Regulation of chloride self exchange by cAMP in cortical collecting tubule.
The hormonal control of Cl transport was examined in rabbit cortical collecting tubules using the lumen-to-bath 36Cl tracer rate coefficient (KCl, nm/s). Tracer movement via Cl-HCO3 exchange was minimized by using HCO3-CO2-free solutions. The electrical driving force was minimized by treating with amiloride. Under these conditions, net Cl transport was zero, yet there was a large KCl that fell 88% on removing bath (trans) Cl. These results are consistent with the mechanism of tracer flux being predominantly Cl self exchange. KCl fell spontaneously with time in vitro; after this decline KCl could be stimulated with 8-bromo-cAMP. cAMP present from the onset of perfusion prevented the time-dependent fall in KCl. When tracer movement was restricted to diffusion by eliminating Cl self exchange (0 Cl bath), cAMP had no effect on KCl. Although both isoproterenol and vasopressin are known to stimulate adenylate cyclase in this epithelium, only isoproterenol mimicked the cAMP effect on KCl. The isoproterenol effect was blocked by either propranolol or prostaglandin E2. Lumen addition of the disulfonic stilbene DIDS had no effect on KCl. Lumen addition of furosemide or trichloromethiazide had minimal or no effect. Taken together, these results indicate that Cl self exchange is regulated by beta-adrenergic agents acting via cAMP. The lack of an effect of vasopressin suggests cellular heterogeneity in this response to cAMP.


ENRICHMENT PROCEDURE FOR USE WITH THE MEMBRANE FILTER FOR THE ISOLATION AND ENUMERATION OF FECAL STREPTOCOCCI IN WATER.
By the use of PYC enrichment medium, the recovery of fecal streptococci from river water has been increased more than twofold over that of M-Enterococcus Agar. Of the isolates tested, 94.6% could be classified as enterococci or enterococcus biotypes. This method seems to yield a larger number of strains which would not normally be revealed. Serological typing of atypical streptococcus strains isolated indicates that the majority of these "biotypes" can be placed in the enterococcus group.


Autoantibodies Against the Complement Regulator Factor H in the Serum of Patients With Neuromyelitis Optica Spectrum Disorder.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies against the main water channel in the CNS, aquaporin 4 (AQP4). NMOSD is frequently associated with additional autoantibodies and antibody-mediated diseases. Because the alternative pathway amplifies complement activation, our aim was to evaluate the presence of autoantibodies against the alternative pathway C3 convertase, its components C3b and factor B, and the complement regulator factor H (FH) in NMOSD. Four out of 45 AQP4-seropositive NMOSD patients (~9%) had FH autoantibodies in serum and none had antibodies to C3b, factor B and C3bBb. The FH autoantibody titers were low in three and high in one of the patients, and the avidity indexes were low. FH-IgG complexes were detected in the purified IgG fractions by Western blot. The autoantibodies bound to FH domains 19-20, and also recognized the homologous FH-related protein 1 (FHR-1), similar to FH autoantibodies associated with atypical hemolytic uremic syndrome (aHUS). However, in contrast to the majority of autoantibody-positive aHUS patients, these four NMOSD patients did not lack FHR-1. Analysis of autoantibody binding to FH19-20 mutants and linear synthetic peptides of the C-terminal FH and FHR-1 domains, as well as reduced FH, revealed differences in the exact binding sites of the autoantibodies. Importantly, all four autoantibodies inhibited C3b binding to FH. In conclusion, our results demonstrate that FH autoantibodies are not uncommon in NMOSD and suggest that generation of antibodies against complement regulating factors among other autoantibodies may contribute to the complement-mediated damage in NMOSD.


Quality Initiative to Increase Delivery of Adolescent Hospital-Based Reproductive Health Care.
Hospitals are an important nontraditional setting in which to address adolescent reproductive health. However, opportunities for intervention are frequently missed, especially for boys and patients hospitalized for noningestion complaints. Our global aim was to increase delivery of reproductive health care to adolescents hospitalized through our children's hospital Pediatric Hospital Medicine service. We performed 2 quality improvement intervention cycles: (1) provider education and monthly reminder e-mails and (2) an automated electronic health record (EHR) adolescent history and physical note template with social history prompts while discontinuing reminder e-mails. The primary outcome measure was sexual history documentation (SHD). Secondary measures were sexually transmitted infection (STI) testing and contraception provision. Statistical process control charts were used to analyze effectiveness of interventions. From July 2018 through June 2019, 528 Primary Hospital Medicine encounters were included in this study and compared with published baseline data on 150 encounters. Control charts revealed a special cause increase in SHD from 60% to 82% overall, along with 37% to 73% for boys and 57% to 80% for noningestion hospitalizations. Increased SHD correlated with cycle 1 and was maintained through cycle 2. Percent STI testing significantly increased but did not shift or trend toward special cause variation. Contraception provision, length of stay, and patient relations consultations were not affected. The interventions were successful in increasing SHD, including among boys and noningestion hospitalizations. The EHR enhancement maintained these increases after reminder emails were discontinued. Future interventions should specifically address STI testing and provision of contraception.


Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines.
Coronavirus disease 2019 (COVID-19) is pandemic and has caused illness to many people worldwide. This review aimed to summarize and analyze the herbal formulae provided by the guidelines for their pattern identifications (PIs) and compositions of herbs to treat patients with COVID-19. We searched 7 data sources for eligible traditional medicine guidelines up to March 6, 2020 and found a total of 28 traditional medicine guidelines that provide treatment measures for COVID-19. Of the 28 guidelines, there were 26 government-issued Chinese guidelines and 2 Korean guidelines. After standardizing the terminology of the PIs and herbal formulae, there were 8 PIs and 23 herbal formulae for the mild stage, 11 PIs and 31 herbal formulae for the moderate stage, 8 PIs and 21 herbal formulae for the severe stage, and 6 PIs and 23 herbal formulae for the recovery stage in the Chinese guidelines. In the Korean guidelines, there were 4 PIs and 15 herbal formulae for the mild stage, 3 PIs and 3 herbal formulae for the severe stage, and 2 PIs and 2 herbal formulae for the recovery stage. In the frequency analysis of herbs, Glycyrrhizae Radix et Rhizoma was found to be the herb with the highest frequency of usage in the Chinese guidelines. This review can be used as guidance for the traditional medicine treatment of COVID-19. Clinical evidence is needed in the future to evaluate the efficacy of traditional medicine.


Hierarchical modelling of immunoglobulin coated bacteria in dogs with chronic enteropathy shows reduction in coating with disease remission but marked inter-individual and treatment-response variability.
Chronic enteropathies are a common problem in dogs, but many aspects of the pathogenesis remain unknown, making the therapeutic approach challenging in some cases. Environmental factors are intimately related to the development and perpetuation of gastrointestinal disease and the gut microbiome has been identified as a contributing factor. Previous studies have identified dysbiosis and reduced bacterial diversity in the gastrointestinal microbiota of dogs with chronic enteropathies. In this case-controlled study, we use flow cytometry and 16S rRNA sequencing to characterise bacteria highly coated with IgA or IgG in faecal samples from dogs with chronic enteropathy and evaluated their correlation with disease and resolution of the clinical signs. IgA and IgG-coated faecal bacterial counts were significantly higher during active disease compared to healthy dogs and decreased with the resolution of the clinical signs. Characterisation of taxa-specific coating of the intestinal microbiota with IgA and IgG showed marked variation between dogs and disease states, and different patterns of immunoglobulin enrichment were observed in dogs with chronic enteropathy, particularly for Erysipelotrichaceae, Clostridicaceae, Enterobacteriaceae, Prevotellaceae and Bacteroidaceae, families. Although, members of these bacterial groups have been associated with strong immunogenic properties and could potentially constitute important biomarkers of disease, their significance and role need to be further investigated.


The use of antibiotics in biliary tract disease.
Antibotics are often used in the treatment of patients with biliary tract disease. Certain drugs are relatively contraindicated if there is preexisting liver dysfunction. Not all antibiotis achieve a high level in bile, and knowledge of their individual excretion rate is important for intelligent use.


Challenges in evaluating Welfare to Work policy interventions: would an RCT design have been the answer to all our problems?
UK policy direction for recipients of unemployment and sickness benefits is to support these people into employment by increasing 'into work' interventions. Although the main aim of associated interventions is to increase levels of employment, improved health is stated as a benefit, and a driver of these interventions. This is therefore a potentially important policy intervention with respect to health and health inequalities, and needs to be validated through rigorous impact evaluation.We attempted to evaluate the Pathways Advisory Service intervention which aims to provide employment support for Incapacity Benefit recipients, but encountered a number of challenges and barriers to evaluation. This paper explores the issues that arose in designing a suitable evaluation of the Pathways Advisory Service. The main issues that arose were that characteristics of the intervention lead to difficulties in defining a suitable comparison group; and governance restrictions such as uncertainty regarding ethical consent processes and data sharing between agencies for research. Some of these challenges threatened fundamentally to limit the validity of any experimental or quasi-experimental evaluation we could design - restricting recruitment, data collection and identification of an appropriate comparison group. Although a cluster randomised controlled trial design was ethically justified to evaluate the Pathways Advisory Service, this was not possible because the intervention was already being widely implemented. However, this would not have solved other barriers to evaluation. There is no obvious method to perform a controlled evaluation for interventions where only a small proportion of those eligible are exposed. Improved communication between policymakers and researchers, clarification of data sharing protocols and improved guidelines for ethics committees are tangible ways which may reduce the current obstacles to this and other similar evaluations of policy interventions which tackle key determinants of health. The evaluation of social interventions is hampered by more than their suitability to randomisation. Data sharing, participant identification and recruitment problems are common to randomised and non-randomised evaluation designs. These issues require further attention if we are to learn from current social policy.


Is There Neural Evidence for an Evidence Accumulation Process in Memory Decisions?
Models of evidence accumulation have been very successful at describing human decision making behavior. Recent years have also seen the first reports of neural correlates of this accumulation process. However, these studies have mostly focused on perceptual decision making tasks, ignoring the role of additional cognitive processes like memory retrieval that are crucial in real-world decisions. In this study, we tried to find a neural signature of evidence accumulation during a recognition memory task. To do this, we applied a method we have successfully used to localize evidence accumulation in scalp EEG during a perceptual decision making task. This time, however, we applied it to intracranial EEG recordings, which provide a much higher spatial resolution. We identified several brain areas where activity ramps up over time, but these neural patterns do not appear to be modulated by behavioral variables such as the amount of available evidence or response time. This casts doubt on the idea of evidence accumulation as a general decision-making mechanism underlying different types of decisions.


Developmental conditions and culture medium influence the neuromodulated response of in vitro cortical networks.
Goal of this work is to show how the developmental conditions of in vitro neuronal networks influence the effect of drug delivery. The proposed experimental neuronal model consists of dissociated cortical neurons plated to Micro-Electrode Arrays (MEAs) and grown according to different conditions (i.e., by varying both the adopted culture medium and the number of days needed to let the network grow before performing the chemical modulation). We delivered rising amount of bicuculline (BIC), a competitive antagonist of GABAA receptors, and we computed the firing rate dose-response curve for each culture. We found that networks matured in BrainPhys for 18 days in vitro exhibited a decreasing firing trend as a function of the BIC concentration, quantified by an average IC50 (i.e., half maximal inhibitory concentration) of 4.64 ± 4.02 µM. On the other hand, both cultures grown in the same medium for 11 days, and ones matured in Neurobasal for 18 days displayed an increasing firing rate when rising amounts of BIC were delivered, characterized by average EC50 values (i.e., half maximal excitatory concentration) of 0.24 ± 0.05 µM and 0.59 ± 0.46 µM, respectively.Clinical Relevance- This research proves the relevance of the experimental factors that can influence the network development as key variables when developing a neuronal model to conduct drug delivery in vitro, simulating the in vivo environment. Our findings suggest that not considering the consequences of the chosen growing conditions when performing in vitro pharmacological studies could lead to incomplete predictions of the chemically induced alterations.


Cell migration capability of vascular endothelial growth factor into the root apex of a root canal model in vivo.
Once a tooth develops deep caries and the dental pulp tissue is irreversibly infected, the infected dental pulp tissue should be removed, and filling material should be placed in the root canal. Endodontically treated teeth are prone to root fracture or periapical periodontitis; however, dental pulp tissue has the potential to prevent root fracture or periapical periodontitis. Therefore, dental pulp regeneration after pulpectomy may help prolong tooth life. In this study, a new method of dental pulp regeneration was developed. Vascular endothelial growth factor-adsorbed collagen gel was injected into the root canal of a prepared root canal model, placed into the dorsum of a rat, and cultured for 3 weeks. After retrieving the implant, histological analysis was performed. It was found that rat somatic cells were recruited into the root apex of the transplanted root canal model. These findings suggest a new potential technique for engineering dental pulp tissue.


Assembly-driven protection from hydrolysis as key selective force during chemical evolution.
The origins of biopolymers pose fascinating questions in prebiotic chemistry. The marvelous assembly proficiencies of biopolymers suggest they are winners of a competitive evolutionary process. Sophisticated molecular assembly is ubiquitous in life where it is often emergent upon polymerization. We focus on the influence of molecular assembly on hydrolysis rates in aqueous media and suggest that assembly was crucial for biopolymer selection. In this model, incremental enrichment of some molecular species during chemical evolution was partially driven by the interplay of kinetics of synthesis and hydrolysis. We document a general attenuation of hydrolysis by assembly (i.e., recalcitrance) for all universal biopolymers and highlight the likely role of assembly in the survival of the 'fittest' molecules during chemical evolution.


Evaluation of Salivary Uric Acid and pH in Human Immunodeficiency Virus Infected Patients: A Historical Cohort Study.
Antioxidants protect the body against cellular damage. Saliva has immunological, enzymatic and antioxidant defense systems. Uric acid is the main and predominant salivary antioxidant. The aim of this study was to evaluate salivary uric acid levels and pH in HIV-infected patients in the west of Iran. HIV-infected patients were selected from behavioral advisory centers of Hamadan and Kermanshah Provinces, west of Iran. Saliva was collected between 8 and10 in the morning. Five mL of whole unstimulated saliva was collected in 5 minutes by spitting into sterilized Falcon tubes based on Navazesh method; pH was measured with a pH meter and uric acid was assessed with spectrophotometric method. Data were analyzed with STATA 12. Salivary pH in the HIV-positive group was lower (6.99±0.46) than the healthy controls (7.14±1.03) but the difference was not statistically significant (P=380). Uric acid concentrations in HIV-infected patients (2.94±2.14) were significantly lower in comparison to the healthy controls (5.21±2.30). The results showed a statistically significant decrease in the case group (P=0.001). Mean age and DMFT index of the case group were higher than the control group. Uric acid, the main antioxidant of saliva, was significantly lower in HIVinfected individuals; pH also was lower in these patients. HIV can alter salivary antioxidant status, which can influence patients' oral health status. Diet with antioxidant properties might be helpful in these patients. More research is necessary to discover true antioxidant and salivary changes and their relation with HIV consequences in future.


Outcomes of inoperable symptomatic aortic stenosis patients not undergoing aortic valve replacement: insight into the impact of balloon aortic valvuloplasty from the PARTNER trial (Placement of AoRtic TraNscathetER Valve trial).
The aim of this report is to characterize the impact of balloon aortic valvuloplasty (BAV) in patients not undergoing aortic valve replacement in the PARTNER (Placement of AoRtic TraNscathetER Valves) trial. The PARTNER trial is the only randomized trial with independently adjudicated data of inoperable severe symptomatic aortic stenosis patients, allowing outcome analysis of unoperated-on patients. The design and initial results of the PARTNER trial (Cohort B) were reported previously. After excluding patients with pre-randomization BAV, we compared patients undergoing BAV within 30 days of randomization (BAV group) with those not having BAV within 30 days of randomization (no BAV group) to characterize the use and impact of BAV. In the PARTNER Cohort B study, 179 inoperable patients were randomized to standard treatment including 39 patients (21.8%) who had undergone a BAV before randomization (previous BAV group). Of the 140 patients who did not have BAV before enrollment in the study, 102 patients (73%) had BAV within 30 days of study randomization (BAV group). Survival at 3 months was greater in the BAV group compared with the no BAV group (88.2%; 95% confidence interval [CI]: 82.0% to 94.5% vs. 73.0%; 95% CI: 58.8% to 87.4%). However, survival was similar at 6-month follow-up (74.5%; 95% CI: 66.1% to 83.0% vs. 73.1%; 58.8% to 87.4%). There was improvement in quality of life parameters when paired comparisons were made between baseline and 30 days and 6 months between the BAV and no BAV groups, but this effect was lost at 12-month follow-up. BAV improves functional status and survival in the short term, but these benefits are not sustained. BAV for aortic stenosis patients who cannot undergo aortic valve replacement is a useful palliative therapy. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894).


Equipment developed for simplifying routine phototesting in dermatology.
Some people react abnormally when exposed to sunlight by getting easily burned or develop a rash. When testing a patient's level of photosensitivity in the clinic, the UVR dose to provoke erythema is determined by the minimal erythema dose (MED) test. Subsequently, a photoprovocation test is performed to detect abnormal skin reactions by daily exposing the skin to UVR for several consecutive days. Associated problems in MED testing include choice of an even skin area for testing, patients keeping still during the test, testing with different UVR doses simultaneously, and securing clear borders of erythema. To address these issues, a MED Test Patch was developed which adheres closely to the skin to ensure sharp erythema borders and provides six irradiation fields with decremental doses of 20%. For MED testing, we constructed a solar simulator and LED lamps with peak emissions at 309 and 370 nm, small enough to be mounted directly on to the MED Test Patch and accommodate patient movements. These lamps and a 415 nm LED can also be used for provocation testing which is best performed on the back where the skin is assumed to have identical UVR sensitivity, and the area is large enough for adjacent MED and provocation test fields. Reading of erythema is still performed by visual and tactile evaluation. The UVA and UVB MED test can be performed in 1 h. The advantage of these developments is an easy-to-use, standardized test method with improved accuracy of the results.


Is cumulative frequency of mitochondrial DNA variants a biomarker for colorectal tumor progression?
To examine the relationship between mitochondrial DNA (mtDNA) alterations and colorectal tumorigenesis, we used high-resolution restriction endonucleases and sequencing to assess the mitochondrial genome from three histologic subtypes of colorectal adenomas (tubular = 8; tubulovillous = 9; and villous = 8), colorectal cancer (CRC) tissues = 27, and their matched surrounding normal tissue (MSNT) = 52. The mitochondrial genomes were amplified using 9 pairs of overlapping primers and systematically analyzed by means of high-resolution analysis. DNA fragments showing a shift in banding patterns between the three adenomas, CRC, in comparison to the MSNT were sequenced to identify the mtDNA alterations. A total of thirty-eight germ-line mtDNA variants were observed in this study. Twenty-two of the thirty-eight were identified as mutations and 59% (13 of 22) were silent mutations and one was a 1-bp insertion. Sixteen of thirty-eight were distinct SNPs in flanking regions of the restriction sites and, 6 of the 16 (37%) SNPs were not previously reported. Most of these mutations/SNPs were homoplasmic and distributed in various regions of mitochondrial genes including the 16S and 12S rRNA. Based on our results, mtDNA germline variants increased in prevalence with adenoma CRC progression. To the best of our knowledge, this is the first report to show an increased prevalence of mitochondrial gene variants in CRC tumorigenesis.


Metabolism of arachidonic acid in human lung cancer cell lines.
The metabolism of arachidonic acid (AA) was studied in two pulmonary bronchioloalveolar-carcinoma cell lines (NCI-H322 and NCI-H358) and two small cell lung carcinoma cell lines (NCI-H69 and NCI-H128). Exogenous AA was metabolized only in the NCI-H322 and NCI-H358 cells. There was no detectable metabolism of AA in NCI-H69 or NCI-H128 cells, either in the presence or the absence of the calcium ionophore A23187. The major metabolite of AA isolated from both NCI-H322 and NCI-H358 cells was prostaglandin E2 (PGE2). Prostaglandin endoperoxide synthase activities, expressed as immunoreactive PGE2 (pmol/min/mg protein), were 10.3 +/- 0.28 (SD) and 4.8 +/- 0.48 in NCI-H358 and NCI-H322 cells, respectively. The rate of production of PGE2 by both NCI-H358 and NCI-H322 cells was linear up to 10 min. Production of PGE2 in both cell lines was dependent upon substrate concentration and was maximal above 17 microM AA. Moreover, PGE2 did not undergo further metabolism by either the NCI-H358 or the NCI-H322 cells. Aspirin (0.1 mM), a cyclooxygenase inhibitor, decreased PGE2 production by 77 and 60% in NCI-H358 and NCI-H322 cells, respectively. In the presence of exogenous AA the calcium ionophore, A23187 (20 microM), stimulated PGE2 production in NCI-H322 cells by almost 2-fold, although it did not affect PGE2 production in the NCI-H358 cells. In contrast, A23187 stimulated the endogenous production of PGE2 in both NCI-H322 and NCI-H358 cells by 4- and 9-fold respectively. In addition, both the NCI-H358 and NCI-H322 cell lines were susceptible to the cytotoxic effects of the anticancer agent mitoxantrone in both a time and concentration dependent manner. In contrast, the two cell lines lacking detectable prostaglandin synthesis activity, NCI-H69 and NCI-H128 were unaffected by treatment with mitoxantrone. These results illustrate that there are major differences in the abilities of human lung cancer cell lines to biosynthesize and release PGE2. It is conceivable that such differences might have exploitable diagnostic and/or therapeutic implications.


Comparative analysis of von Willebrand factor profiles in pulsatile and continuous left ventricular assist device recipients.
A higher rate of nonsurgical bleeding has been observed in nonpulsatile left ventricular assist device (LVAD) recipients. von Willebrand factor (vWF) profiles were compared for nonpulsatile and pulsatile LVAD recipients to explore mechanisms that may contribute to the development of postimplant nonsurgical bleeding. The nonpulsatile mechanism may impair vWF function by creating a deficiency in vWF high molecular weight multimers (HMWMs), essential for hemostasis. High molecular weight multimer deficiency should result in low ristocetin cofactor (RCo) to vWF antigen ratios (vWF:RCo/vWF:Ag) because of impaired platelet (plt)-binding ability. von Willebrand factor profiles and HMWM were measured pre- and post-LVAD placement in 11 nonpulsatile (HeartMate II [HM II[) and 3 pulsatile (HeartMate XVE [HM XVE]) recipients. All the nonpulsatile LVAD recipients exhibited loss of HMWM 30 days postimplant. The vWF:RCo/vWF:Ag ratio was significantly lower after LVAD placement in the nonpulsatile group when compared with the pulsatile group. In addition, the vWF:RCo/vWF:Ag ratio decreased significantly from baseline 30 days postimplant within the nonpulsatile recipients. All nonpulsatile LVAD recipients had low vWF:RCo/vWF:Ag ratios 30 days post-LVAD even if the values were normal at baseline. These data suggest that nonpulsatile HM II recipients develop HMWM loss and impaired vWF platelet (plt)-binding ability after LVAD placement. Similar results were not observed in our small series of pulsatile HM XVE recipients. This finding could suggest a contributing factor to the increase in nonsurgical bleeding observed in nonpulsatile LVAD patients. Further investigation is ongoing to identify specific causes of vWF impairment.


Differential induction of the Arabidopsis thaliana Thi2.1 gene by Fusarium oxysporum f. sp. matthiolae.
The Arabidopsis thaliana Thi2.1 gene is inducible by necrotrophic fungi through a signal transduction pathway different from that for pathogenesis-related (PR) proteins. We have identified three ecotypes that are susceptible (Col-2, Ler, and Ws) and two ecotypes that are resistant (Mt-0 and Uk-4) to spray inoculation with Fusarium oxysporum f. sp. matthiolae. The Thi2.1 transcript level after infection correlates with resistance, being 5 to 10 times higher in the resistant than in the susceptible ecotypes. The beta-glucuronidase (GUS) expression of a Thi2.1-promoter-uidA fusion (with a promoter derived from Col-2) is on the average almost 10 times higher in the Uk-4 background than in the Col-2 background. This confirms the results obtained by Northern (RNA) blots and indicates that Uk-4, and probably other resistant ecotypes too, might have a more sensitive recognition system for F. oxysporum f. sp. matthiolae or might have a signal transduction system that gives a higher amplification of the original recognition signal. Our results suggest a role of the Thi2.1 gene in resistance against F. oxysporum f. sp. matthiolae and perhaps other necrotrophic fungi.


Global Assessment of Gastrointestinal Endoscopic Skills (GAGES): a valid measurement tool for technical skills in flexible endoscopy.
Simulators may improve the efficiency, safety, and quality of endoscopic training. However, no objective, reliable, and valid tool exists to assess clinical endoscopic skills. Such a tool to measure the outcomes of educational strategies is a necessity. This multicenter, multidisciplinary trial aimed to develop instruments for evaluating basic flexible endoscopic skills and to demonstrate their reliability and validity. The Global Assessment of Gastrointestinal Endoscopic Skills (GAGES) Upper Endoscopy (GAGES-UE) and Colonoscopy (GAGES-C) are rating scales developed by expert endoscopists. The GAGES scale was completed by the attending endoscopist (A) and an observer (O) in self-assessment (S) during procedures to establish interrater reliability (IRR, using the intraclass correlation coefficient [ICC]) and internal consistency (IC, using Cronbach's alpha). Instrumentation was evaluated when possible and correlated with total scores. Construct and external validity were examined by comparing novice (NOV) and experienced (EXP) endoscopists (Student's t-test). Correlations were calculated for GAGES-UE and GAGES-C with participants who had performed both. For the 139 completed evaluations (60 NOV, 79 EXP), IRR (A vs. O) was 0.96 for GAGES-UE and 0.97 for GAGES-C. The IRR between S and A was 0.78 for GAGES-UE and 0.89 for GAGES-C. The IC was 0.89 for GAGES-UE, and 0.95 for GAGES-C. There were mean differences between the NOV and the EXP endoscopists for GAGE-UE (14.4 +/- 3.7 vs. 18.5 +/- 1.6; p < 0.001) and GAGE-C (11.8 +/- 3.8 vs. 18.8 +/- 1.3; p < 0.001). Good correlation was found between the scores for the GAGE-UE and the GAGE-C (r = 0.75; n = 37). Instrumentation, when performed, demonstrated correlations with total scores of 0.84 (GAGE-UE; n = 73) and 0.86 (GAGE-C; n = 45). The GAGES-UE and GAGES-C are easy to administer and consistent and meet high standards of reliability and validity. They can be used to measure the effectiveness of simulator training and to provide specific feedback. The GAGES results can be generalized to North American and European endoscopists and may contribute to the definition of technical proficiency in endoscopy.


[The skin as an immunological organ].
The skin is our largest organ. Its physico-chemical properties are adapted to its function as a non-specific general defense line against infections and injury from the environment. Through evolution the skin has developed a second line of highly specific immune defense comprising epidermal Langerhans cells, T lymphocytes and keratinocytes as the most distinct cellular elements. On the basis of available research data and reviews, an overview on the skin as an immunological organ is presented. Antigens penetrating into the epidermis are bound to dendritic Langerhans cells, processed and presented to T lymphocytes. Certain memory T cells are able to remember where they first encountered antigen. Skin homing T cells are CLA+ and circulate between the skin, peripheral blood and skin draining lymph nodes. Keratinocytes produce a wide spectre of cytokines, in particular interleukin-1, which has a key role in the skin immune function. The most common inflammatory skin disorders are mediated by T lymphocytes, usually Th1 cells, as in psoriasis, or Th2 cells, as in atopic dermatitis. Systemic treatment with T cell specific suppressive drugs, such as cyclosporine, has been successful in certain dermatoses. Promising cyclosporine analogues for topical treatment (tacrolimus and pimecrolimus) have been developed and may soon be introduced.


Steric and Electronic Effects of Electrochemically Generated Aryl Radicals on Grafting of the Graphite Surface.
Grafting of aryl radicals generated by electrochemical reduction of aryldiazonium salts has been extensively studied on various surfaces. However, there exists two unclear aspects; the first one is the generality of the blocking ability of simple functional groups toward multilayer growth, and the second one is the electronic impact of substituent groups of aryl radicals on grafting efficiency. To address these aspects, we have studied the electrochemical functionalization of graphite using aryldiazonium salts having electron-donating or electron-withdrawing groups at the 3,4,5-positions. Atomic force microscopy investigation of the functionalized surfaces revealed the formation of monolayers for all aryldiazonium salts, and thus, nitro, carboxy, ester, methyl, and methoxy groups at the 3,4,5-positions of the benzene ring suppress polyaryl growth. The degree of grafting estimated by scanning tunneling microscopy imaging and Raman spectroscopy of the functionalized surfaces depends on the electronic state of the aryl radicals, in which the radicals with electron-donating groups show a high degree of functionalization, whereas those with electron-withdrawing groups exhibit a low degree of functionalization. We discuss several possibilities that affect grafting density. Though there are several factors, we hypothesize that one factor to explain the observed reactivity trend is the electronic property of the aryl radicals, namely, the relative position of the singly occupied molecular orbital energy levels of the aryl radicals with respect to the graphite Fermi energy level.


[Medical tele-imaging: a good chance for the future].
Tele-imaging is an important part of telemedicine: it includes the transmission of medical digital images and plays a role in all fields of telemedicine, such as expertise, consultation, teaching and research. Tele-imaging has been made possible through the digitalization of medical imaging. There are two possibilities: either digitalization of conventional radiological film or direct acquisition of digital images. The transmission of medical imaging requires a high data rate so as to obtain a good quality transmission of the initial images in a reasonable delay. In order to deal with the great amount of information to be stocked and transmitted, a compression of the data, without loss of information, is usually necessary. Interactivity is very important in all these types of transmissions. These tele-transmission techniques are already used world wide, especially in Japan and in the United States, to help in therapeutic or diagnostic decisions. In France, we have been performing real time interactive tele-imaging sessions between radiology and endocrinology departments of Hotel Dieu in Montréal and Hôpital Cochin in Paris. This experimental device includes a visual-conference link between the medical teams and a real time link between two CT scanners. The CT scanner slices appear simultaneously both CT scanner screens; it is even possible to guide a CT scanner examination using remote control from the other hospital. We have successfully repeated the experiment between Cochin and a private hospital in Paris. In the case of the "Prison de la Santé", we have been using telemedicine in order to reduce problematic transfers of prison inmates. Moreover, access to doctors in the prison is sometimes difficult. The system ensures the daily transmission of X-rays, which are immediately read by radiologists at Cochin. In the past, 50 to 70 X-rays had to be read during one weekly visit. Medical tele-imaging raises certain legal, ethical and economic issues, such as problems concerning confidentiality, the right to compensation, patient information. It would be interesting in this context to open a discussion on the possible dangers of telemedicine, its value for the patients and the physicians, its role in emergency care, and the possibility of creating imaging data storage that may help radiologists in making diagnoses, especially for unusual images. Drawbacks not to be ignored: Poor digital images could lead to difficulties in their reading and interpretation. There is still a debate as to whether tele-diagnosis is reliable or not. Further evaluations must be made to as certain the effectiveness of these techniques. A certain dehumanization of medicine due to an increase in the distance between the physician and patient is another difficult issue. The great number of people involved in the process of tele-imaging could confuse the issue of determining individual responsibility. Such consultations of experts may reduce the freedom of patients to choose their doctor. Tele-consultation must not be performed without the patient's consent. If consent was not obtained before tele-transmission, the patient should be informed after the procedure; and the use of tele-consultation should be mentioned in the report. The utilization of public networks could lead to the manipulation of data as well as undermine confidentiality. These pitfalls must be avoided. Lastly, the financial ramifications of these new technologies must not be overlooked.


High fat feeding and dietary L-arginine supplementation differentially regulate gene expression in rat white adipose tissue.
Dietary L-arginine (Arg) supplementation reduces white-fat gain in diet-induced obese rats but the underlying mechanisms are unknown. This study tested the hypothesis that Arg treatment affects expression of genes related to lipid metabolism in adipose tissue. Four-week-old male Sprague-Dawley rats were fed a low-fat (LF) or high-fat (HF) diet for 15 weeks. Thereafter, lean or obese rats continued to be fed their same respective diets and received drinking water containing 1.51% Arg-HCl or 2.55% L: -alanine (isonitrogenous control). After 12 weeks of Arg supplementation, rats were euthanized to obtain retroperitoneal adipose tissue for analyzing global changes in gene expression by microarray. The results were confirmed by RT-PCR analysis. HF feeding decreased mRNA levels for lipogenic enzymes, AMP-activated protein kinase, glucose transporters, heme oxygenase 3, glutathione synthetase, superoxide dismutase 3, peroxiredoxin 5, glutathione peroxidase 3, and stress-induced protein, while increasing expression of carboxypeptidase-A, peroxisome proliferator activated receptor (PPAR)-alpha, caspase 2, caveolin 3, and diacylglycerol kinase. In contrast, Arg supplementation reduced mRNA levels for fatty acid binding protein 1, glycogenin, protein phosphates 1B, caspases 1 and 2, and hepatic lipase, but increased expression of PPARgamma, heme oxygenase 3, glutathione synthetase, insulin-like growth factor II, sphingosine-1-phosphate receptor, and stress-induced protein. Biochemical analysis revealed oxidative stress in white adipose tissue of HF-fed rats, which was prevented by Arg supplementation. Collectively, these results indicate that HF diet and Arg supplementation differentially regulate gene expression to affect energy-substrate oxidation, redox state, fat accretion, and adipocyte differentiation in adipose tissue. Our findings provide a molecular mechanism to explain a beneficial effect of Arg on ameliorating diet-induced obesity in mammals.


Femtosecond laser-assisted posterior capsulotomy for the treatment of capsular block syndrome.
We present a novel use of femtosecond laser to treat capsular block syndrome (CBS) in a patient with dense opaque capsular block, who presented 16 years postcataract surgery. The extensive posterior capsular distension and densely opaque, milky fluid trapped behind the intraocular lens (IOL) prevented the use of neodymium-doped yttrium aluminum garnet (Nd: YAG) laser posterior capsulotomy as primary treatment. Intra-operative optical coherence tomography enabled visualization of the posterior capsule and iris hooks were used to increase the pupillary diameter to enable femtosecond laser-assisted posterior capsulotomy to be performed in a minimally invasive technique. CBS was relieved successfully and Nd: YAG laser performed subsequently to remove residual posterior capsule opacification safely and with good visual outcomes. This method avoids risks associated with posterior vitrectomies and compromised IOL stability from inadvertent capsular bag damage, and adds to the expanding uses of femtosecond laser technology.


Continuous positive airway pressure titration for obstructive sleep apnoea: automatic versus manual titration.
Manual laboratory continuous positive airway pressure (CPAP) titration for obstructive sleep apnoea (OSA) is costly, time intensive and delays access to treatment. Automatic positive airway pressure (APAP) titration has the potential to reduce cost and improve access to treatment. The aim of this study was to assess the clinical efficacy and costs of APAP titration compared with manual titration in moderate-severe OSA. Patients with moderate-severe OSA (apnoea/hypopnoea index >15 and Epworth Sleepiness Score > or = 8) who were free of co-morbidities that could impair APAP titration were eligible. 249 participants were randomised to manual titration, home APAP or laboratory APAP titration to determine a fixed pressure for CPAP. Clinical and direct cost outcomes were assessed after 4 weeks of treatment. Average nightly CPAP use, subjective sleepiness, SF36 quality of life, Trails A and B cognitive function and polysomnographic outcomes were similar among the per-protocol groups. Non-hypertensive patients had a lower resting heart rate (and greater reduction in heart rate) at 4 weeks after laboratory APAP titration compared with home APAP titration. Costs per patient were highest in manual (AU$817.84), followed by laboratory (AU$647.56) and home (AU$132.09) APAP titration. An intention-to-treat analysis confirmed the effectiveness of APAP titration compared with manual titration in the standard clinical setting. Among patients with moderate-severe OSA without serious co-morbidities, outcomes at 1 month indicate that APAP titration is more cost-effective than manual laboratory titration to determine an appropriate pressure for CPAP for long-term use; with the largest savings occurring in the home APAP patients.


HLA-B*27 and Ankylosing Spondylitis: 50 Years of Insights and Discoveries.
To commemorate the 50th anniversary of the groundbreaking discovery of a remarkably strong association between HLA-B*27 and ankylosing spondylitis (AS). In addition to HLA-B*27, more than 116 other recognized genetic risk variants have been identified, while epigenetic factors largely remain unexplored in this context. Among patients with AS who carry the HLA-B*27 gene, clonally expanded CD8 + T cells can be found in their bloodstream and within inflamed tissues. Moreover, the α and β chain motifs of these T-cell receptors demonstrate a distinct affinity for certain self- and microbial-derived peptides, leading to an autoimmune response that ultimately results in the onset of the disease. These distinctive peptide-binding and presentation characteristics are a hallmark of the disease-associated HLA-B*27:05 subtype but are absent in HLA-B*27:09, a subtype not associated with the disease, differing by only a single amino acid. This discovery represents a significant advancement in unraveling the 50-year-old puzzle of how HLA-B*27 contributes to the development of AS. These findings will significantly accelerate the process of identifying peptides, both self- and microbial-derived, that instigate autoimmunity. This, in return, will pave the way for the development of more accurate and effective targeted treatments. Moreover, the discovery of improved biomarkers, in conjunction with the emerging technology of electric field molecular fingerprinting, has the potential to greatly bolster early diagnosis capabilities. A very recently published groundbreak paper underscores the remarkable effectiveness of targeting and eliminating disease-causing T cells in a HLA-B*27 patients with AS. This pivotal advancement not only signifies a paradigm shift but also bolsters the potential for preventing the disease in individuals carrying high-risk genetic variants.


Opportunities Missed: A Cross-Sectional Survey of the Provision of Smoking Cessation Care to Pregnant Women by Australian General Practitioners and Obstetricians.
Similar to other high-income countries, smoking rates in pregnancy can be high in specific vulnerable groups in Australia. Several clinical guidelines exist, including the 5A's (Ask, Advice, Assess, Assist, and Arrange), ABCD (Ask, Brief advice, Cessation, and Discuss), and AAR (Ask, Advice, and Refer). There is lack of data on provision of smoking cessation care (SCC) of Australian General Practitioners (GPs) and Obstetricians. A cross-sectional survey explored the provision of SCC, barriers and enablers using the Theoretical Domains Framework, and the associations between them. Two samples were invited: (1) GPs and Obstetricians from a college database (n = 5571); (2) GPs from a special interest group for Indigenous health (n = 500). Dimension reduction for the Theoretical Domains Framework was achieved with factor analysis. Logistic regression was carried out for performing all the 5A's and the AAR. Performing all of the 5A's, ABCD, and AAR "often and always" was reported by 19.9%, 15.6%, and 49.2% respectively. "Internal influences" (such as confidence in counselling) were associated with higher performance of the 5A's (Adjusted OR 2.69 (95% CI 1.5, 4.8), p < .001), whereas "External influences" (such as workplace routine) were associated with higher performance of AAR (Adjusted OR 1.7 (95% CI 1, 2.8), p = .035). Performance in providing SCC to pregnant women is low among Australian GPs and Obstetricians. Training clinicians should focus on improving internal influences such as confidence and optimism. The AAR may be easier to implement, and interventions at the service level should focus on ensuring easy, effective, and acceptable referral mechanisms are in place. Improving provision of the 5A's approach should focus on the individual level, including better training for GPs and Obstetricians, designed to improve specific "internal" barriers such as confidence in counselling and optimism. The AAR may be easier to implement in view of the higher overall performance of this approach. Interventions on a more systemic level need to ensure easy, effective, and acceptable referral mechanisms are in place. More research is needed specifically on the acceptability of the Quitline for pregnant women, both Indigenous and non-Indigenous.


Ubiquitination and SUMOylation of Amyloid and Amyloid-like Proteins in Health and Disease.
Post-translational modifications (PTMs) play important roles in altering the structure and function of proteins. In this article, we focus on ubiquitination and SUMOylation of amyloidogenic proteins. We discuss the functional contributions of PTMs on proteins involved in amyloid-related diseases as well as the aberrant PTM signatures of the disease agents. In addition, we extend our discussion to the nascent field of functional amyloids, a subclass of amyloids that perform physiological functions. Here, we present examples from mammals and yeast to gain insight into physiological regulation of amyloid-like proteins.


Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease.
Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders.


Detection of Bacillus globigii spores using a Fourier transform infrared-attenuated total reflection method.
The use of an alumina-coated ZnSe internal reflection element (IRE) to detect spores by attenuated total reflection infrared spectroscopy (FTIR-ATR) was investigated. Two methods for coating the IRE with alumina are described. It is shown that the adsorption proceeds through an interaction of the carboxylate groups on Bacillus globigii (BG) and positively charged sites on the alumina. The amount adsorbed is highly dependent on solution pH and passes through a maximum value near pH 5, which is dictated by the charge density on the spores and the charge density on the alumina surface. Furthermore, it is shown that lateral-lateral repulsion between the spores limits the maximum adsorbed amount, giving rise to a detection limit of 10(7) spores per cm2 of the IRE.


Fractionation and polypeptide analysis of phloem tissue of Pinus sabiniana Dougl.
The polypeptide complement of phloem tissue and xylem tissue in trunks of Pinus sabiniana collected in spring was compared by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Two polypeptides at 24 and 25 kdalton represented over 20% of the total polypeptide complement of the phloem but were absent in xylem tissue. In an attempt to relate the 24- and 25-kdalton phloem polypeptides (PPP) to cellular constitutents, phloem tissue was fractionated by sequential differential and density-gradient centrifugation utilizing the PPP as biochemical markers. In borate buffer, the fractions containing PPP pelleted at less than 12,000 g and were subsequently enriched in sucrose gradients at densities greater than 1.22. However, the cytological entities containing the PPP were almost completely dissociated when phloem tissue was processed with a 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) buffer containing mercaptoethanol, and the PPP were then found in the supernatant of material spun at 45,000 g for 3 h. In electron micrographs of PPP-enriched fractions processed with borate buffer an assortment of structures that are associated with mature sieve cells of pine were found, including filaments, cup-shaped arrays, polyhedral crystals, and paracrystalline bodies. Similar structures were not found in identically processed xylem tissue or in phloem tissue processed with the Tris buffer. It is suggested that the PPP represent a proteinaceous component common to these phloem structures.


Prediction of the Future Need for Institutional Care in Finnish Older People: A Comparison of Two Birth Cohorts.
More recent birth cohorts of older people have better physical and cognitive status than earlier cohorts. As such, this could be expected to diminish the need for institutional care. The prediction of the future need for institutional care provides essential information for the planning and delivery of future care and social services as well as the resources needed. To predict the future need for institutional care among older Finnish people born in 1940. Representative samples of home-dwelling 70-year-olds from Turku, Finland were examined with similar methods in 1991 (those born in 1920) (n = 1,032) and in 2011 (those born in 1940) (n = 956). Predictors of institutionalization rates from the earlier 1920 cohort, together with data of sociodemographic factors, health, psychosocial and physical status, the need for help, and health behavior, were used to predict the future institutionalization rate among the 1940 cohort in this study using Cox regression models. Health as well as psychosocial and physical status were significantly better in the 1940 cohort compared to the earlier cohort. In the 1940 cohort, the predicted rates of institutionalization were 1.8, 10.4, and 26.0% at the ages of 80 (year 2020), 85 (year 2025), and 90 years (year 2030), respectively. At every age (80, 85, and 90 years), the predicted rates of institutionalization by Mini-Mental State Examination (MMSE) were about two-fold among those with MMSE scores 18-26 (3.0-38.8%) compared to those with scores 27-30 (1.6-23.7%) and those with a body mass index (BMI) <25 (2.5-34.3%) compared to those with a BMI of 25-29.9 (1.4-20.9%), and about three-fold among participants with several falls (5.3-57.0%) compared to participants with no falls (1.5-23.1%). The 1940 cohort performed better in health as well as psychosocial and physical status than the 1920 cohort. Nevertheless, the predicted rates of future need for institutional care were high, especially at the ages of 85 and 90 years, among those with a lowered cognitive or physical status.


Advances in nonhuman primate alcohol abuse and alcoholism research.
Advances in our understanding of the biological basis of alcohol abuse and alcoholism and the development of prevention and therapeutic intervention require appropriate animal models. Nonhuman primates are important to the study of complex biomedical disease processes. Genetic, anatomical, physiological, and behavioral similarities to humans offer unique opportunities for translational research along with the advantage of a degree of experimental control that is not possible in human studies. The purpose of this review is to outline the approaches taken with nonhuman primates as subjects in alcohol research and to highlight our current understanding of data on organismal variables that can be uniquely studied in these complex organisms. We review literature on alcohol self-administration to provide an integrative framework for discussion of progress in 2 important areas of research. Designs that incorporate self-administration provide a context for studying excessive alcohol consumption, including the organismal and environmental factors that influence risk for heavy drinking. We then review the use of monkeys to identify aspects of adverse biomedical consequences that follow excessive alcohol consumption. One of the primary conclusions to be drawn from this review is that nonhuman primates are a central part of the translational bridge in alcohol research, providing powerful and unique opportunities for experimental work that can address the biomedical complexities of alcohol abuse and alcoholism.


Quantification of patellar tendon reflex using portable mechanomyography and electromyography devices.
Deep tendon reflexes are one of the main components of the clinical nervous system examinations. These assessments are inexpensive and quick. However, evaluation can be subjective and qualitative. This study aimed to objectively evaluate hyperreflexia of the patellar tendon reflex using portable mechanomyography (MMG) and electromyography (EMG) devices. This study included 10 preoperative patients (20 legs) who had a pathology that could cause bilateral patellar tendon hyperreflexia and 12 healthy volunteers (24 legs) with no prior history of neurological disorders. We attached MMG/EMG sensors onto the quadriceps and tapped the patellar tendon with maximal and constant force. Our results showed a significantly high amplitude of the root mean square (RMS) and low frequency of the mean power frequency (MPF) in the rectus femoris, vastus medialis, and vastus lateralis muscles in both EMG and MMG with both maximal and constant force. Especially in the patients with cervical and thoracic myelopathy, the receiver operating characteristic (ROC) curve for diagnosing hyperreflexia of the patellar tendon showed a moderate to very high area under the curve for all EMG-RMS, EMG-MPF, MMG-RMS, and MMG-MPF values. The use of EMG and MMG for objectively quantifying the patellar tendon reflex is simple and desirable for future clinical applications and could help diagnose neurological disorders.


Spinal Cord Resting State Activity in Individuals With Fibromyalgia Who Take Opioids.
Chronic pain coincides with myriad functional alterations throughout the brain and spinal cord. While spinal cord mechanisms of chronic pain have been extensively characterized in animal models and in vitro, to date, research in patients with chronic pain has focused only very minimally on the spinal cord. Previously, spinal cord functional magnetic resonance imaging (fMRI) identified regional alterations in spinal cord activity in patients (who were not taking opioids) with fibromyalgia, a chronic pain condition. Here, in patients with fibromyalgia who take opioids (N = 15), we compared spinal cord resting-state fMRI data vs. patients with fibromyalgia not taking opioids (N = 15) and healthy controls (N = 14). We hypothesized that the opioid (vs. non-opioid) patient group would show greater regional alterations in spinal cord activity (i.e., the amplitude of low frequency fluctuations or ALFF, a measure of regional spinal cord activity). However, we found that regional spinal cord activity in the opioid group was more similar to healthy controls, while regional spinal cord activity in the non-opioid group showed more pronounced differences (i.e., ventral increases and dorsal decreases in regional ALFF) vs. healthy controls. Across patient groups, self-reported fatigue correlated with regional differences in spinal cord activity. Additionally, spinal cord functional connectivity and graph metrics did not differ among groups. Our findings suggest that, contrary to our main hypothesis, patients with fibromyalgia who take opioids do not have greater alterations in regional spinal cord activity. Thus, regional spinal cord activity may be less imbalanced in patients taking opioids compared to patients not taking opioids.


Antibacterial activity of AM-1155 against penicillin-resistant Streptococcus pneumoniae.
AM-1155, a novel fluoroquinolone, exhibited potent activity against Streptococcus pneumoniae, including penicillin-resistant strains; the MIC90 for 48 clinical isolates was 0.25 mg/L. The antibacterial activity of AM-1155 against S. pneumoniae was higher than that of levofloxacin (MIC90 1 mg/L) and comparable with that of sparfloxacin. The MIC90s of penicillin G and erythromycin were 2 and > 4 mg/L, respectively. AM-1155 showed no cross-resistance to penicillin or erythromycin. For experimental murine pneumonia with S. pneumoniae intermediately resistant to penicillin, oral administration of AM-1155 showed efficacy higher than that of levofloxacin and equal to that of sparfloxacin. The efficacy of AM-1155 was also equal to that of subcutaneous penicillin G administration at the same dosage.


A Non-Canonical Cortico-Amygdala Inhibitory Loop.
Discriminating between auditory signals of different affective value is critical for the survival and success of social interaction of an individual. Anatomical, electrophysiological, imaging, and optogenetics approaches have established that the auditory cortex (AC) by providing auditory information to the lateral amygdala (LA) via long-range excitatory glutamatergic projections has an impact on sound-driven aversive/fear behavior. Here we test the hypothesis that the LA also receives GABAergic projections from the cortex. We addressed this fundamental question by taking advantage of optogenetics, anatomical, and electrophysiology approaches and directly examining the functional effects of cortical GABAergic inputs to LA neurons of the mouse (male/female) AC. We found that the cortex, via cortico-lateral-amygdala somatostatin neurons (CLA-SOM), has a direct inhibitory influence on the output of the LA principal neurons. Our results define a CLA long-range inhibitory circuit (CLA-SOM inhibitory projections → LA principal neurons) underlying the control of spike timing/generation in LA and LA-AC projecting neurons, and attributes a specific function to a genetically defined type of cortical long-range GABAergic neurons in CLA communication.SIGNIFICANCE STATEMENT It is very well established that cortical auditory inputs to the lateral amygdala are exclusively excitatory and that cortico-amygdala neuronal activity has been shown to be involved in sound-driven aversive/fear behavior. Here, for the first time, we show that the lateral amygdala receives long-range GABAergic projection from the auditory cortex and these form direct monosynaptic inhibitory connections onto lateral amygdala principal neurons. Our results define a cellular basis for direct inhibitory communication from auditory cortex to the lateral amygdala, suggesting that the timing and ratio of excitation and inhibition, two opposing forces in the mammalian cerebral cortex, can dynamically affect the output of the lateral amygdala, providing a general mechanism for fear/aversive behavior driven by auditory stimuli.


Interstitial cells of Cajal: pacemaker cells of the pancreatic duct?
Ramon y Cajal discovered interstitial cells in the pancreas associated with intrinsic nerves. It was our aim to provide evidence for or against the hypothesis that the pancreatic duct harbors interstitial cells of Cajal (ICCs) that may function as pacemakers for duct motility. We used immunohistochemistry using c-Kit as the ICC marker and protein gene product 9.5 for nerves. Electron microscopy further characterized the cells and their interrelationships. c-Kit-positive cells were associated with smooth muscle cells and nerve fibers of the duct wall and were rich in mitochondria, rough endoplasmic reticulum, and intermediate filaments; they possessed occasional caveolae and had a discontinuous basal lamina. They were connected by small gap junctions to each other and to smooth muscle cells. c-Kit-positive cells around large blood vessels were similar. c-Kit-positive cells within acini were similar in structure but were not associated with smooth muscle cells. The c-Kit-positive cells around the main duct were identified as ICCs and have the morphological criteria to likely function as pacemaker cells for the previously observed spontaneous rhythmic pancreatic duct contractions. Interstitial cells of Cajal around the large blood vessels likely affect vessel wall rhythmicity.


Delay Analysis in Closed-Loop EEG Phase-Triggered Transcranial Magnetic Stimulation.
The recent development of closed-loop EEG phase-triggered transcranial magnetic stimulation (TMS) has advanced potential applications of adaptive neuromodulation based on the current brain state. Closed-loop TMS involves instantaneous acquisition of the EEG rhythm, timing prediction of the target phase, and triggering of TMS. However, the accuracy of EEG phase prediction algorithms is largely influenced by the system's transport delay, and their relationship is rarely considered in related work. This paper proposes a delay analysis that considers the delay of the closed-loop EEG phase-triggered TMS system as a primary factor in the validation of phase prediction algorithms. An in-silico validation using real EEG data was performed to compare the performance of commonly used algorithms. The experimental results indicate a significant influence of the total delay on the algorithm performance, and the performance ranking among algorithms varies at different levels of delay. We conclude that the delay analysis framework should be widely adopted in the design and validation of phase prediction algorithms for closed-loop EEG phase-triggered TMS systems.


Advanced Functional Tumor Imaging and Precision Nuclear Medicine Enabled by Digital PET Technologies.
The purpose of this article is to provide a brief overview of the background, basic principles, technological evolution, clinical capabilities, and future directions for functional tumor imaging as PET evolves from the conventional photomultiplier tube-based platform into a fully digital detector acquisition platform. The recent introduction of solid-state digital photon counting PET detector is the latest evolution of clinical PET which enables faster time-of-flight timing resolution that leads to more precise localization of the annihilation events and further contributes to reduction in partial volume and thus makes high definition and ultrahigh definition PET imaging feasible with current standard acquisition procedures. The technological advances of digital PET can be further leveraged by optimizing many of the acquisition and reconstruction methodologies to achieve faster image acquisition to improve cancer patient throughput, lower patient dose in accordance with ALARA, and improved quantitative accuracy to enable biomarker capability. Digital PET technology will advance molecular imaging capabilities beyond oncology and enable Precision Nuclear Medicine.


LncRNA NEAT1 Promotes the Progression of Gastric Cancer Through Modifying the miR-1224-5p/RSF1 Signaling Axis.
The therapy of patients with advanced phase gastric cancer is still a huge threat, with extremely imperfect therapies authorized. Even if the amassed indications have validated the significance of lncRNA in gastric cancer, few understandings are stated concerning nuclear paraspeckle assembly transcript 1 (NEAT1) practical functions and molecular mechanisms. In this research, the expression of NEAT1 and miR-1224-5p in gastric cancer tissues was measured by qRT-PCR analysis, and the expression of remodeling and spacing factor 1 (RSF1) was measured by IHC assay. Then, the bioinformatics prediction software ENCORI was applied to envisage the assumed binding sites. The monitoring roles of NEAT1 or miR-1224-5p on the cell proliferation and migration capacity were verified by CCK-8, wound healing and transwell assay, correspondingly. The interactions among NEAT1, miR-1224-5p and RSF1 were investigated via luciferase analysis. Our findings revealed high expression levels of NEAT1, RSF1 and a decreased expression level of miR-1224-5p in gastric cancer. Upregulation of NEAT1 or knockdown of miR-1224-5p elevated gastric cancer cell proliferation, and migration. Bioinformatics and luciferase analyses simplified that NEAT1 directly cooperated with miR-1224-5p to weaken miR-1224-5p binding to the RSF1 3'-UTR region. Likewise, the mechanical inquiries ratified that initiation of the miR-1224-5p/RSF1 regulatory loop by miR-1224-5p knockdown or overexpressed RSF1 validated the functions of NEAT1 in endorsing gastric cancer cell malignancy. Our research initially validated that NEAT1 may regulate the expression of RSF1 competitive sponge to miR-1224-5p, contributed to the supervision of gastric cancer evolution, which exposed new brightness for diagnosis and therapy of gastric cancer.


Health utility scores in Alzheimer's disease: differences based on calculation with American and Canadian preference weights.
Health utility scores quantify health-related quality-of-life (HRQOL) in Alzheimer's disease (AD). These scores are calculated by using preference weights derived from general population samples. We recruited persons with AD and their primary informal caregivers and examined differences in health utility scores calculated by using two sets of published preference weights. We recruited participants from nine clinics across Canada and administered the EuroQol five-dimensional (EQ-5D) questionnaire HRQOL instrument. We converted participants' EQ-5D questionnaire responses into two sets of health utility scores by using US and Canadian preference weights. We assessed agreement between sets by using the intraclass correlation coefficient. Bland-Altman plots depicted individual-level differences between sets. For 216 persons with AD and their caregivers, mean health utility scores were higher when calculated with US instead of Canadian preference weights (P < 0.0001). The intraclass correlation coefficient (95% CI) was 0.79 (0.05-0.93) in the persons with AD group and 0.83 (0.30-0.94) in the caregiver group. Ninety-five percent of the individual differences in utility score fell between -0.16 and 0.03 for persons with AD and -0.15 and 0.05 for caregivers. Forty-three percent of these differences exceeded a minimum clinically important threshold of 0.074. In AD studies, researchers should calculate health utility scores by using preference weights obtained in the general population of their country of interest. Using weights from other countries' populations could bias the utilities and adversely affect the results of economic evaluations of AD treatments.


Time-of-Flight Measurements as a Possible Method to Observe Anyonic Statistics.
We propose a standard time-of-flight experiment as a method for observing the anyonic statistics of quasiholes in a fractional quantum Hall state of ultracold atoms. The quasihole states can be stably prepared by pinning the quasiholes with localized potentials and a measurement of the mean square radius of the freely expanding cloud, which is related to the average total angular momentum of the initial state, offers direct signatures of the statistical phase. Our proposed method is validated by Monte Carlo calculations for ν=1/2 and 1/3 fractional quantum Hall liquids containing a realistic number of particles. Extensions to quantum Hall liquids of light and to non-Abelian anyons are briefly discussed.


Description of an early cognitive behavioral intervention (UPFRONT-intervention) following mild traumatic brain injury to prevent persistent complaints and facilitate return to work.
Many patients with mild traumatic brain injury do not fully return to work owing to persistent posttraumatic complaints. Research suggests that preventing chronic complaints might be prevented by giving cognitive behavioral therapy early after injury. Therefore, a new cognitive behavioral intervention (UPFRONT-intervention) was developed to not only prevent chronic complaints but to also establish a more successful return to work. The intervention is currently being evaluated in a multicenter randomized controlled trial design (trial number ISRCTN86191894) in mild traumatic brain injury patients who are at-risk of negative outcomes (patients with high numbers of early complaints). Two case examples are presented to demonstrate the application of the intervention. Psychological factors, like cognitive appraisal and coping, play an important role in the persistence of posttraumatic complaints. Some patients are less able to adapt and thus to cope with the injury and its initial consequences than others. Dealing with the injury in a passive, avoidant way, focusing on negative feelings, will hamper recovery and is therefore a valuable target for an intervention. Theory into practice: The UPFRONT intervention is a short cognitive behavioral therapy intervention for patients that are at-risk of developing persistent posttraumatic complaints. Patients will undergo five sessions of cognitive behavioral therapy within 4-10 weeks after trauma. The intervention aims to enhance patients' feeling of competency of dealing with the consequences of mild traumatic brain injury by providing psycho-education, identifying and challenging unrealistic illness perceptions and improving coping style (decreasing maladaptive coping and enhancing adaptive coping).


[Web-ring of sites for pathologists in the internet: a computer-mediated communication environment].
The recently developed Web-ring of pathology-related Web-sites has transformed computer-mediated communications for Russian-speaking pathologists. Though the pathologists may be geographically dispersed, the network provides a complex of asynchronous and synchronous conferences for the purposes of diagnosis, consultations, education, communication, and collaboration in the field of pathology. This paper describes approaches to be used by participants of the pathology-related Web-ring. The approaches are analogous to the tools employed in telepathology and digital microscopy. One of the novel methodologies is the use of Web-based conferencing systems, in which the whole slide digital images of tissue microarrays were jointly reviewed online by pathologists at distant locations. By using ImageScope (Aperio Technologies) and WebEx connect desktop management technology, they shared presentations and images and communicated in realtime. In this manner, the Web-based forums and conferences will be a powerful addition to a telepathology.


A common cause for nystagmus in different congenital stationary night blindness mouse models.
In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e. nystagmus. Given the specific expression of mGluR6 and Cav 1.4 in the photoreceptor to bipolar cell synapses, as well as their clinical association with CSNB, we hypothesize that Grm6nob3 and Cav 1.4-KO mutants show, like the Nyxnob mouse, oscillations in both their RGC activity and eye movements. Using multi-electrode array recordings of RGCs and measurements of the eye movements, we demonstrate that Grm6nob3 and Cav 1.4-KO mice also show oscillations of their RGCs as well as a nystagmus. Interestingly, the preferred frequencies of RGC activity as well as the eye movement oscillations of the Grm6nob3 , Cav 1.4-KO and Nyxnob mice differ among mutants, but the neuronal activity and eye movement behaviour within a strain remain aligned in the same frequency domain. Model simulations indicate that mutations affecting the photoreceptor-bipolar cell synapse can form a common cause of the nystagmus of CSNB by driving oscillations in RGCs via AII amacrine cells. KEY POINTS: In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), their oscillatory eye movements (i.e. nystagmus) are caused by synchronous oscillating retinal ganglion cells. Here we show that the same mechanism applies for two other CSNB mouse models - Grm6nob3 and Cav 1.4-KO mice. We propose that the retinal ganglion cell oscillations originate in the AII amacrine cells. Model simulations show that by only changing the input to ON-bipolar cells, all phenotypical differences between the various genetic mouse models can be reproduced.


Properties of the water to boron nitride interaction: From zero to two dimensions with benchmark accuracy.
Molecular adsorption on surfaces plays an important part in catalysis, corrosion, desalination, and various other processes that are relevant to industry and in nature. As a complement to experiments, accurate adsorption energies can be obtained using various sophisticated electronic structure methods that can now be applied to periodic systems. The adsorption energy of water on boron nitride substrates, going from zero to 2-dimensional periodicity, is particularly interesting as it calls for an accurate treatment of polarizable electrostatics and dispersion interactions, as well as posing a practical challenge to experiments and electronic structure methods. Here, we present reference adsorption energies, static polarizabilities, and dynamic polarizabilities, for water on BN substrates of varying size and dimension. Adsorption energies are computed with coupled cluster theory, fixed-node quantum Monte Carlo (FNQMC), the random phase approximation, and second order Møller-Plesset theory. These wavefunction based correlated methods are found to agree in molecular as well as periodic systems. The best estimate of the water/h-BN adsorption energy is -107±7 meV from FNQMC. In addition, the water adsorption energy on the BN substrates could be expected to grow monotonically with the size of the substrate due to increased dispersion interactions, but interestingly, this is not the case here. This peculiar finding is explained using the static polarizabilities and molecular dispersion coefficients of the systems, as computed from time-dependent density functional theory (DFT). Dynamic as well as static polarizabilities are found to be highly anisotropic in these systems. In addition, the many-body dispersion method in DFT emerges as a particularly useful estimation of finite size effects for other expensive, many-body wavefunction based methods.


Primary intracranial myxoid chondrosarcoma: report of a case and review of the literature.
The authors present a case of primary intracranial extraosseous myxoid chondrosarcoma without any attachment to the cranium or the meninges. The clinical and radiological findings of the primary intraparenchymal tumor are described with a review of the literature concerning cranial and intracranial myxoid chondrosarcoma.


Early Mechanisms of Chemoresistance in Retinoblastoma.
Retinoblastoma is the most common eye cancer in children and is fatal if left untreated. Over the past three decades, chemotherapy has become the mainstay of eye-sparing treatment. Nevertheless, chemoresistance continues to represent a major challenge leading to ocular and systemic toxicity, vision loss, and treatment failure. Unfortunately, the mechanisms leading to chemoresistance remain incompletely understood. Here, we engineered low-passage human retinoblastoma cells to study the early molecular mechanisms leading to resistance to carboplatin, one of the most widely used agents for treating retinoblastoma. Using single-cell next-generation RNA sequencing (scRNA-seq) and single-cell barcoding technologies, we found that carboplatin induced rapid transcriptomic reprogramming associated with the upregulation of PI3K-AKT pathway targets, including ABC transporters and metabolic regulators. Several of these targets are amenable to pharmacologic inhibition, which may reduce the emergence of chemoresistance. We provide evidence to support this hypothesis using a third-generation inhibitor of the ABCB1 transporter.


[Epinephrine, a double-edged sword?]
Although epinephrine has been a cornerstone in resuscitation medicine for over 60 years, its use had never been thoroughly studied until recently, probably because the benefits of epinephrine seemed so obvious. The vasoconstriction of arterioles mediated by α-adrenergic receptors, leading to a higher coronary blood flow during chest compression, which in turn leads to a recovery of the spontaneous circulation, was reason enough for epinephrine to have been given its prominent role. A number of studies in the past 10 years, both randomized trials and large observational studies, have failed to show improved outcomes in patients with out-of-hospital cardiac arrest who had received epinephrine. The PARAMEDIC2 trial was published recently, with 4,015 patients receiving parenteral epinephrine and 3,999 receiving placebo. This study showed a survival benefit for epinephrine; however, there was no significant survival with good neurological outcome. The reasons for this may be related to a disturbed cerebral microcirculation and decreased blood flow in the carotid artery, and to epinephrine-mediated platelet activation, with an increased risk of thrombosis.


Cell-sorting in aggregates of Dictyostelium discoideum.
When Dictyostelium cells are induced to develop between a coverslip and a layer of agarose, they aggregate normally into groups containing up to a thousand cells but are then constrained to form disks only a few cells thick that appear to be equivalent to the three-dimensional mounds formed on top of agarose. Such vertically restricted aggregates frequently develop into elongated motile structures, the flattened equivalent of three-dimensional slugs. The advantage of using this system is that the restricted z-dimension enables direct microscopic visualization of most of the cells in the developing structure. We have used time lapse digital fluorescence microscopy of Dictyostelium strains expressing green fluorescent protein (GFP) under the control of either prestalk or prespore specific promoters to follow cell sorting in these flattened mounds. We find that prestalk and prespore cells expressing GFP arise randomly in early aggregates and then rotate rapidly around the disk mixed with the other cell type. After a few hours, the cell types sort out by a process which involves striking changes in relative cell movement. Once sorted, the cell types move independently of each other showing very little heterotypic adhesion. When a group of prestalk cells reaches the edge of the disk, it moves out and is followed by the prespore cell mass. We suggest that sorting may result from cell type specific changes in adhesion and the consequent disruption of movement in the files of cells that are held together by end-to-end adhesion.


Does preoperative B-type natriuretic peptide better predict adverse outcome and prolonged length of stay than the standard European System for Cardiac Operative Risk Evaluation after cardiac surgery?
Although B-type natriuretic peptide (BNP) strongly predicts cardiac morbidity and mortality, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) has a modest predictive value to identify a composite operative risk after cardiac surgery. The authors tested the hypothesis that a single preoperative BNP measurement would be superior to standard EuroSCORE in predicting composite adverse outcomes after cardiac surgery. A prospective observational study. A teaching university hospital. Two hundred eight adult patients. Conventional cardiac surgery with cardiopulmonary bypass. The preoperative additive EuroSCORE and BNP measurement were performed in all patients. Postoperative nonfatal major adverse cardiac events (malignant ventricular arrhythmia, myocardial infarction, and cardiac dysfunction), all-cause mortality, and prolonged lengths of stay were chosen as study endpoints. Predictive abilities of both EuroSCORE and BNP were assessed using logistic regression and compared with receiver operating characteristic (ROC) curves. Thirty-six (17%, 95% confidence interval [CI], 12%-22%) patients experienced 49 events over the study period. The areas under the ROC curves assessing the utility of EuroSCORE and BNP in predicting adverse outcome and prolonged in-hospital stay were 0.59 (95% CI, 0.48-0.69) versus 0.76 (95% CI, 0.68-0.85; p < 0.001) and 0.65 (95% CI, 0.57-0.74) versus 0.71 (95% CI, 0.63-0.80; p = 0.147), respectively. Using logistic regression, BNP considered as a dichotomized variable was the only independent predictor of adverse cardiac outcome (adjusted odds ratio = 10.7; 95% CI, 4.1-27.8; p < 0.001). Preoperative BNP measurement is a strong, independent, and more accurate predictor of adverse outcome than EuroSCORE in patients undergoing cardiac surgery. BNP could be considered as a simple and objective tool for the detection of high-risk patients after cardiac surgery.


Venous hemodynamic changes after external banding valvuloplasty with varicosectomy in the treatment of primary varicose veins.
To evaluate venous hemodynamic changes after an external banding valvuloplasty in the treatment of primary varicose veins with saphenofemoral incompetence. From June 1996 to December 1997, 79 limbs (10 male and 69 female, age 20-57 years) were treated for primary saphenofemoral incompetence by external banding valvuloplasty. Tightening of the banding was accomplished using a polyester-tailored mesh to narrow the terminal and/or subterminal valve areas of the dilated greater saphenous vein (GSV), same size as its minimum diameter during spasm. Evaluation was done through a pre- and postoperative color-flow duplex scanning and an air-plethysmography (APG). Sixty-three limbs (79.7%) remained patent and were competent. Fourteen limbs (17.7%) remained patent but showed reflux. Two limbs (2.5%) had thrombus within the GSV after surgery. The diameter of GSV of mid-thigh was 6.7+/-1.6 mm preoperatively and 4.1+/-0.9 mm postoperatively (p-value=7.04E-10). Reduction of the diameter was 61.4+/-12.3%. Venous volume was 136.1+/-59.8 ml preoperatively and 103.5+/-39.8 ml postoperatively (p-value=1.6E-20). Reduction of the venous volume was 12.9+/-17.0%. Venous filling index (VFI) was 6.6+11.3 ml/sec preoperatively and 1.9+/-3.3 ml/sec postoperatively (p-value=1.2E-10). Reduction of the VFI was 55.0+/-29.1%. Ejection fraction (EF) was 48.9+/-13.8% preoperatively and 60.1+/-17.2% postoperatively (p-value=2.6E-17). Increase of EF was 29.4+/-43.5%. The residual volume fraction (RVF) was 42.1+/-13.9% preoperatively and 30.2+/-14.5% postoperatively (p-value=5.6E-19). Reduction of RVF was 17.6+/-43.6%. Early evaluation of saphenofemoral external banding valvuloplasty confirms the satisfactory patency and improvement in venous hemodynamics. Long-term evaluation is clearly indicated but the early safety and efficacy of the procedure have been confirmed.


Thermostable allergens in canned fish: Evaluating risks for fish allergy.
Major fish allergens, including parvalbumin (PV), are heat stable and can withstand extensive cooking processes. Thus, the management of fish allergy generally relies on complete avoidance. Fish-allergic patients may be advised to consume canned fish, as some fish-allergic individuals have reported tolerance to canned fish. However, the safety of consuming canned fish has not been evaluated with comprehensive immunological and molecular analysis of canned fish products. We characterized the in vitro immunoreactivity of serum obtained from fish-allergic subjects to canned fish. Seventeen canned fish products (salmon n = 8; tuna n = 7; sardine n = 2) were assessed for the content and integrity of PV using allergen-specific antibodies. Subsequently, the sIgE binding of five selected products was evaluated for individual fish-allergic patients (n = 53). Finally, sIgE-binding proteins were identified by mass spectrometry. The canned fish showed a markedly reduced PV content and binding to PV-specific antibodies compared with conventionally cooked fish. However, PV and other heat-stable fish allergens, including tropomyosin and collagen, still maintained their sIgE-binding capacity. Of 53 patients, 66% showed sIgE binding to canned fish proteins. The canned sardine contained proteins bound to sIgE from 51% of patients, followed by canned salmon (43%-45%) and tuna (8%-17%). PV was the major allergen in canned salmon and sardine. Tropomyosin and/or collagen also showed sIgE binding. We showed that canned fish products may not be safe for all fish-allergic patients. Canned fish products should only be considered into the diet of individuals with fish allergy, after detailed evaluation which may include in vitro diagnostics to various heat-stable fish allergens and food challenge conducted in suitable environments.


The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.
Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.


[Characteristics of the effect of different cardiovasotropic preparations on the contractility of separate sections of the myocardium in acute coronary occlusion].
In acute experiments on cats, the effect of nitroglycerin (0,5 mg/kg), obsidan (0,5 mg/kg) and adrenaline (0,005 mg/kg) on the contractility of various segments of the myocardium in acute ischemia state was studied. It is shown that nitroglycerin increases the contractility of the border zone and decreases the compensatory hyperfunction of intact myocardial zones. Obsidan reduces the contractility of all the zones and adrenaline suppresses the border zone contractility despite the marked growth of contractile function of the intact zones and of the heart on the whole. The central-ischemic myocardial zone responded weakly to drug action.


Effects of paraventricular lesions on stimulated ACTH release and CRF in stalk-median eminence of the rat.
The effects of destroying the paraventricular nucleus (PVN) of the rat hypothalamus on pituitary-adrenal function were studied. Four days after PVN lesions were placed with a rotating knife, the basal plasma corticosterone level was normal, but the corticosterone response to electrical stimulation of the medial basal hypothalamus, surgical trauma, and ether-venesection stress was significantly inhibited. Four and 8 days after PVN lesioning and adrenalectomy, the basal plasma ACTH level was lower, and the rise of plasma ACTH level elicited by a 3-min ether inhalation was significantly smaller than in the adrenalectomized controls. Corticotropin-releasing factor (CRF) activity in the stalk-median eminence extracts from PVN-lesioned rats was significantly less than in the control extracts. The weight of the adrenals was decreased by both 2 and 4 wk after PVN destruction, and 2 wk after hemiadrenalectomy, the compensatory adrenal hypertrophy was inhibited. The plasma corticosterone response to ether-venesection stress was inhibited only temporarily because it returned to normal by the end of the 4th postoperative week. The results are consistent with the hypothesis that a substantial portion of CRF-containing fibers in the stalk-median eminence region either originate from or run though the PVN or its immediate vicinity.


[Regulation of caspase activity in apoptosis].
Intracellular cysteine aspartate-specific proteases (caspases) play both signaling and effector roles in realizing the program of cell death. Caspases function as proteolytic cascades unique for each cell type and signal triggering apoptosis. All parts of the proteolytic cascades are duplicated and controlled by feedback signals. Amplification cycles between pairs of caspases (the third and the sixth, the ninth and the third, the twelfth and the sixth, and others) help multiply the initial apoptotic signal. The presence of physiological inhibitors of apoptosis that directly interact with caspases creates a multilevel regulatory network of apoptosis in cell. The caspase proteolytic cascades are also regulated by sphingolipid secondary messengers, among them ceramide, sphingosine, and their phosphates. Moreover, an association of the caspase signaling with ubiquitin-dependent proteolysis is shown in cells. In particular, the use of extracellular activators and inhibitors of caspases allows irreversible activation of apoptosis in tumor cells or the prevention of neuron death in neurodegenerative diseases.


Plugging in national networks.
National claims processing networks, now in their infancy, will dominate the market as the industry consolidates. Processors are attempting to plug in their larger networks in anticipation of an explosion in automated claims and payment activity.


Evaluation of a formulation of Bacillus subtilis for control of Phytophthora blight of bell pepper.
Phytophthora blight, caused by Phytophthora capsici, is one of the most economically significant diseases of bell pepper in the US. Over the past several decades, isolates of P. capsici exhibiting resistance to mefenoxam and other fungicides have been reported. Fungicide resistance coupled with an increased market for organically grown crops has led to interest in biological control as a disease management option. In this work, an isolate of Bacillus subtilis (AFS032321) was evaluated for control of Phytophthora blight of bell pepper in the greenhouse and field. A 28% active ingredient wettable powder formulation of the strain was applied as a soil drench at transplanting prior to inoculation. Treatment with this formulation of B. subtilis significantly reduced the area under the disease progress curve (AUDPC) by up to 52% compared to untreated control plants in greenhouse tests. Comparisons between applying the biocontrol weekly after seeding for 5 weeks versus a single application at transplanting (5 weeks) indicated no significant benefits of additional applications. The formulation of B. subtilis reduced disease caused by a mefenoxam-resistant isolate of P. capsici, while mefenoxam failed. The biocontrol efficacy of formulated strains was not affected in different soil types or potting media. However, disease was more severe in sandy soils. In field experiments that were conducted with a mefenoxam sensitive isolate, disease incidence and severity of Phytophthora blight were significantly reduced at all rates of B. subtilis in 2019 except the 16.8 kg ha-1. In both years, mefenoxam was more effective than B. subtilis in controlling disease in the field. Bacillus subtilis did not affect the spatial dynamics of pathogen spread within rows. While the precise mechanism(s) of action is unclear, in vitro dual-culture tests suggest direct antagonism, as B. subtilis significantly inhibited colony growth of P. capsici. AgBiome has recently released a new formulation of the AFS032321 strain named Theia®, with higher active ingredients for commercial applications and biocontrol of P. capsici.


[Amanita poisoning during pregnancy].
A pregnant woman at the 28th gestational week and three other members of the family had mushrooms for dinner. One of these mushrooms was an Amanita mushroom. The morning after, three of them suffered from nausea, vomiting and diarrhoea. The pregnant woman was admitted to hospital, and therapy with Penicillin and Silibinin was started immediately. Hepatic and renal blood parameters were observed repeatedly for early detecting of organ failure. Fetal lung maturation was forced by administration of betamethasone. After five days at the intensive care unit mother and unborn child were dismissed at normal physical condition.


Diarrhoea prevalence in children under five years of age in rural Burundi: an assessment of social and behavioural factors at the household level.
Diarrhoea is the second leading cause of child mortality worldwide. Low- and middle-income countries are particularly burdened with this both preventable and treatable condition. Targeted interventions include the provision of safe water, the use of sanitation facilities and hygiene education, but are implemented with varying local success. To determine the prevalence of and factors associated with diarrhoea in children under five years of age in rural Burundi. A cross-sectional survey was conducted among 551 rural households in northwestern Burundi. Areas of inquiry included 1) socio-demographic information, 2) diarrhoea period prevalence and treatment, 3) behaviour and knowledge, 4) socio-economic indicators, 5) access to water and water chain as well as 6) sanitation and personal/children's hygiene. A total of 903 children were enrolled. The overall diarrhoea prevalence was 32.6%. Forty-six per cent (n=255) of households collected drinking water from improved water sources and only 3% (n=17) had access to improved sanitation. We found a lower prevalence of diarrhoea in children whose primary caretakers received hygiene education (17.9%), boiled water prior to its utilisation (19.4%) and were aged 40 or older (17.9%). Diarrhoea was associated with factors such as the mother's age being less than 25 and the conviction that diarrhoea could not be prevented. No gender differences were detected regarding diarrhoea prevalence or the caretaker's decision to treat. Diarrhoea prevalence can be reduced through hygiene education and point-of use household water treatment such as boiling. In order to maximise the impact on children's health in the given rural setting, future interventions must assure systematic and regular hygiene education at the household and community level.


Identification of a spinal circuit for light touch and fine motor control.
Sensory circuits in the dorsal spinal cord integrate and transmit multiple cutaneous sensory modalities including the sense of light touch. Here, we identify a population of excitatory interneurons (INs) in the dorsal horn that are important for transmitting innocuous light touch sensation. These neurons express the ROR alpha (RORα) nuclear orphan receptor and are selectively innervated by cutaneous low threshold mechanoreceptors (LTMs). Targeted removal of RORα INs in the dorsal spinal cord leads to a marked reduction in behavioral responsiveness to light touch without affecting responses to noxious and itch stimuli. RORα IN-deficient mice also display a selective deficit in corrective foot movements. This phenotype, together with our demonstration that the RORα INs are innervated by corticospinal and vestibulospinal projection neurons, argues that the RORα INs direct corrective reflex movements by integrating touch information with descending motor commands from the cortex and cerebellum.