomes in autoimmune and genetic demyelinating neuropathies: Pathogenic pathway assessment of nerve demyelination.
The pathogenesis of autoimmune demyelinating neuropathies is poorly understood compared to inherited demyelinating forms. We performed whole transcriptome (RNA-Seq) using nerve biopsy tissues of patients with different autoimmune and inherited demyelinating neuropathies (CIDP n = 10, POEMS n = 18, DADS n = 3, CMT1 n = 3) versus healthy controls (n = 6). A limited number of differentially expressed genes compared to healthy controls were identified (POEMS = 125, DADS = 15, CMT = 14, CIDP = 5). Divergent pathogenic pathways including inflammatory, demyelinating and neurite regeneration such as with the triggering receptor expressed on myeloid cells (TREM1) part of the immunoglobulin superfamily and RhoGD1 are found. Shared and discordant pathogenic injury are discovered between autoimmune and inherited forms.


Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning.
The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.


Guidelines for the diagnosis and treatment of peri-implant diseases.
Although some risk factors of peri-implant disease are well defined, the lack of efficient and predictable approaches to treat peri-implantitis has created difficulty in the management of those complications. The aim of this review was to evaluate the reliability of the diagnosis methods and to provide a set of guidelines to treat peri-implant diseases. A search of PubMed and a hand search of articles related to peri-implant diseases were conducted up to August 2013. A summary of the current methods for the diagnosis of peri-implantitis, its potential risk factors, and a flow chart to guide the clinical management of these conditions are presented.


[Ethische Orientierung durch interkulturelle Kompetenz in interkulturellen Behandlungssituationen].
In many European countries, intercultural treatment situations are an integral part of everyday medical practice. In this context, the appearance of different interest and decision-making conflicts, which result from communication barriers, cultural practice or moral diversity, are not uncommon. In this paper, the characteristics of intercultural treatment situations with their ethical relevance are presented. Some skills and abilities of intercultural competence are also described and their function is demonstrated by a clinical ethical case. The opportunities and limitations of intercultural competence for an ethical orientation are subject of reflection.


Coccidioidomycosis in compromised hosts. Experience at Stanford University Hospital.
To determine the frequency and clinical characteristics of infection with Coccidioides immitis in immunosuppressed patients at Stanford University Hospital, clinical records of 14 years were examined. Thirteen cases met the diagnostic criteria. Half had Hodgkin's disease. In six the infection was disseminated; five of the six died early in the course of their infectious illness, frequently without diagnosis. Conclusions include: 1. The occurrence of coccidioidomycosis in immunosuppressed patients seen at institutions in or adjacent to the endemic area is not as rare as the literature suggests. 2. Dissemination is frequently explosive and the radiographic appearance of pulmonary involvement may appear late. Widespread pulmonary dissemination may occur within 24 hours after a negative x-ray. 3. Although the skin test loses its diagnostic value, the serology remains valid. Thus immunosuppressed patients with febrile illnesses (with or without radiographically evident pulmonary involvement) who have a history of travel to an endemic area should have serological examinations. 4. Lymphocytopenia correlates with risk of dissemination of coccidioidomycosis. 5. The administration of immunsuppressive chemotherapy correlates with such risk while radiotherapy and the malignant or non-malignant nature of the disease do not.


Suprapatellar versus infrapatellar intramedullary nailing for treatment of tibial shaft fractures in adults.
Numerous studies have compared suprapatellar (SP) nailing to infrapatellar (IP) nailing for treatment of tibial shaft fractures; however, the best strategy remains controversial. The aim of this meta-analysis is to assess whether SP or IP nailing is more effective for tibial shaft fractures in adults. Literature searches of PubMed, Embase, OVID, Cochrane Library, Web of Science, Chinese Biomedical Literature, Wanfang, Weipu Journal, and CNKI databases were performed up to July 2017. Only randomized controlled trials (RCTs) comparing SP versus IP intramedullary nailing for tibial shaft fractures were included. Data collection and extraction, quality assessment, and data analyses were performed according to the Cochrane standards. Twelve RCTs were selected for analysis. SP intramedullary nailing reduced knee joint pain, visual analog score, fluoroscopy time, and sagittal angle, resulting in better Harris hip score, Lysholm knee score, short-form 36 questionnaire, range of motion, and rates of "excellent" and "good" outcome. There were no significant differences in operative time, blood loss, length of hospital stay, union time, and coronal angle between groups. The present meta-analysis indicates that SP intramedullary nailing has obvious advantages over IP intramedullary nailing for treatment of tibial shaft fractures in adults. However, owing to the low-quality evidence currently available, additional high-quality RCTs are needed to confirm these findings.


Chronic rapamycin treatment exacerbates metabolism and does not down-regulate mTORC2/Akt signaling in diabetic mice induced by high-fat diet and streptozotocin.
Rapamycin, a classical inhibitor of the mammalian target of rapamycin (mTOR), has been intensively studied for its role in metabolism and verified to induce metabolic defects through mTORC2/Akt pathway. However, disparity of the results exists depending on the differences of the animal models or the detailed procedures. Moreover, data regarding the effect of rapamycin treatment in diabetic models are sparse. Therefore, we investigated its influence on glucose and lipid metabolism, and further analyzed its effect on the mTORC2/Akt pathway in a high-fat diet- and streptozotocin-induced diabetic mice model. Three-weeks old C57BL/6J mice were fed with a high fat diet (60 kcal% fat) and intraperitoneally injected with streptozotocin (100 mg/kg) at 6 weeks of age. Rapamycin (2 mg/kg) was orally given to the mice daily for consecutive 6 weeks. Body weight, blood lipid parameters and HbA(1c)% values were evaluated. Oral glucose test and insulin tolerance test were performed. Furthermore, western blot assay was applied to investigate the protein epression levels of Akt and PKCα, two key targets of the mTORC2/Akt pathway. Rapamycin-treated diabetic mice demonstrated less weight gain, more profound symptoms of polydipsia, polyphagia and polyuria, significant liver fat accumulation and exacerbated metabolic disorders including insulin resistance, hyperglycemia and dyslipidemia. Contrary to what have been expected, though significantly inhibiting mTORC1/S6K1 signaling, chronic rapamycin treatment failed to down-regulate mTORC2/Akt pathway. Our findings provide evidence that chronic rapamycin treatment may exacerbate metabolism in diabetic subjects and does not down-regulate mTORC2/Akt signialing in a high-fat diet- and streptozotocin-induced diabetic mice model.


An aromatic-rich loop couples DNA binding and ATP hydrolysis in the PriA DNA helicase.
Helicases couple ATP hydrolysis to nucleic acid binding and unwinding via molecular mechanisms that remain poorly defined for most enzyme subfamilies within the superfamily 2 (SF2) helicase group. A crystal structure of the PriA SF2 DNA helicase, which governs restart of prematurely terminated replication processes in bacteria, revealed the presence of an aromatic-rich loop (ARL) on the presumptive DNA-binding surface of the enzyme. The position and sequence of the ARL was similar to loops known to couple ATP hydrolysis with DNA binding in a subset of other SF2 enzymes, however, the roles of the ARL in PriA had not been investigated. Here, we show that changes within the ARL sequence uncouple PriA ATPase activity from DNA binding. In vitro protein-DNA crosslinking experiments define a residue- and nucleotide-specific interaction map for PriA, showing that the ARL binds replication fork junctions whereas other sites bind the leading or lagging strands. We propose that DNA binding to the ARL allosterically triggers ATP hydrolysis in PriA. Additional SF2 helicases with similarly positioned loops may also couple DNA binding to ATP hydrolysis using related mechanisms.


Urachal abscess mimicking malignant tumor: can imaging tell them apart?
The urachus is an embryonic remnant that usually involutes before birth. Abnormal persistence of this structure can lead to infectious or neoplastic complications later in life. We report a case of an 84-year-old man that presented with a urachal complex mass which, after proper investigation, revealed to be a urachal abscess. Urachal abscesses are rare and usually occur in severe infections. Urachal abscesses can be indistinguishable from urachus carcinoma on imaging studies. This article reviews the clinical and imaging aspects of urachal abscess and carcinoma and possible differentiating elements in imaging. However, definitive diagnosis usually depends on a biopsy or fluid aspiration.


Neural Efficiency in Athletes: A Systematic Review.
According to the neural efficiency hypothesis (NEH), professionals have more effective cortical functions in cognitive tasks. This study is focusing on providing a systematic review of sport-related NEH studies with functional neuroimaging or brain stimulation while performing a sport-specific task, with the aim to answer the question: How does long-term specialized training change an athlete's brain and improve efficiency? A total of 28 studies (N = 829, Experimental Group n = 430) from 2001 to 2020 (Median = 2014, SD = 5.43) were analyzed and results were organized into four different sections: expert-novice samples, perceptual-cognitive tasks and neuroimaging technologies, efficiency paradox, and the cluster analysis. Researchers examined a wide range of sport-specific videos and multiple object tracking (MOT) specific to 18 different sports and utilized blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), and electroencephalogram (EEG). Expert-novice comparisons were often adopted into investigations about the variations in general about optimal-controlled performance, neurophysiology, and behavioral brain research. Experts tended to perform at faster speeds, more accurate motor behavior, and with greater efficiency than novices. Experts report lower activity levels in the sensory and motor cortex with less energy expenditure, experts will possibly be more productive. These findings generally supported the NEH across the studies reviewed. However, an efficiency paradox and proficient brain functioning were revealed as the complementary hypothesis of the NEH. The discussion concentrates on strengths and key limitations. The conclusion highlights additional concerns and recommendations for prospective researchers aiming to investigate a broader range of populations and sports.


Epidemiology of anxiety disorders in Florence.
A structured interview designed to diagnose anxiety disorders according to DSM-III (plus infrequent panic attacks and generalized anxiety disorder using DSM-III-R criteria) was given to 1110 people registered with 6 general practitioners (GPs), whether they consulted the doctor or not. As each citizen in Italy has to be registered with a GP, the sample was representative of the population. The interviews were carried out by the GPs, who were also third- or fourth-year trainees in psychiatry. The lifetime prevalence and point prevalence were: 0.36% and 0.27% for agoraphobia; 0.90% and 0.72% for agoraphobia with panic; 1.35% and 0.27% for panic disorder; 0.63% and 0.45% for simple phobia; 0.49% and 45% for social phobia, 5.41% and 2.79% for generalized anxiety disorder; and 0.72% and 0.63% for obsessive-compulsive disorder. These figures are lower than those reported in other surveys; possible explanations may be the use of a hierarchical diagnostic model and the fact that diagnosticians were psychiatrists instead of lay interviewers as in most studies in the United States. On the whole, 62% of anxiety cases consult a GP, 50% consult a psychiatrist and 7% are hospitalized.


[Behçet's disease revealed by bilateral femoral aneurysm].
Behçet's disease is a chronic vascularitis characterized by recurrent ulcers of the mouth and genitalia and iridocyclitis. Vascular complications involving venous thrombosis and arterial lesions are rare. We report a case of Behçet's disease in 30 year-old man revealed by a voluminous right femoral aneurysm and a thrombosed aneurysm of the left iliofemoral trunk. Disease exacerbation was marked by oral ulceration and ocular lesions that delayed surgical cure for 7 days. After surgical resection of the aneurysm, a femoro-femoral bypass was constructed with a polytetrafluoroethylene graft. The left iliofemoral aneurysm was left intact. After 4 years of regular follow-up, there have been no surgical complications. The timing of surgery in patients with a voluminous aneurysm is debated during phases of active disease.


Obtention of monoclonal antibodies against human IgG4 using two different immunization strategies: development of a biotin-based ELISA for IgG4 quantitation.
Several monoclonal antibodies (MAbs) against human IgG4 have been produced in two fusion experiments. In fusion I, Balb/c mice were conventionally immunized and most of the antibodies obtained recognized IgG class-specific epitope(s). Therefore, a second fusion experiment was performed using IgG4-immunized mice that had been made tolerant to epitopes shared by the four IgG subclasses, and most of the hybridomas derived from this second fusion secreted antibodies specific for IgG4. Five MAbs which were found to be specific for both IgG4 isoallotypes (4a and 4b) were selected from the two fusion experiments. These antibodies define at least two non-overlapping epitopes located on the Fab and Fc regions of IgG4 molecule, respectively. Two MAbs were used to develop a two-site ELISA for IgG4 quantitation, in which one MAb (anti-Fab) was immobilized in the solid phase and the other one (anti-Fc) was biotin-labeled. The assay had a detection limit below 1 ng/ml and a practical working range between 4 and 200 ng/ml. The use of these MAbs should improve our understanding of the role of IgG4 in different clinical conditions.


Longitudinal Mediation Analysis with Time-varying Mediators and Exposures, with Application to Survival Outcomes.
In this paper, we study the effect of a time-varying exposure mediated by a time-varying intermediate variable. We consider general longitudinal settings, including survival outcomes. At a given time point, the exposure and mediator of interest are influenced by past covariates, mediators and exposures, and affect future covariates, mediators and exposures. Right censoring, if present, occurs in response to past history. To address the challenges in mediation analysis that are unique to these settings, we propose a formulation in terms of random interventions based on conditional distributions for the mediator. This formulation, in particular, allows for well-defined natural direct and indirect effects in the survival setting, and natural decomposition of the standard total effect. Upon establishing identifiability and the corresponding statistical estimands, we derive the efficient influence curves and establish their robustness properties. Applying Targeted Maximum Likelihood Estimation, we use these efficient influence curves to construct multiply robust and efficient estimators. We also present an inverse probability weighted estimator and a nested non-targeted substitution estimator for these parameters.


Modulated fluorescence correlation spectroscopy with complete time range information.
Two methods to combine fluorescence correlation spectroscopy (FCS) with modulated excitation, in a way that allows extraction of correlation data for all correlation times have been developed and experimentally verified. One method extracts distortion-free correlation data from measurements acquired with standard hardware correlators provided the fluorescence does not change systematically within the excitation pulses. This restriction does not apply to the second method, which, however, requires time-resolved acquisition of the fluorescence intensity. Modulation of the excitation in an FCS experiment is demonstrated to suppress triplet population buildup more efficiently than a corresponding reduction in continuous wave excitation intensity (shown for the dye rhodamine 6G in aqueous solution). Excitation modulation thus offers an additional means to optimize the FCS measurement conditions with respect to the photophysical properties of the dyes used. This possibility to suppress photoinduced states also provides a useful tool to distinguish additional processes occurring in the same time regime in the FCS measurements, as demonstrated here for the protonation kinetics of fluorescein at different pH. In general, the proposed concept opens for FCS measurements with a complete correlation timescale in a range of applications where a modulated excitation is either necessary or brings specific advantages.


Bulk Ferroelectric Metamaterial with Enhanced Piezoelectric and Biomimetic Mechanical Properties from Additive Manufacturing.
Three-dimensional (3D) ferroelectric materials are electromechanical building blocks for achieving human-machine interfacing, energy sustainability, and enhanced therapeutics. However, current natural or synthetic materials cannot offer both a high piezoelectric response and desired mechanical toughness at the same time to meet the practicality. Here, a lamellar ferroelectric metamaterial was created with a ceramic-like piezoelectric property and a bone-like fracture toughness through a low-voltage-assisted 3D printing technology. The one-step printed bulk structure, consisting of periodically intercalated soft ferroelectric and hard electrode layers, exhibited a significantly enhanced longitudinal piezoelectric charge coefficient (d33) of over 150 pC N-1, as well as a superior fracture resistance of ∼5.5 MPa·m1/2, more than three times higher than conventional piezo-ceramics. The excellent printability together with the combination of both high piezoelectric and mechanical behaviors allowed us to create a bone-like structure with tunable anisotropic piezoelectricity and bone-comparable mechanical properties, showing a potential of manufacturing practical, high-performance, and smart biological systems.


Does information form matter when giving tailored risk information to patients in clinical settings? A review of patients' preferences and responses.
Neoliberal emphasis on "responsibility" has colonized many aspects of public life, including how health care is provided. Clinical risk assessment of patients based on a range of data concerned with lifestyle, behavior, and health status has assumed a growing importance in many health systems. It is a mechanism whereby responsibility for self (preventive) care can be shifted to patients, provided that risk assessment data is communicated to patients in a way which is engaging and motivates change. This study aimed to look at whether the form in which tailored risk information was presented in a clinical setting (for example, using photographs, online data, diagrams etc.), was associated with differences in patients' responses and preferences to the material presented. We undertook a systematic review using electronic searching of nine databases, along with handsearching specialist journals and backward and forward citation searching. We identified eleven studies (eight with a randomized controlled trial design). Seven studies involved the use of computerized health risk assessments in primary care. Beneficial effects were relatively modest, even in studies merely aiming to enhance patient-clinician communication or to modify patients' risk perceptions. In our paper, we discuss the apparent importance of the accompanying discourse between patient and clinician, which appears to be necessary in order to impart meaning to information on "risk," irrespective of whether the material is personalized, or even presented in a vivid way. Thus, while expanding computer technologies might be able to generate a highly personalized account of patients' risk in a time efficient way, the need for face-to-face interactions to impart meaning to the data means that these new technologies cannot fully address the resource issues attendant with this type of approach.


Intravitreal low molecular weight heparin and 5-Fluorouracil for the prevention of proliferative vitreoretinopathy following retinal reattachment surgery.
Proliferative vitreoretinopathy (PVR) is a significant cause of failure in retinal reattachment surgery. Various pharmacological agents have shown potential benefit in reducing postoperative PVR risk. This review aimed to compare the use of intravitreal low molecular weight heparin (LMWH) alone or with 5-Fluorouracil (5-FU) versus placebo, as an adjunct in the prevention of PVR following retinal reattachment surgery. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), MEDLINE (January 1950 to October 2012), EMBASE (January 1980 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 October 2012. We only included randomised controlled trials (RCTs) that compared intravitreal LMWH alone or with 5-FU, versus placebo for the prevention of postoperative PVR in patients undergoing primary vitrectomy for rhegmatogenous retinal detachment repair. Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information. We included two RCTs (with a total of 789 participants) comparing LMWH with 5-FU infusion and placebo. However, we did not perform a meta-analysis because of significant heterogeneity between these studies. One study found a significant beneficial effect of LMWH with 5-FU in reducing postoperative PVR compared to placebo (RR: 0.48, 95% confidence interval: 0.25 to 0.92), in 174 patients who were viewed at high-risk of developing postoperative PVR. The other study included 615 unselected cases of rhegmatogenous retinal detachment and could not show a difference between LMWH with 5-FU infusion and placebo in reducing PVR rates (RR:1.45, 95% confidence interval: 0.76 to 2.76). Results from this review indicate that there is inconsistent evidence from two studies on patients at different risk of PVR on the effect of LMWH and 5-FU used during vitrectomy to prevent PVR. Future research should be conducted on high risk patients only, until a benefit is confirmed at least in this patient subgroup.


Nicotine and carbon monoxide intake from high- and low-yield cigarettes.
We measured daily nicotine intake in 11 habitual smokers who smoked their usual brand or commercial high-yield (Federal Trade Commission [FTC] yield 1.2 mg nicotine, 16 mg tar) or low-yield (0.4 mg nicotine, 5 mg tar) cigarettes. Daily nicotine intake was measured from metabolic clearance data in conjunction with blood and urinary concentrations of nicotine during 24-hr smoking periods. On the average, subjects consumed 35 mg nicotine while smoking their usual cigarettes and 26 mg while smoking either high- or low-yield commercial cigarettes different from their usual brand. This level of nicotine consumption from low-yield cigarettes was because smokers obtained 60% more nicotine per cigarette than predicted by FTC yield and they smoked 25% more cigarettes a day. Although there was considerable variability in nicotine intake between subjects, there was a correlation within subjects between intake while smoking their usual brand and experimental cigarettes. Nicotine intake between the two commercial high- or low-yield cigarettes also correlated (r = 0.86). These findings are consistent with a minimal level of acceptable daily intake of nicotine for individuals that is related to usual intake. We suggest that our protocol provides a better quantitative estimate of the yield of different cigarette brands and potential health hazards than those currently provided by the FTC.


Ultracold Fermi gases with emergent SU(N) symmetry.
We review recent experimental and theoretical progress on ultracold alkaline-earth Fermi gases with emergent SU(N) symmetry. Emphasis is placed on describing the ground-breaking experimental achievements of recent years. The latter include (1) the cooling to below quantum degeneracy of various isotopes of ytterbium and strontium, (2) the demonstration of optical Feshbach resonances and the optical Stern-Gerlach effect, (3) the realization of a Mott insulator of (173)Yb atoms, (4) the creation of various kinds of Fermi-Bose mixtures and (5) the observation of many-body physics in optical lattice clocks. On the theory side, we survey the zoo of phases that have been predicted for both gases in a trap and loaded into an optical lattice, focusing on two and three dimensional systems. We also discuss some of the challenges that lie ahead for the realization of such phases such as reaching the temperature scale required to observe magnetic and more exotic quantum orders. The challenge of dealing with collisional relaxation of excited electronic levels is also discussed.


[Experimental and clinical research on the Russian Vitaflon blood vessel prosthesis].
The authors have performed an experimental and clinical assessment of a new graft. In 37 mongrel dogs 49 experiments were carried out with the implantation of grafts "Vitaflon" into different parts of the arterial and venous bed. It was shown that the domestic graft from modified polytetraftoroethylene had high biological inertia, good plastic properties, zero surgical porosity, strength and reliable "taking" by the recipient's organism. Following the experimental work the prosthesis "Vitaflon" (30-50 cm long and 8 mm diameter) was implanted in the femoro-popliteal-tibial position to 15 patients suffering from obliterating atherosclerosis of the lower extremity arteries. The period of follow-up observations was about 12 months. Thrombosis took place in two grafts in the early postoperative period. Other shunts were functioning well which was confirmed by the clinical picture and dopplerography.


Influence of the calf presence during milking on dairy performance, milk fatty acid composition, lipolysis and cheese composition in Salers cows during winter and grazing seasons.
The milking of Salers cows requires the presence of the calf. The removal of the calf would simplify the milking routine, but it could also modify the milk yield and the milk and cheese composition. Therefore, the aim of this experiment was to evaluate the effect of calf presence during milking during sampling period (winter or grazing periods), on dairy performance, milk fatty acid (FA) composition, lipolysis and cheese yield and composition. Nine and 8 Salers lactating cows were milked in the presence (CP) or absence (CA) of their calves respectively. During winter, the cows were fed a hay-based diet and then they only grazed a grassland pasture. Calf presence during milking increased milk yield and milk 16:0 concentration and decreased milk fat content and milk total odd- and branched-chain FA (OBCFA) concentrations. Calf presence only increased initial lipolysis in milk collected during the winter season. Milk from CP cows compared to CA cows resulted in a lower cheese yield and ripened cheeses with lower fat content. Milk from the grazing season had lower saturated medium-chain FA and OBCFA concentrations and higher 18:0, cis-9-18:1, trans-11-18:1 and cis-9, trans-11-CLA concentrations than that from the winter season. Initial milk lipolysis was higher in the winter than in the grazing season. These variations could be due to seasonal changes in the basal diet. Furthermore, the effect of calf presence during milking on milk fat composition was lower than that on dairy performance, cheese yield and composition. Removing the calf during the milking of Salers cows seems feasible without a decrease in milked milk, and with a positive effect on cheese yield and fat content, under the condition that we are able to select cows having the capacity to be milked easily without the calf.


Highly stable keto-enamine salicylideneanilines.
[reaction: see text] Highly stable NH salicylideneanilines have been prepared by reaction of 1,3,5-triformylphloroglucinol with aniline derivatives. The NH form was confirmed by X-ray crystallographic data, as well as by NMR studies. A convenient one-step synthesis of triformylphloroglucinol is also reported.


Polypeptide growth factors in bone matrix.
The presence of many types of polypeptide growth factors in the mineralized extracellular matrix of bone is now well established. These factors are generally referred to as bone-derived growth factors (BDGFs), and are similar, or possibly identical, to the following species; platelet-derived growth factor (PDGF); acidic and basic forms of fibroblast growth factor (aFGF, bFGF); transforming growth factor beta (TGF-beta); and insulin-like growth factor 1 (IGF-1). Several osteoinductive factors, such as bone morphogenetic protein (BMP) and osteogenin, a skeletal growth factor (SGF), and osteoblast-derived BDGFs, have also been identified. Complete description of the biological functions of these BDGFs which are relevant to bone will ultimately require specific bioassays involving specific cell types in vitro, as well as in vivo animal implant models. Studies with primary rat osteoblast-like cells exposed either to mixed BDGFs, pure TGF-beta, or heparin-purified PDGF, aFGF, or bFGF from bovine bone have shown a general dose-dependent mitogenic effect. Phenotypic changes which accompany the BDGF-induced wave of proliferation include: decreased osteocalcin secretion and a reduction in 1,25-(OH)2 vitamin D3-stimulated osteocalcin synthesis; reduced alkaline phosphatase specific activity; decreased cyclic AMP responsiveness to parathyroid hormone (PTH); and increased collagen synthesis. Bone exhibits the most complex spectrum of growth factor activities of any tissue yet described. In bovine bone powder free of blood and cartilage contamination, the volume concentration of mitogens is up to 20 times greater than that in serum. Bone cells and other indigenous cell types must be considered as possible sources of the BDGFs, in addition to sequestration from blood. Mechanisms for the unmasking or release of BDGFs from the mineralized matrix that result in local action on osteoblasts, endothelial cells, and other target cells are undoubtedly important for the development and maintenance of bone tissue.


Radiological and functional assessment of radiation-induced lung injury in the rat.
The purpose of this study is to develop an experimental model to measure localized radiation-induced lung injury using multiple end-points including breathing frequency, high-resolution computed tomography (CT), and radionuclide perfusion. The rats were anesthetized and the right lung irradiated with a single dose of 18 Gy using 200-kVp x-rays. The lung function of the animals was measured every 2 weeks after irradiation with the breathing rate assay. CT scanning and radionuclide lung perfusion assay were performed prior to and 2, 4, 10, 16, and 34 weeks after irradiation. Significant elevation in breathing rate occurred after 16 weeks, with a maximal increase between 22 and 28 weeks. An increase in the right lung density started 4 weeks after irradiation. Regional measurements indicated a relatively uniform increase in density at 4 and 10 weeks, while foci of high-density areas were observed at the later time points. Changes in rat lung volume indicated shrinkage of the irradiated right lung and accompanying compensatory hypertrophy of the shielded left lung. Radionuclide perfusion assay showed significant decrease in relative blood flow in the irradiated right lung 4 weeks after hemithoracic irradiation. Changes in breathing rate provide an index of overall lung function while changes in lung density, volume, and perfusion are of particular importance for evaluating loco-regional differences in lung sensitivity. This study is the first demonstration that CT can be used to measure volume changes after thoracic irradiation in rats.


Malayalam language translation and validation of oral health-related early childhood quality of life tool (OH-ECQoL).
The objective of this study was to adapt the Oral Health-related Early Childhood Quality of Life (OH-ECQoL) tool for the Malayalam-speaking community and investigate its validity and reliability. Malayalam language version of OH-ECQoL was derived through a forward-backward translation and tested for content validity. A convenient sample (n = 300) was recruited by including children with and without early childhood caries (ECC). Parents of these children completed the derived Malayalam OH-ECQoL measure. The properties of translated OH-ECQoL were evaluated by determining its validity and reliability using concurrent validity, construct validity, discriminant validity, internal consistency, and test-retest reliability. OH-ECQoL scores varied with ECC and caries-free groups (P < 0.001), supporting the ability to distinguish between patient groups. Discriminant validity tests show that children with ECC have greater median scores and interquartile range (21 ± 8) compared to children without ECC (14 ± 2). Concurrent validity was observed to be 0.72 and 0.71, respectively, for child section (P < 0.001). Convergent validity demonstrates a strong positive correlation between child impact and family impact with a Spearman's correlation coefficient significant of 0.73 (P ≤ 0.01). Cronbach's alpha for the child impact section and family impact section showed good internal consistency at 0.92 and 0.83, respectively. Test-retest reliability at 0.87 shows good reliability. The Malayalam version of the OH-ECQoL tool demonstrated acceptable validity and reliability. The study also shows that ECC presents a negative impact on the QoL of preschool children and their parents.


Spectroscopic evidence for ultrahigh-pressure polymorphism in SiO2 glass.
Acoustic wave velocities of SiO2 glass were measured up to pressures of 207 GPa using newly developed Brillouin scattering spectroscopic techniques to address the nature of pressure-induced structural changes. The acoustic wave velocity data suggests three distinct pressure regimes, two of which correspond to changes in the Si-O coordination number with pressure, and one of which indicates the stability of sixfold-coordinated Si over a broad pressure interval from approximately 40-140 GPa. An anomalous increase in the effect of pressure on velocity at 140 GPa most likely corresponds to the onset of structural densification associated with an increase in coordination number from sixfold to a higher coordination state.


A voxel-based method for designing a numerical biomechanical model patient-specific with an anatomical functional approach adapted to additive manufacturing.
Here, we describe an original and efficient geometry design approach, based on voxels resulting in a validated model for printability in additive manufacturing. The proposed approach is also designed to be accessible to non-specialists as it does not require specialist skills in computer-assisted-design (CAD). It focuses on biomedical applications, particularly the geometry design of a configurable digital biomechanical model with selected anatomical features based on medical imaging compatible with customization, as might be needed for prosthetic elements. The methodology is based on two main steps. First, an accessible parametrization to medical employees of a configurable biomechanical model is matched specifically to the patient. The configurable model is designed to palliate any kind of potential lack of information from the Digital Imaging and Communication in Medicine (DICOM) file of the medical imaging or partial topological defects but with the least and sufficient number of parameters. For this purpose, the configurable model is segmented in topological areas with a complexity facing solely the desired specification, without regards of potential numerical errors prior AM such as boundary edges, intersecting faces and non-manifold edges. The second step is the voxel-based modelling, easily accessible for medical employees unfamiliar with CAD. Voxels stores the geometric information in a discrete format to facilitate customization by topological operations such as addition and subtraction. The voxelization representation coupled with a smoothing filter, results in a more realistic, robust and closed triangulated model, freed from errors of printability. This method is presented in the context of a trapezium replacement prosthesis prior to selective laser melting (SLM) and diverse post-treatments.


Strategies for Prevention and Treatment of Trichomonas vaginalis Infections.
The last estimated annual incidence of Trichomonas vaginalis worldwide exceeds that of chlamydia and gonorrhea combined. This critical review updates the state of the art on advances in T. vaginalis diagnostics and strategies for treatment and prevention of trichomoniasis. In particular, new data on treatment outcomes for topical administration of formulations are reviewed and discussed.


Progress in zero-fluoroscopy implantation of cardiac electronic device.
Fluoroscopy is the imaging modality routinely used for cardiac device implantation. Due to the rising concern regarding the harmful effects of radiation exposure to both the patients and operation staffs, many efforts have been made to develop alternative techniques to achieve zero-fluoroscopy implantation. In this review, we describe the different methods aimed at avoiding the application of fluoroscopy in recent years, and evaluate their feasibility and safety in cardiac electronic device implantation.


A bacterial identification teaching exercise revisited.
Bacterial Identification, first described by Bryant (1986), is a program that provides a novel way of enhancing the teaching of systematic bacteriology and numerical identification procedures. A student is assigned an unknown isolate from a list of bacteria. The student's objective is to identify the unknown isolate using the least number of tests from the set of tests available. Simultaneously the computer tries to identify the unknown using optimised and random selection of tests. A student can compare their progress against that of the computer. The program has been improved and the data matrix on which it was based has been revised by the addition of 14 more species, an additional test and by updating the original probability matrix. The program, Bacterial Identification, is available as 'freeware' and has been placed with organisations that distribute such software.


Combined radiofrequency ablation and adjuvant liposomal chemotherapy: effect of chemotherapeutic agent, nanoparticle size, and circulation time.
To evaluate the effects of liposomal chemotherapeutic agent, nanoparticle size, and liposome circulation time on tissue coagulation and intratumoral drug uptake when radiofrequency (RF) ablation is combined with adjuvant intravenous liposomal chemotherapy in an animal breast tumor model. Ninety-one R3230 mammary adenocarcinoma nodules were implanted in 48 Fischer rats. First, standardized RF ablation was combined with intravenous liposomal doxorubicin, cisplatin, or 5-fluorouracil (35 tumors each). Second, three different-sized doxorubicin-containing nanoparticle preparations were combined with standardized RF ablation. Last, two doxorubicin-containing liposome preparations with different blood elimination half-lives were combined with RF ablation. Coagulation diameter and interstitial doxorubicin concentration were measured 48 hours after treatment and compared with use of statistical analysis. All combinations of RF with liposomal chemotherapy caused significantly greater tumor necrosis than RF alone (P<.05). Significantly increased necrosis was observed with intravenous liposomal RF/doxorubicin and RF/cisplatin compared with intravenous liposomal RF/5-fluorouracil (P<.01). Greater coagulation was observed with RF combined with 100-nm nanoparticles compared with 20-nm or 250-nm nanoparticles (P=.01 and P=.04, respectively). Additionally, greater intratumoral doxorubicin uptake was observed in the group treated with 20-nm nanoparticles compared with those treated with other sizes of nanoparticles (P<.05). RF plus liposomal doxorubicin produced greater coagulation and intratumoral doxorubicin uptake than RF plus 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid (P<.05). When combined with RF ablation, modification of adjuvant intravenous liposomal chemotherapy, including nanoparticle size, circulation time, and chemotherapeutic agent, can influence intratumoral drug accumulation and tissue coagulation.


[Myocardial revascularization at the acute phase of myocardial infarction in the octogenarian].
Elderly patients are at high risk of complications in acute myocardial infarction (AMI). In this population, myocardial reperfusion at the acute phase improves the prognostic. The mortality rate is above 50% in the absence of reperfusion strategy, and decreases at less than 20% in case of such treatment. The thrombolytic use is limited in those patients, coronary angioplasty is taking an important place in this reperfusion therapy, but is not well evaluated in patients older than 80 years. Prospective registry of patients older than 80 years admitted in Hôpital Bichat for acute myocardial infarction within the first 6 hours (n = 92), between 1990 january to 1999 december. Eight patients (10%) received a thrombolytic therapy. Coronary angiogram was achieved in eighty patients (87%). In 58 (63%) patients a coronary angioplasty was performed. The success rate of the coronary angioplasty was 86%. In-hospital mortality rate was 26% (death in 24 patients), 20% in the absence of cardiogenic shock and 62% when this complication was noted. Two patients (2%) were treated by emergent coronary artery bypass surgery. The results comparison between the periods of 1990 to 95 and 1955 to 99 showed, a real trend of decrease mortality rate (28 to 13% in the absence of cardiogenic shock, p = 0.10), an increase of the proportion of patients treated by angioplasty. These results are more and more encouraging. Coronary reperfusion by primary angioplasty in possible in patients older than 80 years with a low rate of complications. Technical progress such as stents and GpIIb/IIIa inhibitors must be evaluated in this population.


Reliability study of reporting of days since last sexual intercourse in Matlab, Bangladesh.
The accuracy of responses to a question on the frequency of sexual intercourse in the 4-week period prior to an interview is expected to be low. This paper examines the reliability of an alternative question: 'How many days since you last had sexual intercourse?'. This was a part of a larger longitudinal study of fertility dynamics in Matlab, Bangladesh. The response pairs of 61 women who were asked the same question by an interviewer and on the next day by a supervisor, were analysed. Refusals were more common among older women and among women who gave a response at the extremes of the distribution for the other interview. Of the pairs of two responses, 78% had a difference of 3 days or less. Further study and use of the question on days since last intercourse is recommended.


Suicide and self-harm following prescription of SSRIs and other antidepressants: confounding by indication.
To identify the incidence and risk of suicide and self harm, among patients prescribed antidepressant drugs. A retrospective cohort study, with nested case control, of patients identified from a nonrandom sample of general practices in New Zealand from 1996 to 2001. A total of 57 361 patients who received a prescription for a single antidepressant were identified from the RNZCGP Research Unit Database. Suicides within 120 days of a prescription were identified from the New Zealand National Mortality Database and self-harm events within 120 days of a prescription were identified from the New Zealand Hospital discharge database. 26 suicides and 330 episodes of self-harm were identified within 120 days of an antidepressant prescription. On univariate analysis the association, expressed as OR (95% CI), between selective serotonin reuptake inhibitors (SSRIs) and self harm and suicide were 2.26 (1.27-4.76) and 1.92 (0.77-4.83), respectively. When corrected for the confounding effects of age, gender and depression/suicidal ideation there was an association between SSRIs and self harm, OR 1.66 (95% CI 1.23-2.23), but not for suicide, 1.28 (0.38-4.35). Paroxetine was a significant risk factor for suicide on univariate analysis, 4.23 (1.19-14.95), but not when corrected for age, gender and depression/suicidal ideation, 2.76 (0.30-24.87). Age, gender and pre-existing depression/suicidal ideation are important confounders in observational studies of the association between antidepressants and suicide or self harm.


[Electrocardiographic Q wave is of no significance after myocardial infarction].
A Q wave has high specificity in identifying acute myocardial infarction and is associated with infarcts of a larger size. A considerable number of studies have addressed the prognostic value of the presence of a Q wave in the electrocardiogram before and after the introduction of thrombolytic therapy. Overall, these studies have demonstrated that a Q wave has slight, or even no, prognostic impact, especially in studies performed since the introduction of thrombolytic therapy. Some therapeutic choices have been suggested according to the presence or absence of Q waves. These suggestions depend basically on subgroup analysis with different results and hence have not documented that a Q wave has any value in therapeutic choices. A pathological Q wave has no significant prognostic value after a myocardial infarction and there is very doubtful documentation that a Q wave has any value for therapeutic choice.


What nephrologists need to know about vascular access cannulation.
This article describes cannulation events, especially problems, common and rare, minor and major, to aid the nephrologist (and mid-level providers e.g. nurse practitioner and physician's assistant) in decision-making to prevent or treat cannulation-related adverse outcomes. The usual management, potential outcomes, nephrologist intervention, and prevention are discussed and include: assessment of arteriovenous (AV) access and readiness for cannulation; initial cannulation of both arteriovenous fistulas and grafts; needle size and adequacy; needle direction and potential for recirculation; limited cannulation sites/buttonhole; pain and fear of pain; prevention of bleeding; management of infiltrations/extravasations; prevention and management of "one-site-itis"; prevention and management of infection. It concludes with the importance of the medical director as the leader of the continuous quality improvement (CQI) team in preventing/reducing cannulation-related adverse events.


A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways.
Overexpression of cyclooxygenase 2 (COX2) and uncontrolled wingless and Int (Wnt)-signaling pathway have long been suggested to play crucial roles in colorectal cancer. Studies show that selective COX2 inhibitors possess great potential as chemopreventive agents for colon cancer. Recent studies suggest that targeting COX2 and epidermal growth factor receptor (EGFR) may provide better therapeutic strategy than inhibiting either single target and that this may alleviate the problem of COX2 inhibitor-associated side effects. Therefore, there have been intensive efforts to develop novel dietary substances that target COX2 and EGFR activation. Fisetin is a naturally occurring flavonoid commonly found in various vegetables and fruits. We found that the treatment of COX2-overexpressing HT29 human colon cancer cells with fisetin (30-120 microM) resulted in induction of apoptosis, downregulation of COX2 protein expression without affecting COX1 and inhibited the secretion of prostaglandin E2. Treatment of cells with fisetin also inhibited Wnt-signaling activity through downregulation of beta-catenin and T cell factor 4 and decreased the expression of target genes such as cyclin D1 and matrix metalloproteinase 7. Fisetin treatment of cells also inhibited the activation of EGFR and nuclear factor-kappa B (NF-kappaB). Finally, the formation of colonies in soft agar was suppressed by fisetin treatment. Taken together, we provide evidence that the plant flavonoid fisetin can induce apoptosis and suppress the growth of colon cancer cells by inhibition of COX2- and Wnt/EGFR/NF-kappaB-signaling pathways. We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer.


APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.
Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.


Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury.
The integrity of the blood-brain barrier (BBB) is critical for normal brain function, and its compromise contributes to the pathophysiology of a number of CNS diseases and injuries. Using a rodent model of brain injury, the present study examines the pathophysiology of BBB disruption. Western blot and immunohistochemical analyses indicate that brain injury causes a loss of capillary endothelial cells and tight junction proteins, two critical components of the BBB. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) by sulforaphane, a naturally occurring compound present in high levels in cruciferous vegetables, significantly increased the expression of endogenous cytoprotective genes in brain tissue and microvessels as indicated by real-time PCR analysis. Postinjury administration of sulforaphane reduced the loss of endothelial cell markers and tight junction proteins and preserved BBB function. These protective effects were dependent on the activity of Nrf2. Injured rats pretreated with decoy oligonucleotides containing the binding site of Nrf2, and mice lacking the nrf2 gene, did not benefit from sulforaphane administration. These findings indicate a potential therapeutic usefulness for Nrf2-activating molecules to improve the function of the neurovascular unit after injury.


Evaluation of approaches to detect quantitative trait loci for growth, carcass, and meat quality on swine chromosomes 2, 6, 13, and 18. II. Multivariate and principal component analyses.
The merits of complementary multivariate techniques to identify QTL associated with multiple traits were evaluated. Records from 806 F2 pigs pertaining to a Berkshire x Duroc three-generation population were available. Six multitrait groups on SSC 2, 6, 13, and 18 with information on 30 markers were studied. Multivariate techniques studied included multivariate models and principal components analysis of each multitrait group. All models included, in addition to systematic effects, additive, dominance, and imprinting coefficients corresponding to a one-QTL model and a random family effect. Multivariate analysis identified QTL associated with genomewise significant variation in four of the multitrait groups. The majority of the multivariate analysis provided greater precision of parameter estimates and higher statistical significance in some cases than univariate approaches, because of the greater parameterization of the multivariate models and moderate information content of the data. Principal component analysis results were consistent with univariate and multivariate analyses and recovered the levels of statistical significance observed in univariate analyses on the original data. In addition, principal component analysis was able to provide a location associated with LM area not detected by other analyses. The relative advantage of multivariate over the univariate approaches varied with the level of genetic covariance between traits because of the modeled QTL effect and information contained in the data; however, multivariate approaches have the unique capability to identify pleiotropic effects or multiple linked QTL.


Caspase-Dependent Apoptosis of Retinal Ganglion Cells During the Development of Diabetic Retinopathy.
Diabetic retinopathy constitutes the most frequent cause of vision loss in professionally active individuals. Progressive impairment of visual acuity results from massive fibrovascular proliferation involving the fundus of the eye, as well as from the apoptosis of the neuronal structures of the retina. The results of many clinical studies, both on experimental models and on human material, confirmed evident enhancement of this process in the course of diabetes. The programmed cell death of retinal ganglion cells predominantly occurs secondarily to caspase-dependent intracellular processes. This paper presents evidence for the considerable involvement of the caspase-dependent mechanism of apoptosis of retinal ganglion cells in the early stages of retinal changes associated with progressive impairment of visual acuity. The authors emphasize the necessity of comprehensive understanding of mechanisms that underlie the programmed death of neural cells in the eyes of patients with diabetes. This clinical problem becomes of vital importance in view of the constantly increasing incidence of diabetes and severe impairment associated with the disorders of carbohydrate metabolism. Identification of a key component involved in this process would enable attempts oriented at pharmacological blockade of apoptosis in the retinal ganglion cells of patients with diabetes.


Subcellular distribution of components of the ubiquitin-proteasome system in non-diseased human and rat brain.
Our aim was to investigate and to compare the intracellular distribution of ubiquitin, 20S proteasome, and all six proteasomal regulatory ATPases in non-diseased human and rat brains. Ubiquitin and ATPases S4 and S7 show dominant nuclear immunostaining, whereas subunits S6a, S6b, and S10b show mainly cytoplasmic immunostaining in both species. However, S8 localization is inconsistent, prevailing nuclear in rat and cytoplasmic in human. In rat brain, small clastosome-like nuclear bodies demonstrate strong ubiquitin, 20S, and S6a immunoreactivity both in neurons and glial cells. Prominent nuclear immunolocalization of members of the ubiquitin-proteasome system provides morphological evidence for function of these proteins in transcription regulation and/or DNA repair.


CT detection of dry peritoneal seeding in patients with advanced gastric cancer.
To determine the significant CT findings of dry peritoneal seeding (DPS) in patients with advanced gastric cancer (AGC) and to assess whether radiologists' performance in the detection of DPS can be improved using these significant CT findings. Two radiologists reviewed CT images of AGC patients with DPS and without seeding for the presence or absence of various CT findings suggesting peritoneal seeding, in consensus. Significant CT findings for DPS were determined using Fisher's exact test. Two other observers, blinded to the results of the consensus review during the first session but not during the second session, evaluated the presence or absence of DPS independently on a five-point scale. Each observer's performance was evaluated using a pair-wise comparison of the receiver operating characteristic (ROC) curves. Soft tissue nodule or plaque on the peritoneal surface was the only significant CT finding of DPS (p=0.014). The areas under the ROC curves of the two observers were not significantly different between the two review sessions. Soft tissue nodule or plaque on the peritoneal surface was a significant CT finding for the detection of DPS. However, radiologists' performance for the detection of DPS did not improve despite knowledge of this finding.


New Contributions to the Diversity of Hypotrichous Ciliates: Description of a New Genus and Two New Species (Protozoa, Ciliophora).
Ciliated protists (ciliates) are extremely diverse and play important ecological roles in almost all kinds of habitats. In this study, two new hypotrichs, Wilbertophrya sinica n. g. and n. sp. and Bakuella xianensis n. sp., from China are investigated. Wilbertophrya n. g. can be separated from related genera mainly by the combination of lacking a buccal cirrus, pretransverse cirri, and caudal cirri, while possessing frontoterminal cirri. Analyses based on morphological and molecular data confirm the validity of the species, W. sinica n. sp., which is characterized as follows: body 50-115 μm × 15-35 μm in vivo; midventral complex comprises four or five cirral pairs only and terminates above mid-body; three frontal, two frontoterminal cirri, and two to four transverse cirri; about 15 macronuclear nodules; colorless cortical granules sparsely distributed. Another new species, B. xianensis n. sp., was isolated from a freshwater wetland and is defined as follows: body 115-150 μm × 40-65 μm in vivo; about 70 macronuclear nodules; dark-brownish cortical granules in groups; midventral complex comprises 8-12 cirral pairs forming a row that terminates posteriorly in mid-body region and two or three short midventral rows that are continuous with the row of midventral pairs; three frontal, four to six frontoterminal, and three to five fine transverse cirri; three bipolar dorsal kineties. Phylogenetic analyses based on small subunit ribosomal DNA (SSU rDNA) sequence data suggest that the new genus Wilbertophrya n. g. belongs to an isolated clade, which might represent an undescribed taxon at the family level, whereas B. xianensis n. sp. groups with several congeners and members of other related genera are within the core urostylids.


Intermittent PTH administration and mechanical loading are anabolic for periprosthetic cancellous bone.
The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and µCT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro-osteoblastic/anti-adipocytic direction, and (2) controlling bone turnover by modulating the RANKL-OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, p < 0.05) and iPTH (+54%, p < 0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, p > 0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies.


Diagnostic value of whole-mount crypt analysis of ileal biopsy specimens for the patients with familial small intestinal neuroendocrine tumors.
Early-stage small intestinal neuroendocrine tumors (SI-NETs) are generally asymptomatic and difficult to diagnose. As a result, patients often present with late-stage incurable disease. SI-NETs originate from enterochromaffin (EC) cells, which develop enteroendocrine cell (EEC) clusters consisting of a subset of EC cells at the crypt bottom at an early stage of tumor progression. In a familial form of SI-NET, EEC clusters arise in a multifocal and polyclonal fashion. We sought to determine whether early detection and analysis of cryptal EEC clusters could provide insight into the development of SI-NETs and allow successful pre-symptomatic screening for at risk family members of patients with SI-NETs. Isolated crypts from endoscopic ileal biopsies or surgically removed specimens from 43 patients with familial SI-NET and 20 controls were formalin-fixed, immunostained for chromogranin A, and examined by confocal three-dimensional analysis for the presence of EEC cluster formations. Examination of multiple areas of macroscopic tumor-free mucosa in surgically resected specimens from patients with familial SI-NET revealed widely distributed, independent, multifocal EEC micro-tumor formations of varying sizes. Consistent with this finding, randomly sampled ileal biopsy specimens identified aberrant crypt containing endocrine cell clusters (ACECs) in patients. ACECs were found exclusively in patients (23/43, 53%) and not in controls (0/20). Furthermore, analysis of positions and numbers of EECs in crypts and ACECs indicated significant increases in EECs at the crypt bottom, predominantly at positions 0 and 1' (p < 0.0001 compared to controls), suggesting the progression of EEC accumulation below +4 position as the early process of ACEC formation. These findings also suggested that ACECs were precursors in the development of micro-tumors and subsequent macro-tumors. This study indicates that SI-NETs develop from deep crypt EC cells to become ACECs, micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease.


Ordered mesoporous ZSM-5 employing an imidazolium-based ionic liquid.
Hierarchically porous ZSM-5 was achieved by using a simple bottom-up strategy combining zeolite seeds with imidazolium-based ionic liquids. The bimodal ZSM-5 with hexagonal arranged mesopores (3 nm) shows important activity in the acid catalysis of bulky compounds relative to conventional ZSM-5.


The biological effects of retinoids on cell differentiation and proliferation.
The retinoids are the natural and synthetic analogues of retinol or vitamin A. These molecules are able to modulate differentiation and proliferation processes in several cell types. The presence of retinoids is essential for inducing or maintaining the differentiation of epithelial cells. On the other hand, when excess retinol is added to the culture medium, the differentiation of some mesenchymal cells is impaired. Retinoids also promote the differentiation of carcinoma cells of various origins: embryonal carcinoma, leukaemic and melanoma cells. While their effect on the proliferation of normal cells appears variable, these molecules inhibit the growth of cells treated with a tumoural promoter, or spontaneously transformed cells, and they prevent tumour promotion. Various mechanisms of action might be involved: retinoids could act at the level of the genome with or without the participation of their binding proteins. They might also influence glycoconjugate biosynthesis and interact, through certain glycosylation reactions, with growth factor receptors. The role of vitamin A and its structural analogues in cell differentiation and growth is of great therapeutic interest.


Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.
Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.


Advances in cognitive theory and therapy: the generic cognitive model.
For over 50 years, Beck's cognitive model has provided an evidence-based way to conceptualize and treat psychological disorders. The generic cognitive model represents a set of common principles that can be applied across the spectrum of psychological disorders. The updated theoretical model provides a framework for addressing significant questions regarding the phenomenology of disorders not explained in previous iterations of the original model. New additions to the theory include continuity of adaptive and maladaptive function, dual information processing, energizing of schemas, and attentional focus. The model includes a theory of modes, an organization of schemas relevant to expectancies, self-evaluations, rules, and memories. A description of the new theoretical model is followed by a presentation of the corresponding applied model, which provides a template for conceptualizing a specific disorder and formulating a case. The focus on beliefs differentiates disorders and provides a target for treatment. A variety of interventions are described.


Symptomatic bradycardia 2: assessment and management.
This is the second in a two-part unit on managing bradycardia. Part 1 discussed the physiology of the condition and examined its main causes. This second part outlines adverse signs, drug treatment options, transcutaneous pacing and nursing care.


[Analysis of antibiotic susceptibility of foodborne Listeria monocytogenes in China].
To study the antibiotic susceptibility of foodborne Listeria monocytogenes in China. The susceptibilities of 476 strains of foodborne Listeria monocytogenes to antibiotics were determined in Broth Microdilution Susceptibility Testing in Clinical and Laboratory Standards Institute. The antibiotics of gentamicin, ampicillin, penicillin, tetracycline, doxycycline, imipenem, erythromycin, ciprofloxacin, levofloxacin, cephalothin, rifampin, vancomycin, chloramphenicol, Trimethoprim-sulfamethoxazole, ampicillin-sulbactam were used. The rates of antibiotic resistance in 467 is olates were 4.5%. Tetracycline resistance was most prevalent, accouting for 4.07% . The foods that the rates of antibiotic resistance were highest were vegetable (10%). Among 14 provinces, Jilin, Hubei and Hebei were the third top, the rate of which were 19.6% and 9.1% and 8%, respectively. It was suggested that antibiotic resistance exists in foodborne Listeria monocytogenes to a certain extent in China. It should pay more attention to the use of drugs in prevention and clinic treatment to reduce the antibiotic resistant strains.


The one-sided explanations of a multifactorial coronavirus disease.
Short-term interventions to suppress COVID-19 completely dominate the public, political and even the professional discussion on what explains observed differences in mortality and morbidity across countries. This leads to an exaggerated view of what such measures can accomplish. Factors such as housing and social conditions as well as travel patterns are equally important but neglected aspects of the COVID-19 development. A multifactorial disease needs a multivariate analytical approach.


Multiscale hydrodynamic investigation to intensify the biogas production in upflow anaerobic reactors.
Hydrodynamics plays a main role for the performance of an anaerobic reactor involving three phases: wastewater, sludge granules and biogas bubbles. The present work was focused on an original approach to investigate the hydrodynamics at different scales and then to intensify the performance of such complex reactors. The experiments were carried out respectively in a 3D reactor at macroscale, a 2D reactor at mesoscale and a 1D anaerobic reactor at microscale. A Particle Image Velocimetry (PIV), a micro-PIV and a high-speed camera were employed to quantify the liquid flow fields and the relative motion between sludge granules and bubbles. Shear rates exerted on sludge granules were quantified from liquid flow fields. The optimal biogas production is obtained at mean shear rate varying from 28 to 48s(-1), which is controlled by two antagonistic mechanisms. The multiscale approach demonstrates pertinent mechanisms proper to each scale and allows a better understanding of such reactors.


[On the State of Training in Parent-Infant/Toddler Psychotherapy in Germany].
Regulation disorders in early childhood and postpartum mental disorders of parents can be effectively treated by interventions that involve parents and child (so-called parent-infant psychotherapy, PIP). Availability of PIP in routine care remains low, even though the intervention is in high demand. This study aims to map the current situation of psychotherapy training in PIP in Germany, to record existing obstacles from the perspective of the institutes, and to obtain indications for improving training. Contact persons of training institutes all over Germany were invited to participate in an online survey. N = 95 persons answered questions about possible training in PIP and related advantages and hurdles as well as conditions for a future implementation. Nineteen (22.4 %) of the institutions indicated that PIP was part of their training concept. In 84.2 % of the cases this was aimed at child and adolescent psychotherapists. In 63.6 % of the institutes PIP was treated comprehensively. On average, 2.55 barriers were perceived, most frequently of an organizational nature. 75.9 % of the institutes that did not yet offer PIP would be willing to do so in the future under at least one condition. Among those conditions, information on PIP curricula and specific training content was most frequent (40.7 %).The low implementation of PIP in training seems to be mainly due to barriers of an organizational nature that can be overcome by some simple means, such as the dissemination of model curricula.


Cardiac Dysfunction in a Porcine Model of Pediatric Malnutrition.
Half a million children die annually of severe acute malnutrition and cardiac dysfunction may contribute to the mortality. However, cardiac function remains poorly examined in cases of severe acute malnutrition. To determine malnutrition-induced echocardiographic disturbances and longitudinal changes in plasma pro-atrial natriuretic peptide and cardiac troponin-T in a pediatric porcine model. Five-week old piglets (Duroc-x-Danish Landrace-x-Yorkshire) were fed a nutritionally inadequate maize-flour diet to induce malnutrition (MAIZE, n = 12) or a reference diet (AGE-REF, n = 12) for 7 weeks. Outcomes were compared to a weight-matched reference group (WEIGHT-REF, n = 8). Pro-atrial natriuretic peptide and cardiac troponin-T were measured weekly. Plasma pro-atrial natriuretic peptide decreased in both MAIZE and AGE-REF during the first 3 weeks but increased markedly in MAIZE relative to AGE-REF during week 5-7 (p ≤ 0.001). There was overall no difference in plasma cardiac troponin-T between groups. However, further analysis revealed that release of cardiac troponin-T in plasma was more frequent in AGE-REF compared with MAIZE (OR: 4.8; 95%CI: 1.2-19.7; p = 0.03). However, when release occurred, cardiac troponin-T concentration was 6.9-fold higher (95%CI: 3.0-15.9; p < 0.001) in MAIZE compared to AGE-REF. At week 7, the mean body weight in MAIZE was lower than AGE-REF (8.3 vs 32.4 kg, p < 0.001), whereas heart-weight relative to body-weight was similar across the three groups. The myocardial performance index was 86% higher in MAIZE vs AGE-REF (p < 0.001) and 27% higher in MAIZE vs WEIGHT-REF (p = 0.025). Malnutrition associates with cardiac dysfunction in a pediatric porcine model by increased myocardial performance index and pro-atrial natriuretic peptide and it associates with cardiac injury by elevated cardiac troponin-T. Clinical studies are needed to see if the same applies for children suffering from malnutrition.


A novel insertion mutation (A169i) in the CLN1 gene is associated with infantile neuronal ceroid lipofuscinosis in an Italian patient.
Infantile neuronal ceroid lipofuscinosis (INCL) is a progressive encephalopathy characterized by psychomotor deterioration, early visual loss, and an evanishing EEG. Mutations in the CLN1 gene encoding palmitoyl-protein thioesterase (ppt) have been reported in all Finnish INCL patients and in several non-Finnish North European patients. No cases have been contributed from the Mediterranean area thus far. We identified a single adenine insertion at nucleotide position 169 (A169i) in the CLN1 gene in a family in which the proband suffered from an INCL-like syndrome. The novel mutation was homozygous in blood from the proband, heterozygous in his healthy parents, and not found in control alleles. The mutation leads to an early stop codon resulting in an abnormal and truncated ppt protein. Our observations provide the first molecular characterization of an Italian INCL patient and expand the list of the known defects in INCL.


Memory performance-related dynamic brain connectivity indicates pathological burden and genetic risk for Alzheimer's disease.
The incidence of Alzheimer's disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aβ), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk. Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aβ was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status). A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p < 0.008), moderated by ApoE-ε4 (F(9,27) = 2.22, p < 0.005). Inherent node-strength was related to local iron (F(5,30) = 13.2; p < 0.022). Our data indicate that altered dynamic anterior-posterior brain connectivity is a characteristic of low memory performance in the subclinical range and genetic risk for AD in the elderly. As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress.


Effects of sensitizers on cell respiration: II. The effects of hypoxic cell sensitizers on oxygen utilization in cellular and chemical models.
The metabolic activity of nitroheterocyclic sensitizers could limit their usefulness in vivo. Biochemical mechanisms of drug metabolism, toxicity and effects on cell respiration have been studied in microsomes, and the kinetics of the simulated redox reactions determined by pulse radiolysis. Stimulated oxidation of coenzyme, glucose, ascorbate or glutathione substrate radicals by nitroheterocyclic sensitizers, with the concomitant appearance of the respective nitro radical anions, is observed. Under hypoxia, the nitro radical anions decay slowly by second order processes, forming reduced metabolites. In air, the nitro radical anions react with oxygen forming superoxide radical anions, peroxide and regenerating the drug. Nitro radical-anions also react with cytochrome-c indicating a possible interference with mitochondrial energy metabolism.


Respirable dust control in grinding gray iron castings.
High speed grinding of gray iron castings long has been associated with excessive exposure to crystalline silica. Not all workers engaged in these operations are protected by conventional ventilation techniques. Dust in the air that has been entrained by the spinning grinding wheel and not captured in the grinder hood has been postulated to be a major exposure source. A pilot grinding operation was constructed, and the size distribution and concentration of airborne particles were measured with the aerodynamic particle sizer (APS). Various control measures proved effective in reducing the respirable dust concentration: increased exhaust ventilation, and installation of baffles and/or the use of an air jet to deflect the entrained air stream. The concentration of respirable dust is the breathing zone was reduced approximately 20-fold through the combined use of increased ventilation, interior baffles, and an air jet. The air jet and baffle utilized at the base ventilation rate reduced the respirable dust concentration by a factor of three to four, whereas the baffle alone halved the concentration.


Sensing-enabled hippocampal deep brain stimulation in idiopathic nonhuman primate epilepsy.
Epilepsy is a debilitating condition affecting 1% of the population worldwide. Medications fail to control seizures in at least 30% of patients, and deep brain stimulation (DBS) is a promising alternative treatment. A modified clinical DBS hardware platform was recently described (PC+S) allowing long-term recording of electrical brain activity such that effects of DBS on neural networks can be examined. This study reports the first use of this device to characterize idiopathic epilepsy and assess the effects of stimulation in a nonhuman primate (NHP). Clinical DBS electrodes were implanted in the hippocampus of an epileptic NHP bilaterally, and baseline local field potential (LFP) recordings were collected for seizure characterization with the PC+S. Real-time automatic detection of ictal events was demonstrated and validated by concurrent visual observation of seizure behavior. Seizures consisted of large-amplitude 8- to 25-Hz oscillations originating from the right hemisphere and quickly generalizing, with an average occurrence of 0.71 ± 0.15 seizures/day. Various stimulation parameters resulted in suppression of LFP activity or in seizure induction during stimulation under ketamine anesthesia. Chronic stimulation in the awake animal was studied to evaluate how seizure activity was affected by stimulation configurations that suppressed broadband LFPs in acute experiments. This is the first electrophysiological characterization of epilepsy using a next-generation clinical DBS system that offers the ability to record and analyze neural signals from a chronically implanted stimulating electrode. These results will direct further development of this technology and ultimately provide insight into therapeutic mechanisms of DBS for epilepsy.


Unraveling the central proopiomelanocortin neural circuits.
Central proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: how and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.


Stereoselective synthesis of 2,3-difunctionalised thioesters using nucleophilic epoxidation of 1-arylthio-1-nitroalkenes.
Stereoselective nucleophilic epoxidation of protected 3-amino and 3-hydroxy-substituted 1-arylthio-1-nitroalkenes, followed by intramolecular capture involving the amino and hydroxyl protecting groups, has led to the formation of isomeric oxazolidinones 5 and 7, and a cyclic carbonate 11. Together with the oxazolidinone precursor anti-alpha-bromo thioester 15a, the absolute and relative stereochemistry of these compounds has been determined by X-ray crystallography.