Functional remodeling of subtype-specific markers surrounding implanted neuroprostheses.
Microelectrode arrays implanted in the brain are increasingly used for the research and treatment of intractable neurological disease. However, local neuronal loss and glial encapsulation are known to interfere with effective integration and communication between implanted devices and brain tissue, where these observations are typically based on assessments of broad neuronal and astroglial markers. However, both neurons and astrocytes comprise heterogeneous cellular populations that can be further divided into subclasses based on unique functional and morphological characteristics. In this study, we investigated whether or not device insertion causes alterations in specific subtypes of these cells. We assessed the expression of both excitatory and inhibitory markers of neurotransmission (vesicular glutamate and GABA transporters, VGLUT1 and VGAT, respectively) surrounding single-shank Michigan-style microelectrode arrays implanted in the motor cortex of adult rats by use of quantitative immunohistochemistry. We found a pronounced shift from significantly elevated VGLUT1 within the initial days following implantation to relatively heightened VGAT by the end of the 4-wk observation period. Unexpectedly, we observed VGAT positivity in a subset of reactive astrocytes during the first week of implantation, indicating heterogeneity in early-responding encapsulating glial cells. We coupled our VGLUT1 data with the evaluation of a second marker of excitatory neurons (CamKiiα); the results closely paralleled each other and underscored a progression from initially heightened to subsequently weakened excitatory tone in the neural tissue proximal to the implanted electrode interface (within 40 μm). Our results provide new evidence for subtype-specific remodeling surrounding brain implants that inform observations of suboptimal integration and performance.NEW & NOTEWORTHY We report novel changes in the local expression of excitatory and inhibitory synaptic markers surrounding microelectrode arrays implanted in the motor cortex of rats, where a progressive shift toward increased inhibitory tone was observed over the 4-wk observation period. The result was driven by declining glutamate transporter expression (VGLUT1) in parallel with increasing GABA transporter expression (VGAT) over time, where a reactive VGAT+ astroglial subtype made an unexpected contribution to our findings.


Composite glandular-endocrine cell carcinomas of the stomach: clinicopathologic and methylation study.
Four cases of very rare composite glandular-endocrine cell carcinoma of the stomach are presented with methylation findings. All but one of the tumors arose in the antrum and two of them were at the early stage. Each composite carcinoma was accompanied by atrophic and metaplastic gastritis in the adjacent mucosa. Three cases showed lymph nodes metastasis, and one of them showed both glandular and neuroendocrine tumor components within the metastatic nodes. Mucin stains were positive in the adenocarcinoma areas while only the neuroendocrine markers were positive in neuroendocrine tumor components. Of all seven markers tested for, p16INK4A methylation was observed in both components of one composite carcinoma and hMLH1 was methylated in the neuroendocrine tumor component within the same tumor. An additional six gastric large cell neuroendocrine carcinomas showed no methylation. Follow up of patients indicated short survival in patients with poorly differentiated neuroendocrine carcinoma components and advanced stages of tumors, while patients with well-differentiated neuroendocrine tumor components and early stages showed long disease-free survival. Our results suggest that hypermethylation of tumor suppressor genes is rare in gastric composite and neuroendocrine carcinomas, and prognosis of gastric composite carcinomas appears to be related to the histopathology of neuroendocrine components and tumor stage.


The Impact of Esketamine Combined with Dexmedetomidine on Laparoscopic Gallbladder Surgery: A Randomized Controlled Trial.
To assess the efficacy of combining esketamine with dexmedetomidine in laparoscopic gallbladder surgery. We investigated 110 laparoscopic cholecystectomy patients at Jinan Central Hospital, affiliated with Shandong First Medical University, from April 2019 to March 2020. Patients were randomly assigned to the control group (n = 55) or observation group (n = 55). The control group received dexmedetomidine intravenously at 1 μg/kg and a continuous infusion at 0.5 μg•kg-1•h-1. The observation group received esketamine and dexmedetomidine, with intravenous esketamine at 0.4 mg/kg and a continuous infusion at 0.1 mg/(kg•h). We measured heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) at four-time points: before anesthesia (T0), 30 minutes after anesthesia (T1), extubation (T2), and awakening (T3). We also assessed wake time, post-anesthesia care unit (PACU) stay, and Ramasy and visual analogue scale (VAS) scores at 2, 6, 12, and 24 hours post-surgery. At T0, no significant changes occurred in HR, SBP, and DBP in both groups (P > .05). However, at T1 and T2, HR, SBP, and DBP gradually decreased, with the control group exhibiting lower levels than the observation group (P < .05). These levels returned to baseline at T3. PACU residence and wake times showed no significant differences (P > .05). At 2 hours post-operation, Ramasy scores significantly dropped in the observation group versus the control group (P < .05). At 6, 12, and 24 hours post-operation, Ramasy scores exhibited no significant differences (P > .05). Moreover, at 2, 6, and 12 hours post-operation, VAS scores in the observation group were notably lower than in the control group (P < .05). At 24 hours post-operation, VAS scores revealed no significant differences (P > .05). Adverse reactions within 3 days post-operation did not differ significantly between the groups (P > .05). Combining esketamine with dexmedetomidine enhances the quality of laparoscopic cholecystectomy, alleviates postoperative agitation, accelerates cognitive function recovery, reduces cognitive function impairment, and merits clinical consideration.


Response of anterior pituitary cells to culture media.
We examined the ability of four commonly used culture media to support prolactin (PRL), growth hormone (GH), and adrenocorticotropic hormone (ACTH) release, as well as the inhibitory PRL response to dopamine. After a week of primary culture, rat anterior pituitary cells from both genders were studied over a 4 hour period. Whereas ACTH secretion was similar across the various media, PRL and GH release were lessened with M199 and F10, respectively. Dopamine inhibited PRL release under all media conditions which was inconsistant with the reported lack of a dopamine effect with RPMI-1640 medium. These data confirm the postulate that media culture conditions can determine the degree of expression of constituitive phenotypes in anterior pituitary cells.


Turnover intentions and voluntary turnover: the moderating roles of self-monitoring, locus of control, proactive personality, and risk aversion.
This article explores moderators of the relationship between turnover intentions and turnover behavior to better explain why some employees translate intentions into behavior and other employees do not. Individual differences in self-monitoring, locus of control, proactive personality, and risk aversion were examined. Results indicate that self-monitoring and risk aversion moderate the intentions-turnover link. Specifically, the relationship between turnover intentions and turnover is stronger for low self-monitors and those lower in risk aversion. Locus of control moderated the relationship in 1 of 2 samples such that the relationship was stronger for those with an internal locus of control. Proactive personality, however, did not directly moderate the relationship between intentions and turnover behaviors.


[Restrictive cardiomyopathy in childhood].
Restrictive cardiomyopathy is a rare heart muscle disease in childhood. By presenting a case report of a 15 year old adolescent, the aim of this article is to describe diagnosis, pathogenesis and therapy of restrictive cardiomyopathy. A review of the literature comprising pediatric studies on restrictive cardiomyopathy serves as a basis to discuss recommendations for therapeutic strategies in pediatric patients with this rare disease.


Entry Site Is Associated With Aortic Enlargement After Pre-emptive Endovascular Repair for Uncomplicated Type B Aortic Dissection.
We aimed to examine the mid-term results corresponding to the entry site in patients who underwent pre-emptive thoracic endovascular aortic aneurysm repair (TEVAR) for uncomplicated type B aortic dissection (TBAD). We included 27 patients who underwent pre-emptive TEVAR for uncomplicated TBAD between September 2014 and December 2019. We divided the patients into 2 groups depending on the proximal landing zone (zone 2 group, zone ≥3 group) and retrospectively analyzed the risk of all-cause and aorta-related mortality, aortic events (rupture, open conversion, and secondary intervention), and aortic enlargement (≥5 mm). The median age of the patients was 53 (47-65) years. The median duration from the onset of uncomplicated TBAD to TEVAR was 43 (30-99) days, and the median follow-up duration was 48 (36-57) months. The maximum preoperative diameter of the dissected aorta was 40 mm in the zone 2 group and 35 mm in the zone ≥3 group (p=0.134). There was no case of hospital death or spinal cord ischemia; however, there was 1 (3.7%) case of perioperative stroke in the zone 2 group. Multivariate analysis of the risk factors for aortic enlargement following pre-emptive TEVAR for uncomplicated TBAD revealed that only zone 2 landing was an independent risk factor. The estimated Kaplan-Meier curve showed a higher rate of aortic enlargement in the zone 2 group at 4 years after pre-emptive TEVAR (46.4% vs 0%, log-rank test; p=0.011). In this study on TBAD, we found that zone 2 landing was associated with aortic enlargement after pre-emptive TEVAR. In cases where the distance from the left subclavian artery to a major entry point was short, there were more cases of aortic dilatation. The effectiveness of entry closure for type B aortic dissection was demonstrated in the INSTEAD XL trial. The cause of aortic enlargement after pre-emptive endovascular treatment for type B aortic dissection remains controversial. In the present study, zone 2 landing was a risk factor for aortic enlargement after pre-emptive thoracic endovascular aortic aneurysm repair (TEVAR) for uncomplicated type B dissection. Patients with zone 2 landing should be closely followed up after pre-emptive TEVAR.


Molecular Biomarker Identification Using a Network-Based Bioinformatics Approach That Links COVID-19 With Smoking.
The COVID-19 coronavirus, which primarily affects the lungs, is the source of the disease known as SARS-CoV-2. According to "Smoking and COVID-19: a scoping review," about 32% of smokers had a severe case of COVID-19 pneumonia at their admission time and 15% of non-smokers had this case of COVID-19 pneumonia. We were able to determine which genes were expressed differently in each group by comparing the expression of gene transcriptomic datasets of COVID-19 patients, smokers, and healthy controls. In all, 37 dysregulated genes are common in COVID-19 patients and smokers, according to our analysis. We have applied all important methods namely protein-protein interaction, hub-protein interaction, drug-protein interaction, tf-gene interaction, and gene-MiRNA interaction of bioinformatics to analyze to understand deeply the connection between both smoking and COVID-19 severity. We have also analyzed Pathways and Gene Ontology where 5 significant signaling pathways were validated with previous literature. Also, we verified 7 hub-proteins, and finally, we validated a total of 7 drugs with the previous study.


Antibody-based therapies for COVID-19: Can Europe move faster?
Michel Goldman and colleagues call on the European medical and scientific community to coordinate efforts on immunotherapy-based approaches to coronavirus.


Conversion of a C-20-deoxy-C21, steroid, 5-pregnen-3beta-ol, into testosterone by rat testicular microsomes.
5-[7ALPHA-3H] Pregnen-3beta-ol, a C-20-deoxy analog of pregnenolone, was synthesized and tested as a substrate for the enzyme system occurring in testes that cleaves the side chain of C21 steroids between C-17 and C-20. This C-20-deoxy C21 steroid was incubated with a microsomal preparation obtained from rat testis and was converted into testosterone in 5% yield. Another C-20-deoxy analog of pregnenolone, 5,20-pregnadien-3beta-ol, was not converted into testosterone by this enzyme system. The significance of this finding for the natural processes by which pregnenolone is converted by the same subcellular fraction into the male sex hormone is examined in the light of the hypothesis that intermediates involved in steroidogenesis are transient, reactive complexes of the appropriate reactants (steroids, oxygen, etc.) with specific enzymes.


Centrosome-declustering drugs mediate a two-pronged attack on interphase and mitosis in supercentrosomal cancer cells.
Classical anti-mitotic drugs have failed to translate their preclinical efficacy into clinical response in human trials. Their clinical failure has challenged the notion that tumor cells divide frequently at rates comparable to those of cancer cells in vitro and in xenograft models. Given the preponderance of interphase cells in clinical tumors, we asked whether targeting amplified centrosomes, which cancer cells carefully preserve in a tightly clustered conformation throughout interphase, presents a superior chemotherapeutic strategy that sabotages interphase-specific cellular activities, such as migration. Herein we have utilized supercentrosomal N1E-115 murine neuroblastoma cells as a test-bed to study interphase centrosome declustering induced by putative declustering agents, such as Reduced-9-bromonoscapine (RedBr-Nos), Griseofulvin and PJ-34. We found tight 'supercentrosomal' clusters in the interphase and mitosis of ~80% of patients' tumor cells with excess centrosomes. RedBr-Nos was the strongest declustering agent with a declustering index of 0.36 and completely dispersed interphase centrosome clusters in N1E-115 cells. Interphase centrosome declustering caused inhibition of neurite formation, impairment of cell polarization and Golgi organization, disrupted cellular protrusions and focal adhesion contacts-factors that are crucial prerequisites for directional migration. Thus our data illustrate an interphase-specific potential anti-migratory role of centrosome-declustering agents in addition to their previously acknowledged ability to induce spindle multipolarity and mitotic catastrophe. Centrosome-declustering agents counter centrosome clustering to inhibit directional cell migration in interphase cells and set up multipolar mitotic catastrophe, suggesting that disbanding the nuclear-centrosome-Golgi axis is a potential anti-metastasis strategy.


Regulation of hepatitis C virus polyprotein processing by signal peptidase involves structural determinants at the p7 sequence junctions.
The hepatitis C virus genome encodes a polyprotein precursor that is co- and post-translationally processed by cellular and viral proteases to yield 10 mature protein products (C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). Although most cleavages in hepatitis C virus polyprotein precursor proceed to completion during or immediately after translation, the cleavages mediated by a host cell signal peptidase are partial at the E2/p7 and p7/NS2 sites, leading to the production of an E2p7NS2 precursor. The sequences located immediately N-terminally of E2/p7 and p7/NS2 cleavage sites can function as signal peptides. When fused to a reporter protein, the signal peptides of p7 and NS2 were efficiently cleaved. However, when full-length p7 was fused to the reporter protein, partial cleavage was observed, indicating that a sequence located N-terminally of the signal peptide reduces the efficiency of p7/NS2 cleavage. Sequence analyses and mutagenesis studies have also identified structural determinants responsible for the partial cleavage at both the E2/p7 and p7/NS2 sites. Finally, the short distance between the cleavage site of E2/p7 or p7/NS2 and the predicted transmembrane alpha-helix within the P' region might impose additional structural constraints to the cleavage sites. The insertion of a linker polypeptide sequence between P-3' and P-4' of the cleavage site released these constraints and led to improved cleavage efficiency. Such constraints in the processing of a polyprotein precursor are likely essential for hepatitis C virus to post-translationally regulate the kinetics and/or the level of expression of p7 as well as NS2 and E2 mature proteins.


Hierarchical Mesoporous Metal-Organic Frameworks for Enhanced CO2 Capture.
Hierarchical porous materials are promising for catalyst, separation and sorption applications. A ligand-assisted etching process is developed for template-free synthesis of hierarchical mesoporous MOFs as single crystals and well-intergrown membranes at 40 °C. At 223 K, the hierarchical porous structures significantly improve the CO2 capture capacity of HKUST-1 by more than 44 % at pressures up to 20 kPa and 13 % at 100 kPa. Even at 323 K, the enhancement of CO2 uptake is above 25 % at pressures up to 20 kPa and 7 % at 100 kPa. The mesoporous structures not only enhance the CO2 uptake capacity but also improve the diffusion and mass transportation of CO2 . Similarly, well-intergrown mesoporous HKUST-1 membranes are synthesized, which hold the potential for film-like porous devices. Mesoporous MOF-5 crystals are also obtained by a similar ligand-assisted etching process. This may provide a facile way to prepare hierarchical porous MOF single crystals and membranes for wide-ranging applications.


Improved survival of left-sided pancreas cancer after surgery.
Resective therapeutic strategy for left-sided pancreatic adenocarcinoma is open to debate. The post-resection outcomes and factors influencing post-resection survival for adenocarcinoma of the body and tail of the pancreas were analyzed to determine the effectiveness of surgery. A total of 73 patients with adenocarcinoma of the body or tail of the pancreas who underwent resection between 1994 and June 2007 were evaluated for overall survival. Multiple malignancies were present in 34 of 73 patients (47%). Overall 1-, 3- and 5-year survival rates after surgery were 79%, 34%, and 30%, respectively. Presence of symptoms, multiple cancers and level of preoperative tumor marker did not influence post-resection survival. As for tumor characteristics, tumor size, histological tumor differentiation, retroperitoneal invasion, status of residual tumor and UICC staging represented significant prognostic indicators by univariate analysis. Gemcitabine, when administered as an adjuvant settings, strongly worked for improving post-resection outcome (5-year survival rate = 51%). Factors shown to have independent prognostic significance on multivariate analysis were tumor size (<3 vs. >or=3 cm), status of residual tumor (R0 vs. R1, 2), and postoperative administration of gemcitabine. Appropriate patient selection and accurate surgical technique with postoperative adjuvant therapy could benefit survival of patients with carcinoma of the pancreas body and tail.


A comparison between the age patterns and rates of suicide in the Islamic Republic of Iran and Australia.
When planning interventions aimed at preventing suicide, it is important to consider how socioeconomic and cultural factors may affect suicide rates. There has been variability in the accuracy of recording suicide deaths, leading to varying levels of underestimation. Social, cultural and religious elements affect whether deaths resulting from suicide are reported as such and those responsible for reporting a death may avoid providing information that would suggest the death was due to suicide. The aim of this study was to document Iranian suicide patterns in 2006-2010 and 2011-2015, compare them with those in a "Western" country (Australia) and explore whether differences point to factors that affect suicide rates. Data were obtained from Iranian and Australian national statistics offices. Peak Iranian male suicide rates were in young adulthood. There was a modest increase between the 2 quinquennials studied. Australian male rates were much higher, with age peaks in middle age and very late life. From age 30, the female rate was twice as high in Australia, graphs of the age patterns being relatively flat in both countries. Male:female ratios were 2.34 (Islamic Republic of Iran) and 3.25 (Australia). The suicide rate in the Islamic Republic of Iran is low, as in most other predominantly Muslim countries. Higher rates in youth are of concern. A case-control psychological autopsy study comparing cases in Iran and Australia could help answer questions about suicide causation.


Use of sponge-assisted endoluminal vacuum therapy for the treatment of colorectal anastomotic leaks: expert panel consensus.
Anastomotic leaks represent one of the most significant complications of colorectal surgery and are the primary cause of postoperative mortality and morbidity. Sponge-assisted endoluminal vacuum therapy (EVT) has emerged as a minimally invasive technique for the management of anastomotic leaks; however, there are questions regarding patient selection due to the heterogeneous nature of anastomotic leaks and the application of sponge-assisted EVT by surgeons. Seven colorectal surgical experts participated in a modified nominal group technique to establish consensus regarding key questions that arose from existing gaps in scientific evidence and the variability in clinical practice. After a bibliographic search to identify the available evidence and sequential meetings with participants, a series of recommendations and statements were formulated and agreed upon. Thirty-seven recommendations and statements on the optimal use of sponge-assisted EVT were elaborated on and unanimously agreed upon by the group of experts. The statements and recommendations answer 10 key questions about the indications, benefits, and definition of the success rate of sponge-assisted EVT for the management of anastomotic leaks. Although further research is needed to resolve clinical and technical issues associated with sponge-assisted EVT, the recommendations and statements produced from this project summarize critical aspects to consider when using sponge-assisted EVT and to assist those involved in the management of patients with colorectal anastomotic leaks.


Comparison of artificial graft versus autograft in anterior cruciate ligament reconstruction: a meta-analysis.
Critically evaluation and summarization for the outcomes between autografts and artificial grafts using in anterior cruciate ligament (ACL) reconstruction have not been performed currently. The purpose of this study is to compare the clinical outcomes between artificial ligaments and autografts at a short- to mid-term follow-up. A computerized search of the databases was conducted including Medline, Embase, and the Cochrane library. Only prospective or retrospective comparative studies with a minimum 2-year follow-up and a minimum sample size of 15 for each group were considered for inclusion. Two independent reviewers performed data extraction and methodological quality assessment. A Mantel-Haenszel analysis was used for pooling of results. Sensitivity analysis was performed in order to maintain the stability of results. Seven studies were included in this study. The total sample size was 403 (autograft group: 206 patients; synthetic graft group: 197 patients). Four studies were randomized controlled trials. Two studies were retrospective comparative studies and one study was non-randomized prospective comparative study. In terms of instrumented laxity, patient-oriented outcomes and complications, no significant difference was occurred between new artificial ligaments and autografts. But the results of IKDC grades and instrumented laxity were worsen in early artificial ligaments compared to autografts. The outcomes of new generation of artificial ligaments are similar to autografts at a short- to mid-term follow-up. However, the early artificial ligaments are not suggested for ACL reconstruction compared to autografts.


Molecular characterization and expression analysis of nine CC chemokines in half-smooth tongue sole, Cynoglossus semilaevis.
Chemokines are a large, diverse group of small cytokines that can be classified into several families, including the CC chemokine family, which plays a pivotal role in host defense by inducing leukocyte chemotaxis under physiological and inflammatory conditions. Here we studied 9 CC chemokines from half-smooth tongue sole (Cynoglossus semilaevis). Phylogenetic analysis divided these chemokines into four groups. The tissue specific expression patterns of the 9 chemokines under normal physiological conditions varied much, with most chemokines highly expressed in immune organs, while some other chemokines showing high expression levels in non-immune organs. In addition, the 9 chemokines exhibited similar or distinctly different expression profiles in response to the challenge of virus and intracellular and extracellular bacterial pathogens. These results indicate that in tongue sole, CC chemokines may be involved in different immune responses as homeostatic or inflammatory chemokines.


Molecular analysis of glioma and skin-tumour alterations in a xeroderma-pigmentosum child.
Xeroderma pigmentosum (XP) is a rare hereditary disease characterized by a very high frequency of skin tumours due to a defect in the nucleotide-excision-repair process. Some of these patients have also been reported to develop internal tumours with higher frequency than the normal population. Reported here are the clinical features and molecular analysis of an XP patient who developed multiple skin cancers as well as a thalamic glioma. Complementation analysis with recombinant retrovirus, cloning efficiency and unscheduled DNA synthesis after UV-C indicate that the patient belongs to the C group. Characterization of the p53 mutations in the 2 tumours of the patient leads to speculation on the aetiological agents involved in tumour initiation. The skin tumour is clearly induced by the presence of unrepaired UVB-induced DNA damage on the non-transcribed strand of the p53 gene, while the glioma may be induced by unrepaired DNA lesions produced by free radicals.


Relationship between rate of change in acid exposure along the esophagus and length of Barrett's epithelium.
Gastroesophageal reflux disease (GERD) plays a major role in the development of Barrett's esophagus. Recently, we demonstrated that duration of esophageal acid exposure in the distal esophagus correlates with the length of Barrett's mucosa. The aim of this study was to determine whether there is a relationship between the rate of the change in acid exposure along the esophagus and the length of Barrett's esophagus. A total of 17 patients (16 men and one woman; mean age 66 +/- 15 yr, range 41-83 yr) with varying lengths of biopsy-proven Barrett's esophagus were recruited prospectively into the study. Ambulatory 24-h esophageal pH monitoring was performed using a commercially available pH probe with four sensors located 5 cm apart. For each patient, a least squares regression line of the fraction of the study that the pH was <4 against the height of the sensor above the lower esophageal sphincter was fit. The slope of the regression line was used to represent the rate of change in acid exposure. Linear regression analysis was conducted to analyze the relationship between the rate of change in acid exposure and the length of Barrett's mucosa. The mean Barrett's length was 5 +/- 3 cm (range 1-11 cm). Linear regression demonstrated a statistically significant relationship between the rate of change in acid exposure and the length of Barrett's esophagus for the 24-h duration of the study, as well as for the fraction of the study that patients were in the upright position (p = 0.0096 and 0.0076, respectively). For the supine position, the relationship did not reach statistical significance (p = 0.095). We demonstrated a significant relationship between the rate of change in acid exposure and the length of Barrett's mucosa. Thus, as the rate at which recorded acid exposure values increases from the proximal to distal esophagus, the length of Barrett's esophagus significantly increases (for percent total time and upright position).


Axon regeneration impediment: the role of paired immunoglobulin-like receptor B.
Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to the Nogo receptor (NgR), the paired immunoglobulin-like receptor B (PirB) is a recently discovered coreceptor of Nogo, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein. Concurrent blocking of NgR and PirB almost completely eliminates the inhibitory effect of myelin-associated inhibitory molecules on axonal regeneration. PirB participates in a key pathological process of the nervous system, specifically axonal regeneration inhibition. PirB is an inhibitory receptor similar to NgR, but their effects are not identical. This study summarizes the structure, distribution, relationship with common nervous system diseases, and known mechanisms of PirB, and concludes that PirB is also distributed in cells of the immune and hematopoietic systems. Further investigations are needed to determine if immunomodulation and blood cell migration involve inhibition of axonal regeneration.


Mini review on blood-brain barrier penetration of pyridinium aldoximes.
This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are highly charged hydrophilic compounds used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase reactivators. Pyridinium aldoximes have antidotal effects against poisoning with cholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This poses a severe challenge to all innocent and peace-loving people worldwide. This review gives a brief summary of BBB transporters and description of the current in vitro and in vivo methods for the characterization of BBB penetration of established and novel pyridinium aldoximes. The authors provide a putative mechanism of penetration, outline some future ways of formulation and discuss the possible advantages and disadvantages of increasing BBB penetration.


[Overall migartion testing with alternative fatty food simulants].
Overall migration from commercial samples of food plastics packaging into 95% ethanol and isooctane--the alternative fatty food simulants--was determined. Testing conditions--time and temperature of the contact of food packaging material with food simulants reflected real or predicted use of given packaging. The analytical methods according to European Standard EN 1186 were used. Test methods by filling the artiecles, total immersion, forming a pouch or using the cell were used for migration as appropriate to allow contact with liquid food simulant only this surface which will come into the contact with food during normal use of the product. The overall migration from the samples of the tested products into both food simulants (95% ethanol and iso-octane) was well below the limit (10 mg/dm2), except of the migration from plasticized PVC films which markedly exceeded above limit, showing that these films must not be used for packaging of food containing fat. Application of food simulants as a alternative to olive oil markedly shortens analytical procedure and reduces workload, both important in routine testing.


Unpacking immigration in youths' academic and occupational pathways.
This study sought to unpack how immigration is associated with youths' educational choices during the transition to college and adulthood. Surveys and school records were collected on 789 youth (ages 18-25) with Asian Pacific, Latino, African/Afro-Caribbean, and European backgrounds. The results indicated generational differences in educational choices, such that children of immigrants chose courses of study with higher math and science content than that of their peers with U.S.-born parents. Mediation analyses indicated that children of immigrants reported higher social and economic aspirations than did their peers, and their economic aspirations accounted for part of the generational difference in educational choices. Generational differences in educational choices were also mediated by verbal achievement test scores and perceived English skills.


Cooperative Tracking of Networked Agents With a High-Dimensional Leader: Qualitative Analysis and Performance Evaluation.
Cooperative consensus tracking and its -gain performance is investigated in this paper for a class of multiple agent systems (MASs) in the presence of a single high-dimensional leader. Compared with the traditional models for MASs, the inherent dynamics of the leader are allowed to be different with those of the followers in the present framework, which is thus much more favorable in various practical applications. A new kind of distributed controllers associated with a reduced-order state observer are designed for each follower to track the high-dimensional leader under directed switching topology. With the help of -matrix theory and stability analysis methods of switched systems, some efficient criteria are derived for cooperative consensus tracking of MASs without any external disturbance under directed switching topology. Theoretical analysis is further extended to the case of consensus tracking for MASs subject to unknown external disturbances by showing that, a finite -gain performance for tracking errors against external disturbances can be ensured if some suitable conditions are satisfied. At last, the synthesis issue of designing an observer-based controller to achieve a prescribed -gain performance for consensus tracking is studied by using tools from control theory, where the underlying topology is assumed to be undirected and fixed. The effectiveness of theoretical results is verified by performing numerical simulations.


Should all asthma patients be switched to single maintenance and reliever therapy?
Recent data indicate that overuse of short-acting beta2-agonists (SABAs) results in an increased risk of asthma exacerbations and mortality. The use of inhaled corticosteroid-formoterol as both maintenance and reliever therapy has become a preferred regimen for asthma management. Clinicians should be aware of the pharmacology, dosing, and prescribing considerations regarding the use of budesonide-formoterol as the available combination in the United States.


Characteristics and mechanism of surface diffusion in reversed-phase liquid chromatography using various alkyl ligand bonded silica gels.
Kinetic and thermodynamic parameters concerning surface diffusion were derived in reversed-phase liquid chromatography (RPLC) systems using a series of silica gel packing materials bonded with C1, C4, C8, and C18 alkyl ligands. In this paper, a more detailed study on some characteristics and the mechanism of surface diffusion in the RPLC systems using the different alkyl ligand bonded silica gels was made from a thermodynamic point of view by analyzing the surface diffusion data with consideration of the correlation between the parameters concerning surface diffusion and those relating to the retention equilibrium. The mechanism of surface diffusion seems to be the same irrespective of the length of the alkyl ligands because of the presence of the extrathermodynamic relationships, i.e., the enthalpy-entropy compensation and the linear free energy relationship. It was indicated that the surface diffusion coefficient (Ds) of weakly retained compounds was of the same order of magnitude with corresponding molecular diffusivity and that Ds decreased with increasing retention. The activation energy of surface diffusion (Es) was formulated as a linear function of the isosteric heat of adsorption (Qst). A modified Arrhenius equation, which is derived by taking into account the linear correlation between the two thermodynamic parameters Es and Qst, appropriately explains the intrinsic characteristics and mechanism of surface diffusion.


Electro-acoustic performance of the new bone vibrator Radioear B81: a comparison with the conventional Radioear B71.
The objective is to evaluate the electro-acoustic performance of a new audiometric bone vibrator, the B81 from Radioear Corporation, USA. Comparison will be made with the widely used B71 which has well-known limitations at low frequencies. The B81 is based on the balanced electromagnetic separation transducer (BEST) principle where static forces are counterbalanced so that nonlinear distortion forces are reduced and maximum hearing levels can be increased. Maximum hearing level, total harmonic distortion (THD), frequency response, and electrical impedance were measured for six devices of each bone vibrator type on an artificial mastoid. It was found that B81 reaches 10.7-22.0 dB higher maximum (@ THD = 6% or Vin = 6 VRMS) hearing levels than B71 for frequencies below 1500 Hz, and had significantly lower THD up to 1000 Hz. There was no statistically significant difference between their frequency response, except a deviation at the mid frequencies (α = 0.01) where B81 was more efficient and the electrical impedances were practically the same. In general, B81 had an improved electro-acoustic performance compared to B71 and is compatible with same audiometers. In particular, B81 allows for sensorineural hearing loss to be measured at considerably higher hearing levels than with B71 below 1500 Hz.


Effects of enantiomers of indacrinone (MK-196) on cation transport by the loop of Henle and distal tubule studied by microperfusion in vivo.
We have studied the effects of the two enantiomeric forms of the diuretic agent, indacrinone (MK-196), upon transport of sodium and potassium by the loop of Henle and distal tubule, using the technique of continuous microperfusion, in vivo, of individual tubular segments in the rat kidney. In the loop of Henle, both the (+)-and (-)-enantiomers, when included in the tubular perfusion fluid at a concentration of 5 X 10(-4) M, inhibited the reabsorption of sodium and potassium, but the (-)-enantiomer was significantly more effective in this regard than the (+)-enantiomer. Although loop sodium reabsorption was incompletely blocked by either form of the drug, potassium reabsorption by the loop was on average abolished by (-)-MK-196 and was actually converted in some experiments to an appreciable net secretory flux. In the distal tubule, both enantiomers inhibited net sodium reabsorption, but neither affected the control level of potassium secretion. These experiments provide direct evidence that the natriuretic effect of this agent is due to actions on sodium transporting sites in the loop of Henle and distal tubule. Furthermore, because potassium transport was affected only in the loop, they suggest that the nature of the cellular cation transport mechanism influenced by the drug may be different at the two nephron sites studied.


The pursuit of excellence in nursing education.
The National League for Nursing is clear in its mission and its commitment to providing leadership in re-creating the landscape of nursing education. This commitment is grounded in the certainty that excellence in nursing education can be achieved. The initiatives described here are the newest and most exciting programs advanced by the NLN. We look forward to your joining us in this multifaceted effort to advance excellence in all types of nursing programs, and we ask you to remember the words contained in a contemporary piece of advice as you face the challenges inherent in this work: Excellence can be attained if you care more than others think is wise, risk more than others think is safe, dream more than others think is practical, and expect more than others think is possible.


Up-regulation of P-glycoprotein expression by catalase via JNK activation in HepG2 cells.
Overexpression of the MDR1 gene is one of the reasons for multidrug resistance (MDR). Some studies suggested that antioxidants could down-regulate MDR1 expression as a possible cancer treatment. In this report, we try to determine the effects of antioxidants (catalase or N-acetylcysteine [NAC]) on the regulation of intrinsic MDR1 overexpression in HepG2 cells. Adding catalase or N-acetylcysteine to the HepG2 culture led to a significant increase of MDR1 mRNA and P-glycoprotein drug transporter activity. After catalase or NAC treatment, a reduced intracellular reactive oxygen species (ROS) was observed. The JNK inhibitor SP600125 abolished the positive effects of catalase on drug transporter activity in a dose-dependent manner. Furthermore, the up-regulation of P-glycoprotein functions by catalase was only observed in HepG2 cells but not in other cell lines tested (MCF-7, A549, A431). These data suggested that catalase can up-regulate P-glycoprotein expression in HepG2 cells via reducing intracellular ROS, and JNK may mediate this process.


Randomized double-blind study of flunarizine versus placebo in patients with chronic cerebrovascular disorders.
Chronic cerebrovascular disorders (CCVD), as defined by the 1980 Ad Hoc Committee in Paris, constitute both clinically and pathogenetically an extremely complex entity, characterized by a protean symptom pattern. The effects of a daily dose of 10 mg flunarizine orally on CCVD have been evaluated with a neuropsychological methodology during a three-month treatment period in a randomized double-blind study compared with a placebo. The results confirmed the effectiveness of the drug in the improvement of neurological, amnesic, attentive and behavioural symptoms, without evident side-effects even after a long-term treatment.


Arterialization of the portal vein in pediatric liver transplantation. A report of two cases.
Portal vein arterialization (PVA) is an acquired concept in shunt surgery for portal hypertension. This technique, recently described as both a temporary and permanent procedure in adult liver transplantation, is reported by the authors in two cases of pediatric transplantation. The indication was low portal blood flow after reperfusion with poor graft function due to persistence of spontaneous retroperitoneal venous shunts. In both cases described, PVA allowed for satisfactory macroscopic liver reperfusion. The increase in portal blood flow from 150 to 500 ml/min in the second patient enabled the liver to be reperfused correctly and led to successful transplantation. The graft function in both cases improved in the 1st postoperative week, but the 1st patient 2 months after transplantation. Signs of hepatic hyperarterialization occurred in the second patient and this necessitated a dearterialization of the portal vein 2 weeks later. Although the benefit of this procedure appears to be beyond doubt in the immediate post-operative period, we have no data on long-term arterialization. We do think that PVA can be performed in pediatric liver transplantation, but it may need to be done only in special, individual situations when no valid alternative can be proposed, such as in the absence of a mesenteric vein and/or the presence of spontaneous retroperitoneal venous shunts.


Desipramine pharmacokinetics in Chinese and Caucasian volunteers.
In order to better define the role of pharmacokinetic variation in reported cross-ethnic differences in dosing patterns of some psychoactive drugs, single dose kinetics of the tricyclic antidepressant desipramine (DMI) were studied in 14 Chinese and 16 Caucasian healthy volunteers. DMI and 2-OH-DMI concentrations were assayed with h.p.l.c. in serial plasma and 24 h urine samples over 5 days following an oral 100 mg dose of DMI. Mean total clearance of DMI ( CLDMI ) from plasma was significantly (P less than 0.05) higher in the Caucasians (123 +/- 57 l/h) than in the Chinese (73.5 +/- 38.8 l/h). There was no significant difference in the apparent clearance of DMI by hydroxylation, fraction of dose metabolized to the hydroxy metabolite, DMI t1/2 or plasma protein binding between the two groups. Trimodal distribution of CLDMI was found, with 4/14 (29%) Chinese demonstrating slow CL (less than 33 l/h) and 4/16 (25%) Caucasians rapid CL (greater than 195 l/h). Correcting CL values for the greater mean weight of the Caucasians did not alter the pattern of distribution. CLDMI did not correlate with body weight. Although environmental factors cannot be ruled out, these results are consistent with genetically based differences in hepatic metabolism, probably affecting pathways in addition to hydroxylation, and suggest that 30% of Orientals would be at risk for toxicity from routine doses of tricyclics or similarly metabolized drugs.


Heterotrophic Cultivation of Cyanobacteria: Study of Effect of Exogenous Sources of Organic Carbon, Absolute Amount of Nutrients, and Stirring Speed on Biomass and Lipid Productivity.
The production of bioproducts from cyanobacteria with techno-economic feasibility is a challenge to these biotechnological processes. The choice of low-cost raw materials is of great importance for the overall economy of bioprocesses, as they represent a significant percentage in the final cost of the product. The objective of this work was to study the operational parameters of cultivation (exogenous sources of organic carbon and absolute amount of nutrients) to optimize productivity in bioproducts by Aphanothece microscopica Nägeli, for further evaluation of stirring speed. The experiments were performed in a bubble column bioreactor, operating at 30°C, pH of 7.6, C/N ratio of 20, 100 mg/L of inoculum, continuous aeration of 1 volume of air per volume of culture per minute (VVM), and absence of light. The results indicate that absolute amounts of 5,000/250 using cassava starch resulted in improved system performance, reaching biomass productivity of 36.66 mg/L/h in parallel with lipid productivity of 6.65 mg/L/h. Finally, experiments with variation in stirring speed indicate that 200 rpm resulted in better average rate of substrate consumption (44.01 mg/L/h), in parallel to biomass productivity of 39.27 mg/L/h. However, the increase of stirring speed had a negative effect on lipid productivity of the process. The technological route developed indicates potential to production of biomass and bulk oil, as a result of the capacity of cyanobacteria to adapt their metabolism in varying culture conditions, which provides opportunities to modify, control, and thereby maximize the formation of targeted compounds.


Studies in bile salt solutions. The effect of pH on the cholate and taurocholate stimulation of human milk lipase catalyzed hydrolysis of p-nitrophenylacetate.
The pseudo-first-order rate constants of hydrolysis of p-nitrophenylacetate, catalyzed by human milk lipase, have been measured in solutions of 0.01 mol dm-3 Bistris(2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3 -diol) buffer at 310.5 K, containing a range of concentrations of sodium taurocholate and sodium cholate, at pH 8.00 and of sodium cholate at pH 6.5. The effect of pH on the activity of the enzyme has been investigated and the stimulation factors of taurocholate and cholate ions and of cholic acid have been calculated to be equal to 5.3, 3.7 and 10.7, respectively. The essential residues for catalytic activity of the enzyme have ionization constants equal to 6.45-6.46 for pK1 and 8.33-8.40 for pK2. The former value is attributed to the presence of a histidine imidazolium group but the identity of the residue leading to pK2 is not proven.


Mold allergy: a three year investigation (1980-1982) of the airborne fungal spores in Naples, Italy.
The purpose of the study was to examine the seasonal changes of the most important anemophilous species of molds, mainly those of allergenic interest. A spore-mold calendar for Naples, Italy was developed by continuous sampling over a 3-year period (January 1980-December 1982). The results reveal the climatic conditions are favorable for the growth of some fungi with dry spores in Naples and very high atmospheric concentrations of mold spores are to be found in summer months, particularly those of Cladosporium. Allergic sensitization with skin test reactivity and clinical signs of sensitivity to inhaled fungal spores is nevertheless found infrequently and generally not correlated with the seasonal patterns of presence of the spore molds in the atmosphere.


Label-Free and Real-Time Detection of Protein Ubiquitination with a Biological Nanopore.
The covalent addition of ubiquitin to target proteins is a key post-translational modification that is linked to a myriad of biological processes. Here, we report a fast, single-molecule, and label-free method to probe the ubiquitination of proteins employing an engineered Cytolysin A (ClyA) nanopore. We show that ionic currents can be used to recognize mono- and polyubiquitinated forms of native proteins under physiological conditions. Using defined conjugates, we also show that isomeric monoubiquitinated proteins can be discriminated. The nanopore approach allows following the ubiquitination reaction in real time, which will accelerate the understanding of fundamental mechanisms linked to protein ubiquitination.


A Comprehensive Spinal Cord Injury Treatment Protocol Improves Outcomes and Decreases Complications.
Spinal cord injury (SCI) is a devastating event with a complicated recovery. Through the use of an interdisciplinary team a comprehensive care plan was developed, utilizing all available best practices, to prevent secondary complications. Previous work has shown the benefit of single system protocols or interventions. This study aimed to assess changes in outcomes after implementation of a comprehensive protocol. This was a retrospective cohort study performed at an ACS Level I trauma center. It was based on data abstract from the institutions trauma registry over a 10 year period. Patients with quadriplegia after a traumatic injury were included. Data on hospital outcomes and complications was collected and compared before and after the use of the Spinal cord injury protocol. 58 patients were evaluated. Overall, there was a reduction in complications after the implementation, with significant reductions in pneumonia (47% vs 16%; P = .02) and decubitus ulcers (47% to 11%; P = .005). ICU length of stay decreased by 7 days and hospital length of stay decreased 13 days. There was no difference in mortality. Hospital costs also decreased a mean of $42,000. A comprehensive SCI protocol can reduce secondary complications in quadriplegic patients. This study found significant decreases in pneumonia and decubitus ulcer rates after implementation of the protocol. Lengths of stay and cost were also significantly reduced. Future research using comprehensive SCI protocols is needed to further assess its effects on outcomes for this specific patient population. Similar centers should consider adoption of comprehensive SCI protocols.


Enhanced recovery after surgery in gynecologic oncology.
Enhanced recovery protocols consist of a bundle of concepts including early feeding, opioid-sparing multimodal pain management, and euvolemia, with the overarching goal of hastening postoperative recovery. Enhanced recovery after surgery has been shown to reduce hospital length of stay, reduce costs, and decrease perioperative opioid requirements in benign and oncologic gynecologic surgery. Interventions without supporting evidence of benefit, such as the use of mechanical bowel preparation, routine use of nasogastric tubes and surgical drains, caloric restriction, routine use of intravenous opioid analgesics, and over-vigorous intravenous hydration should be discouraged to improve broader endpoints such as patient satisfaction and overall recovery. Successful implementation requires engagement from a multidisciplinary team including surgeons, anesthesiologists, nurses, and pharmacists.


Effects of rhamnolipids on microorganism characteristics and applications in composting: A review.
Biosurfactant rhmnolipids have been applied in many fields, especially in environmental bioremediation. According to previous researches, many research groups have studied the influence of rhamnolipids on microorganism characteristics and/or its application in composting. In this review, the effects of rhamnolipids on the cell surface properties of microorganisms was discussed firstly, such as cell surface hydrophobicity (CSH), electrical, surface compounds, etc. Moreover, the deeper mechanisms were also discussed, such as the effects of rhamnolipids on the structural characteristics and functional characteristics of the cell membrane, and the effects of rhamnolipids on the related enzymes and genes. Additionally, the application of rhamnolipids in composting was discussed, which is an important way for pollutant biodegradation and resource reutilization. It is believed that rhamnolipids will play more and more important role in composting.


Correlation of neuropathologic findings, computerized tomographic and high-resolution ultrasound scans of canine avian sarcoma virus-induced brain tumors.
The location, size, geometry and neuropathological findings of anaplastic astrocytomas (AA), gliosarcomas and sarcomas induced by the avian sarcoma virus (ASV) in dogs were compared with images generated using computerized tomography (CT) and real time high-resolution ultrasound (HRUS). Seven AA showed a wide range of findings on CT. Pre-contrast CT scans showed that the tumors could be hyper, hypo, or isodense. Three of seven AA had no contrast enhancement; two of these tumors were also isodense which resulted in a false-negative CT exam. Partial enhancement was seen in one tumor. This resulted in a sensitivity of detection of 72%. Real time HRUS was able to define tumor location, size and geometry of the AA missed or incompletely imaged by CT. All tumors were hyperechoic. Inhomogeneity of the echo pattern was due to hemorrhage, cyst formation, and necrosis within the tumors. Such secondary tumor characteristics were more accurately defined by HRUS compared to CT. Vasogenic edema in the brain surrounding tumors was of low density on CT and hypoechoic or indistinguishable from normal brain on US. Similar findings were seen in six gliosarcomas, two of which were not visualized by either pre- or post-contrast enhanced CT scans (sensitivity of 66%). Sarcomas differed in that they were either hyper or isodense; none were hypodense. The area of increased density matched the tumor geometry and correlated with dense cellularity and reticulin deposition. All 13 sarcomas showed contrast enhancement (100% sensitivity), but in two tumors, contrast enhanced CT underestimated the size of the tumor. Because of the large size and multiplicity of the sarcomas, HRUS imaging was not able to resolve the entire tumor volume because of limited imaging access. Intravenously injected horseradish peroxidase (HRP) crossed the tumor blood-brain barrier (BBB) only in those tumors in which contrast enhancement was seen. These studies suggest that intraoperative HRUS imaging may be useful in detecting and delineating human AA incompletely visualized by CT.


Genetic diversity of human respiratory syncytial virus circulating among children in Ibadan, Nigeria.
Human respiratory syncytial virus (HRSV) is the most common viral cause of acute lower respiratory tract infections (LRTIs) in infants and young children however, without an effective vaccine licensed for human use till date. Information on the circulating genotypes of HRSV from regions with high-burden of infection is vital in the global efforts towards the development of protective vaccine. We report here the genotypes of HRSV circulating among children in Ibadan, the first of such from Nigeria.Nasopharyngeal and oropharyngeal swabs collected from 231 children presenting with respiratory infections in some health facilities for care as well as those attending immunization centers for routine vaccination in Ibadan, Nigeria were used for the study. The 2nd hypervariable (HVR2) region of the glycoprotein (G) gene of HRSV was amplified and sequenced using HRSV group specific primers. HRSV was detected in 41 out of the 231 samples. Thirty-three of the isolates were successfully subtyped(22 subtype A and 11 subtype B). Fourteen of the subtype A and all the subtype B were successfully sequenced and genotyped. Phylogenetic analysis showed that genotype ON1 with 72 nucleotide (nt) duplication was the major subgroup A virus (11 of 14) detected together with genotype NA2. All the HRSV subtype B detected belong to the BA genotype with characteristic 60nt duplication. The ON1 genotypes vary considerably from the prototype strain due to amino acid substitutions including T292I which has not been reported elsewhere. The NA2 genotypes have mutations on four antigenic sites within the HVR2relative to the prototype A2. In conclusion, three genotypes of HRSV were found circulating in Ibadan, Nigeria. Additional study that will include isolates from other parts of the country will be done to determine the extent of genotype diversity of HRSV circulating in Nigeria.


The molecular epidemiology of tuberculosis in Zaragoza, Spain: a retrospective epidemiological study in 1993.
The incidence of tuberculosis (TB) in Spain is one of the highest in Europe. In Zaragoza region the incidence rate of tuberculosis and the acquired immune deficiency syndrome (AIDS) are close to the national average. To better define the molecular epidemiology of tuberculosis in an area of Europe where this has not been previously studied. A retrospective epidemiological study on tuberculosis was conducted in Zaragoza, a region of Spain, in 1993. The study population consisted of 226 patients from whom positive culture and complete clinical and demographic data were available. Mycobacterium tuberculosis strains were typed by standard restriction fragment length polymorphism (RFLP). A cluster was defined as two or more isolates with identical RFLP patterns when five or more copies of IS6110 are present. The 137 non-clustered patients were compared with the 89 clustered patients and studied by using univariate analysis. Thirty-nine percent of the patients were clustered, suggesting possible recent transmission. Infection with drug-resistant M. tuberculosis was associated with a decreased risk of being in a cluster. The strains isolated from human immunodeficiency virus (HIV)-positive patients were not associated with clustering. We found that immigration was not a major determinant in the total number of TB cases. Immigration, HIV and drug resistance were not associated with recent transmission. More than 50% of the clusters contained two or three patients, indicating that small outbreaks were responsible for most of the tuberculosis cases. Our RFLP typing results indicate that a TB control programme should be implemented in Spain in order to lower transmission of TB.


[Efficacy evaluation of lafutidine for mild reflux esophagitis in Japanese patients].
To evaluate the efficacy of lafutidine (20mg) , famotidine (40mg) and placebo in patients with mild reflux esophagitis (Grades A and B according to the Los Angeles classification) , a double-blind, multicenter, randomized clinical trial was performed for the first time in Japanese patients. In addition to each physician's evaluation, efficacy was evaluated by judging panels using images submitted by each physician. The healing rate after 8 weeks for lafutidine, famotidine and placebo were 67.7%, 56.6% and 41.2%, respectively. Lafutidine was significantly more effective than placebo (p=0.002, according to the judging panels) . Based on the evaluation of endoscopic images by the judging panels, 91 (27.1%) of 336 images submitted by each physician were judged to not be mucosal breaks. Judging panels are considered one of the ways to resolve the problem of the need to unify the criteria.


Hepatocyte growth factor signaling ameliorates podocyte injury and proteinuria.
Hepatocyte growth factor (HGF) is a potent antifibrotic protein that inhibits kidney fibrosis through several mechanisms. To study its role in podocyte homeostasis, injury, and repair in vivo, we generated conditional knockout mice in which the HGF receptor, c-met, was specifically deleted in podocytes using the Cre-LoxP system. Mice with podocyte-specific ablation of c-met (podo-met(-/-)) developed normally. No albuminuria or overt pathologic lesions were detected up to 6 months of age, suggesting that HGF signaling is dispensable for podocyte maturation, survival, and function under normal physiologic conditions. However, after adriamycin treatment, podo-met(-/-) mice developed more severe podocyte injury and albuminuria than their control littermates. Ablation of c-met also resulted in more profound suppression of Wilms tumor 1 (WT1) and nephrin expression, and podocyte apoptosis after injury. When HGF was expressed ectopically in vivo, it ameliorated adriamycin-induced albuminuria, preserved WT1 and nephrin expression, and inhibited podocyte apoptosis. However, exogenous HGF failed to significantly reduce albuminuria in podo-met(-/-) mice, suggesting that podocyte-specific c-met activation by HGF confers renal protection. In vitro, HGF was able to preserve WT1 and nephrin expression in cultured podocytes after adriamycin treatment. HGF also protected podocytes from apoptosis induced by a lethal dose of adriamycin primarily through a phosphoinositide 3-kinase (PI3K)/Akt-dependent pathway. Collectively, these results indicate that HGF/c-met signaling has an important role in protecting podocytes from injury, thereby reducing proteinuria.


Right Atrial Mass in a Patient With HIV and Hepatitis B: A Case Report.
A 41-year-old man presented to the emergency room for evaluation of substernal chest pain, shortness of breath and generalized failure to thrive. Patient had history of hepatitis B and HIV. During recent evaluation of hepatic mass, patient was found to have hepatocellular carcinoma on biopsy. Patient had no history of cirrhosis of the liver in the past. On Echocardiogram patient was noted to have a large mass filling the right atrial cavity. CT scan of abdomen, pelvis and chest showed a diffusely enlarged heterogeneously enhancing liver consistent with large hepatoma, with portal venous and hepatic vein thrombosis. Tumor thrombus extended through the hepatic veins and upper inferior vena cava into the right atrium. There was 6 cm greatest diameter enhancing mass in the right atrium. Patient had primary hepatocellular carcinoma with extensive invasion into vascular structures. His prognosis was poor and patient opted for palliative care only. In conclusion, patients with co-infection of HIV and Hepatitis B are at risk of developing hepatocellular carcinoma with extension into the right atrium and physicians managing these patients should have high suspicion of right atrial involvement with tumor extension and low threshold to order a screening echocardiogram.


Vibrational study of polymorphism of tetralin derivative for treatment of cardiovascular diseases.
Vibrational spectroscopy coupled with thermogravimetry (TG) and differential scanning calorimetry (DSC) was used to characterize racemic propanoic acid, 2-methyl-5,6,7,8-tetrahydro-6-(methylamino)-1,2-naphthalenediyl ester hydrochloride (CHF-1035), which is a new DA2 dopaminergic receptor/alpha2 agonist and beta blocker under clinical investigation for the treatment of congestive heart failure. Raman spectroscopy disclosed at least two different CHF-1035 polymorphs; the marker bands characteristic of each form were identified. The modifications undergone by the CHF-1035 drug as a consequence of grinding and heating were investigated. Mechanical and gentle thermal treatments caused a polymorphic transformation of the drug crystal form. Raman spectroscopy proved suitable for investigating the possible presence of different polymorphic forms, their relative stability, and interconversion tendency in relation to industrial manufacturing processes undergone by the drug (i.e., grinding, compression, and heating).


Nutritional quality and patterns of lunch menus at child care centers in South Korea and Japan.
This study aimed to investigate the nutritional quality and patterns of lunch menus provided by child care centers in South Korea and Japan. The weekly lunch menus from Monday to Saturday that child care centers provided in November 2014 in South Korea and Japan were analyzed. For Korea, a total of 72 meals provided by 12 centers in Seoul were analyzed by referring to the homepage of the Center for Children's Foodservice Management, which serviced menus for child care centers. For Japan, a total of 30 meals provided by 5 child care centers in Tokyo were analyzed. Nutrient content and pattern in lunch menus were evaluated. The lunch menus in Korea and Japan provided 359.5 kcal (25.7% of the estimated energy requirement) and 376.3 kcal (29.5% of the estimated energy requirement), respectively. 'Rice + Soup + Main dish + Side dish I + Side dish II' were provided in 66.7% of meals in Korea, while various patterns with rice and soup as their bases were provided in Japan. The lunch menus of child care centers in Korea and Japan provide similar amounts of energy, protein, carbohydrate, vitamin A, calcium, and other nutrients. However, there were significant differences in the lunch menu patterns in Korea and Japan. This study provides information about the nutritional content and pattern of lunch menus at child care centers in Asian countries with rice as a staple food.


Cerebral nasitremiasis in a Blainville's beaked whale (Mesoplodon densirostris) stranded in the Canary Islands.
Ten species within the genus Nasitrema (subfamily Nasitrematinae, family Brachycladiidae) have been reported infecting a wide variety of odontocetes worldwide, although there is still a lack of information about their presence in beaked whales (BWs). Nasitrema spp. are commonly described inhabiting the pterygoid sinus, the tympanic cavities, and the middle and inner ear; although aberrant migrations through the brain have been also reported. This trematode may cause different type of lesions, ranging from mild to severe saculitis, neuritis, otitis, and/or meningoencephalitis that may impede cetaceans to survive in the wild, resulting in incoordination, loss of equilibrium, and echolocation dysfunction ending in a stranding event. The presence of Nasitrema sp. was found in an adult female Blainville beaked whale stranded death in Fuerteventura, Canary Islands, on November 2016. The most relevant gross finding was a severe chronic-active multifocal pyogranulomatous and necrotizing encephalitis. Histologically, multiple areas of necrosis, pyogranulomatous and eosinophilic inflammation, haemorrhages and occasional cholesterol crystals were found associated with parasitic structures compatible with an adult trematode and its eggs. Molecular analysis, based on a quantitative polymerase chain reaction (qPCR) of the brain tissue sample detected 99% homology with a partial sequence of the NADH dehydrogenase subunit 3 (ND3) gene of Nasitrema delphini. In addition, liver, kidney, prescapular lymph node and brain samples were positive to herpesvirus (conventional nested PCR). Evidence of the presence of this parasite was not found in any of the 54 beaked whales (n = 54) stranded on the Canary Islands between 1999 and 2017, specifically 35 Cuvier's BWs and 19 specimens belonging to the Mesoplodon genus. To our knowledge, the current study represents the first description of a nasitremiasis in a member of the Ziphiidae family.


Evaluation of the school supplementary feeding program in peninsular malaysia.
This study was conducted to evaluate the implementation of the School Supplement Feeding Program (SSFP) among primary school in terms of financial management and budget disbursement, food preparation, selection of menus and nutrient content of food served. A total of 129 schools comprising 77 national type, 31 Chinese and 21 Tamil vernacular schools in four different regions (northern, eastern, central and southern) of Peninsular Malaysia were selected for this study. The results of this cross-sectional study showed a need to improve the budget disbursement to schools. Most of the schools followed the guidelines provided by the Ministry of Education for selection of eligible children. The quality of food prepared by contracted (local community members) and voluntary (teachers) operators. The use of 10 recommended menus provided for a 2-week cycle by most of the schools has shown increased acceptance and less monotonous feeling towards the food among the children. Nutrient content of food served increased relatively with an increase in budget from RM0.45 to RM0.80 per child. Parents surveyed indicated that the program should continue as this will keep children from low income families from being hungry during school hours. A continued process of monitoring and evaluation is necessary to improve its implementation.


Eye Behavior Associated with Internally versus Externally Directed Cognition.
What do our eyes do when we are focused on internal representations such as during imagination or planning? Evidence from mind wandering research suggests that spontaneous shifts from externally directed cognition (EDC) to internally directed cognition (IDC) involves oculomotor changes indicative of visual disengagement. In the present study, we investigated potential differences in eye behavior between goal-directed forms of IDC and EDC. To this end, we manipulated the focus of attention (internal versus external) in two demanding cognitive tasks (anagram and sentence generation). IDC was associated with fewer and longer fixations and higher variability in pupil diameter and eye vergence compared to EDC, suggesting reduced visual scanning and higher spontaneous eye activity. IDC was further related to longer blinks, lower microsaccade frequency, and a lower angle of eye vergence. These latter changes appear conducive to attenuate visual input and thereby shield ongoing internal processes from external distraction. Together, these findings suggest that IDC is accompanied by characteristic eye behavior that reflects a decoupling of attention from external events and serves gating out visual input.


The Diagnostic Validity of Clinical Tests in Temporomandibular Internal Derangement: A Systematic Review and Meta-analysis.
To assess the diagnostic validity of clinical tests for temporomandibular internal derangement relative to magnetic resonance imaging (MRI). MEDLINE and Embase were searched from 1994 through 2009. Independent reviewers conducted study selection; risk of bias was assessed using Quality Assessment of studies of Diagnostic Accuracy included in Systematic reviews (QUADAS); ≥9/14) and data abstraction. Overall quality of evidence was profiled using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Agreement was measured using quadratic weighted kappa (κw). Positive (+) or negative (-) likelihood ratios (LR) with 95% CIs were calculated and pooled using the DerSimonian-Laird method and a random-effects model when homogeneous (I(2)≥0.40, Q-test p≤0.10). We selected 8 of 36 studies identified. There is very low quality evidence that deflection (+LR: 6.37 [95% CI, 2.13-19.03]) and crepitation (LR:5.88 [95% CI, 1.95-17.76]) as single tests and crepitation, deflection, pain, and limited mouth opening as a cluster of tests are the most valuable for ruling in internal derangement without reduction (+LR:6.37 [95% CI, 2.13-19.03]), (-LR:0.27 [95% CI, 0.11-0.64]) while the test cluster click, deviation, and pain rules out internal derangement with reduction (-LR: 0.09 [95% CI, 0.01-0.72]). No single test or cluster of tests was conclusive and of significant value for ruling in internal derangement with reduction. Findings of this review will assist clinicians in deciding which diagnostic tests to use when internal derangement is suspected. The literature search revealed a lack of high-quality studies; further research with adequate description of patient populations, blinded assessments, and both sagittal and coronal MRI planes is therefore recommended. Purpose: To assess the diagnostic validity of clinical tests for temporomandibular internal derangement relative to magnetic resonance imaging (MRI). Methods: MEDLINE and Embase were searched from 1994 through 2009. Independent reviewers conducted study selection; risk of bias was assessed using Quality Assessment of studies of Diagnostic Accuracy included in Systematic reviews (QUADAS); ≥9/14) and data abstraction. Overall quality of evidence was profiled using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Agreement was measured using quadratic weighted kappa (κw). Positive (+) or negative (−) likelihood ratios (LR) with 95% CIs were calculated and pooled using the DerSimonian–Laird method and a random-effects model when homogeneous (I2≥0.40, Q-test p≤0.10). Results: We selected 8 of 36 studies identified. There is very low quality evidence that deflection (+LR: 6.37 [95% CI, 2.13–19.03]) and crepitation (LR:5.88 [95% CI, 1.95–17.76]) as single tests and crepitation, deflection, pain, and limited mouth opening as a cluster of tests are the most valuable for ruling in internal derangement without reduction (+LR:6.37 [95% CI, 2.13–19.03]), (−LR:0.27 [95% CI, 0.11–0.64]) while the test cluster click, deviation, and pain rules out internal derangement with reduction (−LR: 0.09 [95% CI, 0.01–0.72]). No single test or cluster of tests was conclusive and of significant value for ruling in internal derangement with reduction. Conclusions: Findings of this review will assist clinicians in deciding which diagnostic tests to use when internal derangement is suspected. The literature search revealed a lack of high-quality studies; further research with adequate description of patient populations, blinded assessments, and both sagittal and coronal MRI planes is therefore recommended.


Blood-Brain Barrier Leakage and Microvascular Lesions in Cerebral Amyloid Angiopathy.
Background and Purpose- Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods- Eleven CAA cases (median [IQR] age=69 years [65-79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68-92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results- Our results demonstrated increased IgG positivity in the frontotemporal ( P=0.044) and parietooccipital ( P=0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P=0.005 and P=0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-β-positive vessels (Spearman ρ=0.71, P=0.015 and Spearman ρ=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P=0.005 and Spearman ρ=0.70, P=0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions- Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.


Catalytically Cleavable Detergent for Membrane Protein Studies.
Throughout the in vitro studies of membrane proteins (MPs), proper detergents are essential for the preparation of stable aqueous samples. To date, universally applicable detergents have not yet been reported to accommodate the distinct requirements for the highly diversified MPs and at the different stages of MP manipulation. Detergent exchange often has to be performed. We report herein the catalytically cleavable detergents (CatCDs) that can be efficiently removed to facilitate a complete exchange. To this end, functional groups, like propargyl and allyl, are introduced as branched chains or built in the hydrophobic chain close to the hydrophilic head. The representative CatCDs can be used as usual detergents in the extraction and purification of MPs and later be removed upon the addition of catalytic palladium. Mediated by CatCD-1, reconstitution of a transporter protein MsbA into a series of detergents was achieved. The extension of these designs could facilitate the future optimization of other biophysics studies.


Bruton's tyrosine kinase-mediated interleukin-2 gene activation in mast cells. Dependence on the c-Jun N-terminal kinase activation pathway.
Cross-linking of the high affinity IgE receptor (FcepsilonRI) on mast cells induces secretion of cytokines, including interleukin (IL)-2, through transcriptional activation of cytokine genes. Previously, defects in the gene coding for Bruton's tyrosine kinase (Btk) were shown to result in defective cytokine production in mast cells, and thereby mice carrying btk mutations exhibited diminished anaphylactic reactions in response to IgE and antigen. In this study, we provide evidence that the transcription factors involved in the IL-2 gene expression in T cells are also required for maximal activation of the IL-2 gene in FcepsilonRI-stimulated mast cells. Among them, AP-1 (Jun/Fos) and NF-AT were identified as candidate transcription factors that are regulated by Btk. Consistent with our previous data indicating that Btk regulates stress-activated protein kinases, c-Jun N-terminal kinase (JNK), c-Jun and other JNK-regulatable transcription factors are activated by FcepsilonRI cross-linking in a Btk-dependent manner. Further, FcepsilonRI-induced IL-2 gene activation is dependent on c-Jun and a component, SEK1, of its upstream activation pathway. Collectively, these data demonstrate that Btk regulates the transcription of the IL-2 gene through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast cells.


The role of chemotherapy in brain metastases.
Despite the widely held belief of the resistance to chemotherapy of brain metastases, central nervous system metastases of a malignancy are equally sensitive to chemotherapy as its metastases elsewhere in the body. This is due to the fact that the blood-brain barrier is disrupted in contrast enhancing brain metastases, and does not limit the response to chemotherapy. Therefore, the response rate of the primary tumour. Up-front chemotherapeutic treatment instead of radiotherapy of brain metastases should therefore be based on the chemosensitivity of the primary tumor to the used regimen, and not on the question whether the used agent penetrates an intact blood-brain barrier. First-line chemotherapy for brain metastases or with only minor neurological signs and symptoms, and who have an indication for systematic chemotherapy for metastases elsewhere in the body. In contrast, central nervous system micrometastases may hide behind an intact barrier, and this may be clinically relevant in patients that can be cured with chemotherapy (like in small cell lung cancer). Cytochrome P450 3A4 inducing anti-epileptic drugs like phenytoin, carbamazepine and phenobarbital may significantly increase the metabolism of many chemotherapeutic agents like CPT11 and paclitaxel (but also of newer biological agents like many tyrosine kinase inhibitors). These anti-epileptic drugs should be avoided in patients requiring chemotherapy with agents metabolised through the cytochrome P450.


Glyceraldehyde 3-phosphate dehydrogenase mutants of Escherichia coli.
We describe glyceraldehyde 3-phosphate dehydrogenase mutants of Escherichia coli. The gene (gap) is at approximately 34 min, with the transductional order gap-fadD-eda. One gap mutant is temperature sensitive and has a heat-labile enzyme. Another is amber.


Hypoxia-Responsive 19F MRI Probes with Improved Redox Properties and Biocompatibility.
19F magnetic resonance imaging (MRI), an emerging modality in biomedical imaging, has shown promise for in vitro and in vivo preclinical studies. Here we present a series of fluorinated Cu(II)ATSM derivatives for potential use as 19F magnetic resonance agents for sensing cellular hypoxia. The synthesized complexes feature a hypoxia-targeting Cu2+ coordination core, nine equivalent fluorine atoms connected via a variable-length poly(ethylene glycol) linker. Introduction of the fluorine moiety maintains the planar coordination geometry of the Cu2+ center, while the linker length modulates the Cu2+/+ reduction potential, 19F NMR relaxation properties, and lipophilicity. In particular, the 19F NMR relaxation properties were quantitatively evaluated by the Solomon-Bloembergen model, revealing a regular pattern of relaxation enhancement tuned by the distance between Cu2+ and F atoms. Finally, the potential utility of these complexes for sensing reductive environments was demonstrated using both 19F MR phantom imaging and 19F NMR, including experiments in intact live cells.


Glandular odontogenic cyst mimicking ameloblastoma in a 78-year-old female: A case report.
Glandular odontogenic cyst (GOC) is a rare, potentially aggressive jaw lesion. The common radiographic features include a well-defined radiolucency with distinct borders, presenting a uni- or multilocular appearance. A cystic lesion in the posterior mandible of a 78-year-old female was incidentally found. Radiographs showed a unilocular lesion with a scalloped margin, external root resorption of the adjacent tooth, and cortical perforation. This lesion had changed from a small ovoid shape to a more expanded lesion in a period of four years. The small lesion showed unilocularity with a smooth margin and a well-defined border, but the expanded lesion produced cortical perforation and a lobulated margin. The provisional diagnosis was an ameloblastoma, whereas the histopathological examination revealed a GOC. This was a quite rare case, given that this radiographic change was observed in the posterior mandible of an elderly female. This case showed that a GOC can grow even in people in their seventies, changing from the unilocular form to an expanded, lobulated lesion. Here, we report a case of GOC with characteristic radiographic features.


Chromatographic methods for the analysis of basic neurotransmitters and their acidic metabolites.
Chromatographic techniques for the determination of trace amounts of neurotransmitters were reviewed. The two techniques found to be most useful were GC-MS and the reversed-phase mode of HPLC with an electrochemical or fluorescent detector. For structure determination or unequivocal peak identification, GC-MS is the method of choice. In addition the limits of detection of GC-MS were better than those obtained by HPLC. However for routine analyses, HPLC is now being used in studies of mental illness and other diseases. Good resolution, reproducibility and sensitivity can be obtained without the derivatisation steps required for GC-MS, and catecholamines, serotonin, and their acidic metabolites can be concomitantly determined in one analysis.


Poisons Implicated In Homicidal, Suicidal And Accidental Cases In North-West Pakistan.
Pakistan has one of the highest prevalence of poisoning in the world. However, limited data exist on the frequency of poisons implicated in homicidal, suicidal, and accidental cases in North-West Pakistan (Khyber Pakhtunkhwa). This retrospective study of 353 cases and biological specimens of poisoning received at the department of Forensic medicine and toxicology, Khyber Medical College Peshawar from 13 districts of Khyber Pakhtunkhwa. Frequency of poisoning was assessed by testing each specimen for 17 different poisons. Of all the specimens, 250 (70.8%) specimens tested positive and the rest didn't show any indication of poisoning (n=103, 29.2%). The most frequent poisons detected were benzodiazepines (total n=75), organophosphates (total n=58), phencyclidine (total n=30) and morphine (total n=23). Gender had a significant association with benzodiazepines (p=0.011), tricyclic antidepressants (p=0.001), and organophosphates (p<0.001). Organophosphates were the most common cause of poisoning in females while benzodiazepines were the most common cause of poisoning in males. Poisoning by benzodiazepines, organophosphates and phencyclidine are the most common causes of intoxication in population of Khyber Pakhtunkhwa. Source of poisoning varies with gender for organophosphates, benzodiazepines and tricyclic antidepressants.


The influence of bone on 45 MV photon dose distributions.
In an attempt to assess the pertubation of 45 MV depth dose distribution in a water phantom equipped with various thicknesses of bone-equivalent plastic. An increased dose was observed immediately behind the bone material and a reduced dose was found for points located greater than 5 cm behind the bone-equivalent plastic. The most significant change of the depth dose curve was produced by bone located in the dose build-up region.


[The surgical treatment of incontinence in the male (author's transl)].
The authors undertake a complete review of the various techniques used for the surgical treatment of urinary incontinence in the male. Urethral repair (Young operation) has been abandoned. Creation of a smooth muscle sphincter in bladder gives approximately 32% continence. Use of the anal sphincter to ensure continence of the urethra gives approximately 60% good results. Urethral or bladder neck suspension by aponeurotic strips have given only 42% good results. Perineal muscular plasty procedures resulting a certain compression of the urethra have given approximately 68% good results. Perineal prostheses, despite a certain number of complications (fistulae, infections, urethral erosions) give 37% good results when all the published series are grouped together. Continence prostheses (Scott or Rosen) have given the same percentage of favourable results: 60%. In this review, the authors report the 13 operations which they have performed with insertion of a Kaufmann prosthesis with, in the long term, 6 continent patients out of the 13. Radiological analysis of micturition in these patients with a good result would appear to suggest to the authors that the Kaufmann prosthesis does not act only by simple compression of the urethra but provides a still tonic urethra with a support which enables it to play a role in continence. So much so that the prior study of the efficacy of urethral compression could be used to choose between the insertion of a Kaufmann prosthesis or the immediate recourse to artificial sphincters.


The use of diacetyl (2,3-butanedione) and related flavoring substances as flavorings added to foods-Workplace safety issues.
In 2001, staff of the National Institute of Occupational Safety and Health (NIOSH) identified diacetyl (2,3-butanedione) as a "marker" of exposure in a microwave popcorn manufacturing facility in which workers developed severe respiratory illness. Subsequent investigations identified additional workers in food and flavor manufacturing facilities also with severe respiratory illness. The flavor industry, NIOSH, and federal and state regulators conducted significant programs to address workplace safety concerns related to the manufacture of flavors and foods containing added flavors. These programs, initiated in 2001, continue today. Key to the success of these programs is understanding what flavors added to foods are and how they are manufactured, how they are incorporated into foods, the specific characteristics of diacetyl and related flavoring substances, and what actions may be taken to assure the safest workplaces possible.


Metabolic efficiency promotes protection from pressure overload in hearts expressing slow skeletal troponin I.
The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In this study, we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. At 2 to 3 months of age, ssTnI mice or their nontransgenic littermates underwent aortic constriction (TAC). TAC induced a 25% increase in nontransgenic heart size but only a 7% increase in ssTnI hearts (P<0.05). Nontransgenic TAC developed diastolic dysfunction (65% increase in E/A ratio), whereas the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from nontransgenic TAC mice showed reduced cardiac function and reduced creatine phosphate:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting nontransgenic TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in nontransgenic TAC hearts. Elevated glucose oxidation was mediated by a reduction in pyruvate dehydrogenase kinase 4 expression, enabling pyruvate dehydrogenase to compete against anaplerotic enzymes for pyruvate carboxylation. Expression of a single fetal myofilament protein into adulthood in the ssTnI-transgenic mouse heart induced downregulation of the gene expression response for pyruvate dehydrogenase kinase to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.


Islet autoantibodies in cord blood from patients who developed type 1 diabetes mellitus at 15-30 years of age.
Islet cell autoantibodies are early markers for type 1 diabetes. The aim of this study was to determine whether islet autoantibodies were present at birth in young adults who developed type 1 diabetes at 15-30 years of age. Cord blood sera from 30 patients who developed type 1 diabetes between 15 and 25 years of age and sera from 320 randomly selected control children were tested for islet cell antibodies (ICA) by indirect immunofluorescence and autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), islet cell antigen-2 (IA-2A) and insulin (IAA) by radiobinding assays. The young adults who developed type 1 diabetes did not differ from controls in the cord blood prevalence of any of the four islet autoantibodies. This is in contrast to our previous findings that children who developed type 1 diabetes below 15 years of age had an increased prevalence of cord blood islet autoantibodies. Our present data suggest that, in contrast to children, pre- and perinatal risk factors are less likely to be involved in the development of type 1 diabetes in young adults.


Altered serum factor VIII-related antigen (VIII : AGN)/von Willebrand factor (VIII : vWf) in haemophiliacs with inhibitors to factor VIII procoagulant activity (VIII : C).
Inhibitors to factor VIII (anti-F VIII) developing in patients with classic haemophilia have apparent specificity for the factor VIII procoagulant activity (VIII : C), rather than the factor VIII-related antigen (VIII : AGN) and von Willebrand factor (VIII : vWf) regions of the factor VIII complex. Since procoagulant function is absent following in vitro clotting, but serum retains VIII : AGN/vWf properties, we searched for differences in VIII : AGN and VIII : vWf of inhibitor serum that might relate to the presence of anti-F VIII. Rocket immunoelectrophoresis and the washed platelet ristocetin assay were performed on the plasma and serum of nine haemophiliacs with inhibitors, 23 non-inhibitor haemophiliacs and six normal subjects. Unlike normal and non-inhibitor haemophilic sera, that from five of nine inhibitor patients demonstrated absent VIII : vWf and significantly lower VIII : AGN (p less than 0.05). Furthermore, VIII : AGN of faster mobility was detected on crossed immunoelectrophoresis of the sera of three inhibitor patients. Thrombin clotting of plasma from haemophiliacs with high titer anti-F VIII was associated with a greater loss of VIII : vWf than seen with non-inhibitor haemophilic plasma. This effect was independent of the presence of platelets. These data indicate that in vitro clotting is associated with alteration in the serum VIII : AGN/vWf of some haemophiliacs with anti-F VIII.


HER2 Overexpression Triggers an IL1α Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance.
Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.Significance: IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040-51. ©2018 AACR.


Trehalose alleviates apoptosis by protecting the autophagy-lysosomal system in alveolar macrophages during human silicosis.
Alveolar macrophages (AMs) are the primary targets of silicosis. Blockade of autophagy may aggravate the apoptosis of AMs. Trehalose (Tre), a transcription factor EB (TFEB) activator, may impact the autophagy-lysosomal system in AMs during silicosis. However, the mechanism by which Tre acts upon AMs in silicosis is unknown. We collected AMs from twenty male workers exposed to silica and divided them into observer and silicosis patient groups. AMs from the two groups were then exposed to Tre. Western blot was used to measure the expression of autophagy-associated proteins. Lysosomal-associated membrane protein 1 (LAMP1) expression was observed using immunofluorescence and western blot. Apoptosis of the AMs was detected by TUNEL assay and western blot. Tre induced localization of TFEB to the nucleus in the AMs of both groups. After Tre exposure, LAMP1 levels increased and LC3 levels decreased in the AMs of both groups, suggesting that Tre may increase the function of the autophagy-lysosomal system. The LC3-II/I ratio in the Tre-exposed AMs was lower than in the AMs not exposed to Tre. The LC3-II/I ratio in AMs subjected to Tre plus Bafilomycin (Baf) was higher than the ratio in cells exposed to Tre or Baf individually. Additionally, p62 levels decreased after Tre stimulation in the AMs of both groups. This indicates that Tre may accelerate the process of autophagic degradation. We also found decreased levels of cleaved caspase-3 after Tre treatment in the AMs of both groups. However, p-mTOR (Ser2448) and p-mTOR (Ser2481) levels did not change significantly after Tre treatment, suggesting that the mTOR signaling pathway was not affected by Tre treatment. Our findings suggest that the restoration of autophagy-lysosomal function by Tre may be a potential protective strategy against silicosis.