Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.
Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.


Influence of lower-limb mechanical axis on the curative effect of medial high tibial osteotomy for knee osteoarthritis.
To investigate the effect of the ratio of the medial tibial plateau width to the total tibial plateau width on the therapeutic efficacy of high tibial osteotomy (HTO) on the medial side for the treatment of knee osteoarthritis. In this study, we retrospectively analyzed information of 278 patients who underwent medial HTO for knee osteoarthritis with varus deformity. The Tinetti Gait and Balance Assessment Tool, the Visual Analog Scale (VAS), and the Knee Society Scoring System (KSS) were used to comprehensively evaluate the function of the knee joint after HTO. After adjusting for potential confounding factors (i.e., age, gender, body mass index/BMI, and surgical site), the Tinetti assessment score was optimized when the degree of correction was 53.67%, with the β-value on the left and right sides of the inflection point of 0.49 (confidence interval, CI: 0.20, 0.78, P = 0.0009) and- 0.26 (95% CI: - 0.30, - 0.22, P < 0.0001), respectively. The KSS score was optimized when the degree of correction was 55.45%, with the β-value on the left and right sides of the inflection point of 2.77 (95% CI: 1.64, 3.90, P < 0.0001) and - 1.18 (95% CI: - 1.46, - 0.91, P < 0.0001), respectively. The VAS score was the lowest when the degree of correction was 55.00%, with the β-value on the left and right sides of the inflection point of - 0.16 (95% CI: - 0.29, - 0.03, P = 0.0146) and 0.08 (95% CI: 0.05, 0.10, P < 0.0001), respectively. Stratified analysis showed that the BMI affected the Tinetti assessment score (β = - 0.14, 95% CI: - 0.24, - 0.04, P = 0.0071). According to the smooth-curve fitting results, when the BMI was > 28, the Tinetti assessment score showed a negative trend. The degree of lower-limb mechanical axis correction correlated with the functional status of the knee joint after MOW HTO. When the ratio of the medial tibial plateau width to the total tibial plateau width was approximately 55%, the post-MOW HTO outcomes were optimized and the patients experienced the highest satisfaction. In addition, very high BMI was not conducive for the postoperative recovery of the knee joint function. III Case-control study/Retrospective comparative study.


Perceptual load, voluntary attention, and aging: an event-related potential study.
The locus of attentional selection is known to vary with perceptual load (Lavie et al., 2004). Under voluntary attention, perceptual load modulates selective visual processing at an early cortical stage, as reflected in the posterior P1 and N1 components of the event-related potentials (ERPs). Adult aging also affects both behavioral and ERP signs of attentional selection. However, it is not known whether perceptual load modulates this relationship. Accordingly, in the present study ERPs were recorded in a voluntary attention task. Young and old participants were asked to discriminate the direction of a target line embedded within a display of four lines that appeared in the left or right visual field. Participants responded faster and more accurately to valid relative to invalid trials and to low-load relative to high-load condition. Older participants responded more slowly and with lower accuracy than young participants in all conditions. The amplitudes of the posterior contralateral P1 and N1 components in valid trials were larger than that in invalid trials in all conditions. N1 amplitude was larger under the high load condition than that in the low load condition. Moreover, in the high perceptual load condition, the old group had a larger N1 than the young group at contralateral sites. The findings suggest that under voluntary attention, perceptual load and aging modulates attentional selection at an early but not the earliest stage, during the N1 (120-200ms) time range. Increased N1 amplitude in older adults may reflect increased demands on target discrimination in high perceptual load.


Pattern and diagnostic evaluation of systemic autoinflammatory diseases other than familial Mediterranean fever among Arab children: a multicenter study from the Pediatric Rheumatology Arab Group (PRAG).
To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1-12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1-10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries.


Use of extracorporeal membrane oxygenation for heart graft dysfunction in adults: incidence, risk factors and outcomes in a multicentric study.
The decision about whether to use venoarterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiac graft dysfunction (GD) is usually made on a case-by-case basis and is guided by the team's experience. We aimed to determine the incidence of VA-ECMO use after heart transplantation (HT), to assess early- and long-term outcomes and to assess risk factors for the need for VA-ECMO and early mortality in these patients. We included adults who underwent heart transplantation at 3 cardiac centres who met the most recent International Society for Heart and Lung Transplantation definition of graft dysfunction (GD) over a 10-year period. Pre-transplant, intraoperative and posttransplant characteristics of the heart recipients as well as donor characteristics were analyzed and compared among recipients with GD treated with and without VA-ECMO. There were 135 patients with GD in this study, of whom 66 were treated with VA-ECMO and 69 were not. The mean follow-up averaged 81.2 months (standard deviation 36 mo, range 0-184 mo); follow-up was complete in 100% of patients. The overall incidence of GD (30%) and of VA-ECMO use increased over the study period. We did not identify any predictive pre-transplantation factors for VA-ECMO use, but patients who required VA-ECMO had higher serum lactate levels and higher inotropes doses after HT. The overall survival rates were 83% and 42% at 1 year and 78% and 40% at 5 years among patients who received only medical treatment and those who received VA-ECMO, respectively. Delayed initiation of VA-ECMO and postoperative bleeding were strongly associated with increased in-hospital mortality. The incidence of GD increased over the study period, and the need for VA-ECMO among patients with GD remains difficult to predict. In-hospital mortality decreased over time but remained high among patients who required VA-ECMO, especially among patients with delayed initiation of VA-ECMO.


Palmitate-induced beta-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms.
Type 2 diabetes often displays hyperlipidemia. We examined palmitate effects on pancreatic islet function in relation to FFA receptor GPR40, NO generation, insulin release, and the PPARgamma agonistic thiazolidinedione, rosiglitazone. Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells and insulin release from MIN6c cells and mouse islets. Culturing islets 24 h with palmitate at 5 mmol/l glucose induced beta-cell iNOS expression as revealed by confocal microscopy and increased the activities of ncNOS and iNOS associated with suppression of glucose-stimulated insulin response. Rosiglitazone reversed these effects. The expression of iNOS after high-glucose culturing was unaffected by rosiglitazone. Downregulation of GPR40 by antisense treatment abrogated GPR40 expression and suppressed palmitate-induced iNOS activity and insulin release. We conclude that, in addition to mediating acute FFA-stimulated insulin release, GPR40 is an important regulator of iNOS expression and dysfunctional insulin release during long-term exposure to FFA. The adverse effects of palmitate were counteracted by rosiglitazone at GPR40, suggesting that thiazolidinediones are beneficial for beta-cell function in hyperlipidemic type 2 diabetes.


[The treatment of Cushing's syndrome by selective excision of pituitary adenoma. 3 cases (author's transl)].
In three patients suffering from Cushing's disease, exploration revealed an enclosed pituitary adenoma in one case and a microadenoma in two cases. Selective excision via a transphenoidal approach resulted in cure of Cushing's disease as reflected by complete regression of clinical signs and the restoration of circadian rythm of cortisol. Regular follow-up over a period of more than two years showed the persistence of normal regulation of the corticotrophic sector of the pituitary.


Androgen receptor expression in a Sri Lankan patient cohort with early breast carcinoma.
Androgen receptor (AR) expression is emerging as a prognostic biomarker in breast carcinoma (BCa). The study aimed to determine the prevalence of AR expression by immunohistochemical analysis among a cohort of Sri Lankan women with early BCa and to evaluate its association with clinicopathological features including immunohistochemical molecular subtype and early survival. We studied the clinical and pathological features and immunohistochemical profile of 141 women undergoing primary surgery for early BCa, followed by standard adjuvant therapy. AR status was assessed by immunohistochemistry in all cases. Overall survival (OS) and disease-free survival (DFS) was determined. The relationship between AR expression and clinical and pathological parameters and immunohistochemical molecular subtype was analyzed using Student T test and chi-square tests. Cox regression analysis was used to analyze the prognostic impact of AR expression. AR expression was seen in 40.8%(95%CI 33.10-49.07%) of the BCa study cohort. None of the clinical data studied showed a significant association with the AR status(p > 0.05). Ductal carcinoma in situ(p = 0.003), oestrogen receptor (ER) (p = 0.001) and progesterone receptor (PR) (p = 0.001) positivity and luminal IHC molecular subtype(p = 0.016) were significantly associated with AR-positive status. AR-negative status was significantly associated with tumour necrosis > 50%(p = 0.031), moderate to extensive lymphocytic infiltrate at the tumour margin(p = 0.025) and basal triple negative breast carcinoma(p = 0.016). The mean duration of patient follow-up was 46.70(95% CI 46.495-46.905) months (3.89 years). On univariate analysis, AR-positivity was associated with better OS among ER-positive tumours(p = 0.047), specifically in postmenopausal women (p = 0.030). In ER-negative tumours, AR positivity was associated with worse DFS (p = 0.036). On multivariate analysis, TNM stage and ER/AR status were predictive of survival. ER-positive/AR-positive (ER+/AR+) tumours demonstrated better OS than ER-positive/AR-negative (ER+/AR-) tumours(p = 0.015). ER-negative/AR-positive (ER-/AR+) tumours (p = 0.014) had a worse DFS than ER-negative/AR-negative (ER-/AR-) tumours. AR prevalence obtained was low. AR positivity was associated with positivity for ER and PR. On multivariate analysis, apart from TNM stage only ER/AR status were predictive of OS and DFS, with concordant expression of ER/AR demonstrating a better, early survival.


An International Delphi Consensus on Diagnostic Criteria for Buerger's Disease.
Buerger's disease (BD) remains a debilitating condition. Despite multiple published diagnostic criteria for BD, none is universally accepted as a gold standard. We conducted a 2-round modified Delphi consensus study to establish a consensus on the diagnostic. The questionnaire included statements from several commonly used diagnostic criteria for BD. Qualitative and quantitative analysis methods were performed. An agreement level of 70% was applied. Twenty nine experts from 18 countries participated in this study. Overall, 75 statements were circulated in Round 1. Of these, 28% of statements were accepted. Following comments, 21 statements were recirculated in Round 2 and 90% were accepted. Although more than 90% of the experts did not agree that the diagnosis of BD can be based only on clinical manifestation, none of the nonclinical manifestations of BD were agreed as a part of the diagnostic criteria. There was an agreement that a history of tobacco consumption in any form, not necessarily confined to the current use, should be a part of the diagnostic criteria of BD. The history of thrombophlebitis migrans, even if not present at presentation, was accepted as a clue for BD diagnosis. It was also agreed that discoloration of the toes or fingers could be included in the diagnostic criteria of BD. Experts agreed that histology results could differentiate BD from atherosclerosis obliterans and other types of vasculitis. The presence of corkscrew collaterals on imaging and burning pain reached the agreement at the first round but not at the second. There was no consensus regarding age cut-off, the requirement of normal lipid profile, and normal blood glucose for BD diagnosis. The present study demonstrated discrepancies in the various published diagnostic criteria for BD and their selective utilization in routine clinical practice worldwide. We propose that all published diagnostic criteria for BD be re-evaluated for harmonization and universal use.


Blood flow-dependent uptake of indium-111 monoclonal antimyosin antibody in canine acute myocardial infarction.
The relation of myocardial blood flow and indium-111 (111In) antimyosin antibody uptake was studied by inducing myocardial infarction in 18 dogs, 8 with closed chest left anterior descending artery balloon occlusion for 3 h followed by reperfusion (group A) and 10 dogs with open chest left anterior descending artery ligation (without reperfusion, group B). The relation of antimyosin uptake to myocardial injury has been documented. However, its relation to tracer delivery by myocardial blood flow has not been studied and has been assumed to be independent. Indium-111 antimyosin antibody, 2 mCi, was injected 20 min after reperfusion and 3 h after coronary artery ligation in groups A and B, respectively. Regional blood flows were determined by radiolabeled microspheres during occlusion and 24 h later in both groups. On day 2, dogs were killed after risk zone delineation with gentian violet. The heart was excised and stained with triphenyltetrazolium chloride solution and graded for increasing severity of tissue injury based on extent of staining. Microsphere activity and 111In antimyosin activity were measured in control tissue (grade 1), noninfarct tissue at risk (grade 2), mixed tissue (grade 3), infarct tissue (grade 4) and hemorrhagic infarct tissue (grade 5, present only in group A dogs). Count activity was normalized to that of the mean value in control tissue (grade 1) and expressed as a ratio of activity. Indium-111 antimyosin activity was high in triphenyltetrazolium chloride grade 4 tissue in both groups but was attenuated in grade 4 tissue in group B dogs (10.6 +/- 5.1 vs. 5.0 +/- 4.5; p < 0.05 group A vs. group B), which had lower blood flow on day 2 (0.51 +/- 0.36 vs. 0.23 vs. 0.22; p < 0.01). Normalizing 111In antimyosin activity for blood flow on day 2 resulted in equivalent 111In antimyosin uptake for infarct tissue (32.6 +/- 21.6 vs. 36.6 +/- 29.8 for group A vs. group B; p = NS). Thus, 111In antimyosin uptake is a specific marker of necrotic tissue with a high signal ratio in reperfused tissue. However, its uptake is dependent on residual blood flow in the infarct territory. Indium-111 antimyosin could potentially serve as a suitable tracer for infarct sizing if myocardial blood flow in the same region were factored simultaneously.


Nurses' Perceptions of the Factors Contributing to the Development of the Love of the Profession: A Qualitative Content Analysis.
As a professional value, the love of the profession can significantly affect nurses' professional practice, behaviors and commitment. Many different factors can affect the love of the profession. The exploration of nurses' experiences of these factors can provide valuable data for development of the love of the profession. The aim of this study was to explore nurses' perceptions of the factors contributing to the development of the love of the profession. This qualitative study was conducted in 2020-2021 using the conventional content analysis approach. The participants were thirteen nurses with different organizational positions purposively recruited from different settings in Iran. The data were collected via semi-structured interviews, and were analyzed via the conventional content analysis approach proposed by Graneheim and Lundman. The factors contributing to the development of the love of the profession were categorized into four main categories, namely the public perception of the profession (with three subcategories), educational variables (with two subcategories), the characteristics of the profession (with four subcategories), and nurses' self-evaluation (with three subcategories). The love of the profession is affected by a wide range of personal, educational, professional and social factors. The manipulation of these factors would help to develop nurses' and nursing students' love of the profession, and encourage people to choose nursing as a career.


Searching for antimicrobial photosensitizers among a panel of BODIPYs.
In recent years, antimicrobial Photodynamic Therapy (aPDT) gained increasing attention for its potential to inhibit the growth and spread of microorganisms, both as free-living cells and/or embedded in biofilm communities. In this scenario, compounds belonging to the family of boron-dipyrromethenes (BODIPYs) represent a very promising class of photosensitizers for applications in antimicrobial field. In this study, twelve non-ionic and three cationic BODIPYs were assayed for the inactivation of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. As expected, S. aureus showed to be very sensitive to BODIPYs and mild conditions were sufficient to reach good rates of photoinactivation with both neutral and monocationic ones. Surprisingly, one neutral compound (named B9 in this study) resulted the best BODIPY to photoinactivate P. aeruginosa PAO1. The photoinactivation of C. albicans was reached with both neutral and mono-cationic BODIPYs. Furthermore, biofilms of the three model microorganisms were challenged with BODIPYs in light-based antimicrobial technique. S. aureus biofilms were successfully inhibited with milder conditions than those applied to P. aeruginosa and C. albicans. Notably, it was possible to eradicate 24-h-old biofilms of both S. aureus and P. aeruginosa. In conclusion, this study supports the potential of neutral BODIPYs as pan-antimicrobial PSs.


Ultrafast inactivation of SARS-CoV-2 with 266 nm lasers.
Disinfection eliminates pathogenic microorganisms and ensures a biosafe environment for human beings. The rapid spread of COVID-19 is challenging traditional disinfection methods in terms of reducing harmful side effects and conducting faster processes. Spraying large-scale chemical disinfectants is harmful to individuals and the environment, while UV lamp and light-emitting diode (LED) disinfection still requires a long exposure time due to the low irradiance and highly divergent beam characteristics. Given that a laser maintains a high irradiance over a long distance, we studied the effectiveness of lasers as a new disinfection method, and the results show the capability for ultrafast inactivation of SARS-CoV-2 virus with a 266 nm laser. This work confirms UV lasers as a good candidate for disinfection.


Treatment of internal iliac artery pseudoaneurysm by an endovascular approach.
Pseudoaneurysms of the internal iliac artery are uncommon and are usually associated with trauma. We report the case of a 32-year-old man with a 15-day history of trauma to the abdomen and edema of the lower left limb. An arteriogram demonstrated proximal occlusion of the popliteal artery and a pseudoaneurysm in the internal iliac artery. Embolization of the pseudoaneurysm was performed using segments of guide wire that occluded the pseudoaneurysm, followed by proximal occlusion, which was accomplished using coils. An arteriogram after the procedure revealed adequate occlusion of the lesion. This association of guide wires and coils is a treatment option in cases of pseudoaneurysm of the internal iliac artery with large volumes needing to be occluded.


Efficient access to conjugated 4,4'-bipyridinium oligomers using the Zincke reaction: synthesis, spectroscopic and electrochemical properties.
The cyclocondensation reaction between rigid, electron-rich aromatic diamines and 1,1'-bis(2,4-dinitrophenyl)-4,4'-bipyridinium (Zincke) salts has been harnessed to produce a series of conjugated oligomers containing up to twelve aromatic/heterocyclic residues. These oligomers exhibit discrete, multiple redox processes accompanied by dramatic changes in electronic absorption spectra.


Providing a specialist nursing service to cardiac patients.
Susanne Christie, Arrhythmia Nurse Specialist, NHS Tayside (firstname.lastname@example.com), runner-up in the Cardiovascular Nurse of the Year category of the BJN Awards 2020.


Utility of cytopathologic diagnosis of adult solid renal lesions: An academic Institution's 10-year experience.
Fine needle aspiration (FNA) and/or needle core biopsy (NCB) are increasingly used for managing patients with renal lesions, especially small renal masses (SRMs). One of the treatment options for SMRs is active surveillance. Hence, accurate diagnosis of renal lesions is critical for treatment planning. The aim of this study is to investigate the utility of FNA and/or NCB in the diagnosis of adult renal lesions at our institute. Laboratory information system was queried over a period of 10 years (2011-2020) to identify cases of FNA and/or NCB with touch preparation (TP) of adult renal masses. Patient demographics, cytopathologic diagnoses, ancillary tests and follow-up surgical resection data were reviewed and correlated. A total 138 cases from 138 patients (male = 80, female = 58) were identified. Sixty-one (44.20%) cases had FNA and NCB, 48 (34.78%) had NCB only and 29 (21.01%) had FNA only. 118 (85.50%) cases had definitive diagnoses and 13 (9.42%) had indeterminant diagnoses and seven cases were non-diagnostic (5.07%). Most common benign and malignant diagnoses were oncocytoma and clear cell renal cell carcinoma (CCRCC). 41/138 (29.71%) cases had follow-up resection. There were no false positive or false negative cases. Subtyping was feasible in majority cases with only 3/138 (2.17%) misclassified cases. Majority of renal masses (85.50%) had definitive cytology diagnoses. Only three had misclassification. FNA and/or NCB are useful methods in diagnosing and subclassifying adult renal masses and showed high accuracy (91.89%) when compared to surgical resections.


Cleft lip-palate deformities in Western China: epidemiology, surgical reconstruction, and cost.
A series of 46 procedures (42 patients) was performed on youth with cleft lip-palate deformities in Lanzhou, China. Patients' ages ranged from 6 months to 18 years. There were no short-term complications in this series, which included many advanced cases. The estimated cost per patient was 1590 US dollars. Youth with unrepaired cleft lip-palate in western China can be treated in a cost-effective manner.


Intermittent ischemia but not ischemic preconditioning is effective in restoring bile flow after ischemia reperfusion injury in the livers of aged rats.
Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of this study was to investigate the effects of IPC and INT on ischemia reperfusion injury in aged livers. A rat model of segmental hepatic ischemia (45 min) and reperfusion (60 min) was used. Bile flow, as an indicator of early hepatocyte damage and dynamic liver function, plasma concentrations of bilirubin, liver marker enzymes, and liver histology were assessed. In young rats (8-13 weeks), IPC regimes of 10 min clamping and 10 min reperfusion, and 5 min clamping and 30 min reperfusion, restored bile flow to 23 and 42%, respectively, of the initial value, compared to 14 and 88% for continuous clamping and controls, respectively. An INT regime of three cycles of alternating 15 min perfusion and 15 min clamping gave a substantially greater (70%) restoration of bile flow. In aged rats (20-24 months), the IPC regimes did not give any restoration of bile flow. By contrast, the INT regime restored bile flow to 68%. Plasma bilirubin concentrations were lowest in the INT groups, whereas alanine transaminase concentrations for the IPC and INT groups compared with the continuous clamping groups showed no significant differences. In young rats, INT is more effective than IPC in restoring the immediate consequences of IP-induced damage to hepatocytes and liver function after ischemia-reperfusion. In aged rats INT, but not IPC, reverses hepatocyte damage and restores liver function. INT may promote better hepatocyte and liver function than IPC following the surgical resection of aged livers.


In Situ Cryo-Electron Tomography: A Post-Reductionist Approach to Structural Biology.
Cryo-electron tomography is a powerful technique that can faithfully image the native cellular environment at nanometer resolution. Unlike many other imaging approaches, cryo-electron tomography provides a label-free method of detecting biological structures, relying on the intrinsic contrast of frozen cellular material for direct identification of macromolecules. Recent advances in sample preparation, detector technology, and phase plate imaging have enabled the structural characterization of protein complexes within intact cells. Here, we review these technical developments and outline a detailed computational workflow for in situ structural analysis. Two recent studies are described to illustrate how this workflow can be adapted to examine both known and unknown cellular complexes. The stage is now set to realize the promise of visual proteomics--a complete structural description of the cell's native molecular landscape.


Assessment of Serum Vitamin D Levels in Patients with Vitiligo in Jordan: A Case-Control Study.
Low vitamin D serum levels have been associated with many autoimmune disorders and several other skin diseases. Vitiligo is an autoimmune disease characterized by destruction of melanocytes by immune mechanisms. Melanocytes express vitamin D receptors, and their function can be affected by vitamin D status. The main objective of this study is to compare vitamin D levels in patients with vitiligo vs normal population and whether vitamin D deficiency is associated with vitiligo. A case-control study was conducted. 100 vitiligo patients and 100 as controls were included in this study. Serum vitamin D level was measured for both vitiligo patients and controls, results were compared, and statistical analysis was done to compare the results. The median age of vitiligo cases was 23 years (ranges, 2-80). 58% of vitiligo patients were females. The median vitamin D level was not significantly different between the two groups (vitiligo = 14.1 (IQR 9.9-20.4) vs control = 16.5 (IQR 10.3-25.3) (P=0.28)). Most vitiligo cases and controls were found to have low levels of vitamin D (either insufficient 20-30 ng/mL or low <20 ng/mL). There was no significant difference in vitamin D levels in vitiligo patients compared to controls. However, vitamin D levels were generally low in both groups.


Influence of phospholipid polyunsatured fatty acid composition on some metabolic disorders induced in rat cardiomyocytes by hypoxia and reoxygenation.
The influence of membrane polyunsaturated fatty acid (PUFA) composition on lactate production, energy status, enzyme leakage and cell defences against oxygen free radical production was studied in cultured rat ventricular myocytes during hypoxia and reoxygenation. After 4 days in a conventional serum-supplemented medium, the cardiomyocytes were incubated for 24 h in synthetic media containing either linoleate and arachidonate (SM6 Medium) or linolenate and eicosapentaenoate (SM3 Medium) as unique source of PUFA. The fatty acid n-6/n-3 ratio of phospholipid was 13.1 in SM6 cells and 0.9 in SM3 cells. Hypoxia induced an increase in lactate production, severe decreases in ATP and ADP, leakage of cellular lactate dehydrogenase and reduction of superoxide dismutase and glutathione peroxidase activities. Reoxygenation of hypoxic cells reduced lactate production to normal aerobic values and allowed slight resynthesis of ATP from AMP. However, lactate dehydrogenase release was not stopped by reoxygenation, and decreases in superoxide dismutase and glutathione peroxidase activities were not avoided. The majority of the biochemical parameters measured during normoxia, hypoxia and reoxygenation were not significantly affected by changes in the fatty acid composition of membrane phospholipids, except for reduced superoxide dismutase activity which appeared earlier in SM3 cells during hypoxia. We conclude that the sarcolemmal PUFA composition of cultured rat ventricular myocytes does not significantly influence altered cell metabolism elicited by hypoxia and reoxygenation.


Molecular analyses of sentinel lymph nodes: an open question.
To detect micrometastases in the sentinel lymph nodes (SLN) of melanoma patients the authors analysed 52 lymph nodes (47 SLNs and five non-sentinel) and 17 corresponding primary skin melanomas using reverse transcriptase-polymerase chain reaction assays in paraffin-embedded tissues to detect the mRNAs of tyrosinase, MAGE1, MAGE3, MIA, MART-1 and mRNA coding for telomerase catalytic component. Our data show that the use of molecular markers for melanoma micrometastases detection in SLN is still in a very preliminary stage. In comparing the molecular analysis results with the pathological staging we did not find any evident correlation with the expression of the analysed genes in SLN. There are no data for judging the prognostic significance of the detection of circulating tumour cells in patients without clinically recognizable metastases. Despite progress in the field with simultaneous detection of several markers it was assumed that tyrosinase mRNA remains the best target for the detection of metastatic melanoma cells.


Humble with God? How Education and Race Shape the Association Between God-Mediated Control and Humility in Later Life.
In contrast to the vibrant interdisciplinary literature on other virtues, such as forgiveness and gratitude, the study of humility has developed more slowly. Over the 2 decades, there has been a proliferation of research on humility. In this study, we assess the interrelationship between a core feature of religious life, God-mediated control, and humility. We assess the interrelationship between God-mediated control (the belief that God is a collaborative partner working together with humans) and humility. We also assess how the relationship between God-mediated control and humility may be conditional on two sociodemographic characteristics among middle-aged and older adults, education and race. Data for this study come from Wave 5 of the Religion, Aging, and Health Study (2013), a nationwide survey of Whites and African Americans (N = 1152). We test our hypotheses with a series of OLS regression models. We find that stronger perceptions of God-mediated control were associated with greater humility among older adults. Results from our moderation analyses also show that the relationship between God-mediated control and greater humility was stronger for low status groups, namely, the less educated and Black older adults. The cognitive belief that God can be trusted as an intimate collaborator in the chaos of human life appears to predict humility among older adults, perhaps by acknowledging one's dependence on a superior being and appreciating the limits of human finitude and acknowledging God's greatness outside one's self. Devoid of secular resources, the less educated and Black Americans might find greater meaning and significance in their association with God and may feel no need to establish their own worth through the attainment of worldly accomplishments or knowledge. Given the centrality of humility to religious/spiritual life, we suggest how future interdisciplinary research can build on the findings of our study.


Geometries of functional group interactions in enzyme-ligand complexes: guides for receptor modelling.
An approach is described which makes use of X-ray structural data from enzyme-ligand complexes in order to obtain information for application in receptor modelling. The atomic surroundings of five different ligand functional groups were determined for all complex structures recorded in the Brookhaven Protein Data Bank. These atomic surroundings were then superimposed with respect to the atoms of the functional groups of the ligands in order to obtain clouds of neighbouring atoms. General principles were sought to describe the orientation or favoured position of groups or atoms around those functional groups when bound to a macromolecule. Some simple conclusions and leads for further modelling were thus derived.


Antimicrobial and Cytotoxic Activity of Extracts of Ferula heuffelii Griseb. ex Heuff. and Its Metabolites.
The antimicrobial and cytotoxic activities of isolates (CHCl3 and MeOH extracts and selected metabolites) obtained from the underground parts of the Balkan endemic plant Ferula heuffelii Griseb. ex Heuff. were assessed. The CHCl3 and MeOH extracts exhibited moderate antimicrobial activity, being more pronounced against Gram-positive than Gram-negative bacteria, especially against Staphylococcus aureus (MIC=12.5 μg/ml for both extracts) and Micrococcus luteus (MIC=50 and 12.5 μg/ml, resp.). Among the tested metabolites, (6E)-1-(2,4-dihydroxyphenyl)-3,7,11-trimethyl-3-vinyldodeca-6,10-dien-1-one (2) and (2S*,3R*)-2-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-2,3-dihydro-7-hydroxy-2,3-dimethylfuro[3,2-c]coumarin (4) demonstrated the best antimicrobial activity. Compounds 2 and 4 both strongly inhibited the growth of M. luteus (MIC=11.2 and 5.2 μM, resp.) and Staphylococcus epidermidis (MIC=22.5 and 10.5 μM, resp.) and compound 2 additionally also the growth of Bacillus subtilis (MIC=11.2 μM). The cytotoxic activity of the isolates was tested against three human cancer cell lines, viz., cervical adenocarcinoma (HeLa), chronic myelogenous leukemia (K562), and breast cancer (MCF-7) cells. The CHCl3 extract exhibited strong cytotoxic activity against all cell lines (IC50 <11.0 μg/ml). All compounds strongly inhibited the growth of the K562 and HeLa cell lines. Compound 4 exhibited also a strong activity against the MCF-7 cell line, comparable to that of cisplatin (IC50 =22.32±1.32 vs. 18.67±0.75μM).


Comparative analysis of 2- versus 3-dimensional sonography of the supraspinatus tendon.
The purpose of this study was to determine the reliability in the analysis of images acquired using a dedicated 3-dimensional (3D) ultrasound transducer and conventional 2-dimensional (2D) images in the detection and characterization of supraspinatus tendon tears. Images of the supraspinatus tendon in 42 patients who had undergone 2D and 3D sonography were classified by two readers independently as no tear, full-thickness tear, or partial-thickness tear. When present, the tear size and location were recorded. Inter- and intra-rater reliability for the two data sets were calculated. There was substantial agreement between the two readers in the classification of supraspinatus tendon tears on 2D images (κ = 0.79) but only moderate agreement on 3D images (κ = 0.48). There was moderate to substantial agreement in the classification of tears between the 2D and 3D images for both readers (reader 1, κ = 0.64; reader 2, κ= 0.54). The most common cause of a discordant result was the interpretation of a small hypoechoic region at the footprint as a partial tear on 3D images, compared to a normal appearance on 2D images. Use of a dedicated 3D ultrasound transducer has poorer inter- and intra-rater reliability for the assessment of supraspinatus tendon tears compared to 2D sonography because of the interpretation of small partial-thickness tears at the footprint on 3D images, a common region affected by anisotropy.


A fusion approach to improve accuracy and estimate uncertainty in cuffless blood pressure monitoring.
A substantial barrier to the clinical adoption of cuffless blood pressure (BP) monitoring techniques is the lack of unified error standards and methods of estimating measurement uncertainty. This study proposes a fusion approach to improve accuracy and estimate prediction interval (PI) as a proxy for uncertainty for cuffless blood BP monitoring. BP was estimated during activities of daily living using three model architectures: nonlinear autoregressive models with exogenous inputs, feedforward neural network models, and pulse arrival time models. Multiple one-class support vector machine (OCSVM) models were trained to cluster data in terms of the percentage of outliers. New BP estimates were then assigned to a cluster using the OCSVMs hyperplanes, and the PIs were estimated using the BP error standard deviation associated with different clusters. The OCSVM was used to estimate the PI for the three BP models. The three BP estimations from the models were fused using the covariance intersection fusion algorithm, which improved BP and PI estimates in comparison with individual model precision by up to 24%. The employed model fusion shows promise in estimating BP and PI for potential clinical uses. The PI indicates that about 71%, 64%, and 29% of the data collected from sitting, standing, and walking can result in high-quality BP estimates. Our PI estimator offers an effective uncertainty metric to quantify the quality of BP estimates and can minimize the risk of false diagnosis.


Comparative carcinogenic and mutagenic activity of coal tar and petroleum asphalt paints used in potable water supply systems.
Coal tar and petroleum asphalt paints are among the products used as coatings for water pipes and storage tanks to retard corrosion. Formulations of these coatings were tested in the Ames mutagenesis and the mouse skin carcinogenesis bioassays. To test the mutagenicity of the paints, six doses ranging from 0.005 to 10 microliters per plate were assayed. In the mouse skin bioassay, doses of the coal tar paints ranging from 0.2 to 200 microliters were administered topically to 30 SENCAR mice per group. These initiating doses were followed by applications of 1.0 micrograms of 12-o-tetradecanoyl-phorbol-13-acetate (TPA) in 0.2 ml acetone topically, three times weekly for 20 weeks. Petroleum asphalt paints were tested in groups of 40 animals at 200 and 600 microliters doses. All coal tar paints showed mutagenic activity after metabolic activation with S-9, with the highest response being in strains TA 98 and TA 100. None of the petroleum asphalt paints gave mutagenic responses. Both types of coatings resulted in positive responses in the initiation/promotion study. The coal tar paints gave rise to 1000-1800 times the tumor response observed with petroleum asphalt products. One coal tar product was positive when tested as a complete carcinogen in the mouse at 2 microliters per application once weekly for 30 weeks, whereas the asphalt paint was negative at 100 times the dose. The biological responses to the products were greater than expected from their polycyclic aromatic hydrocarbon (PAH) content. These findings suggest that the hazard posed by these coatings may not be fully explained by their PAH contents.


[Management and prevention of abuse in Quebec: a program of sociolegal pediatrics at the Sainte-Justine Hospital in Montreal].
In Quebec, the Child's Protection law protects the child from birth until 18 years of age when child abuse or neglect is suspected. Since 1990, the program of the Child Protection Clinic of Sainte-Justine Hospital (Montreal) offers a special unit for evaluation and prevention of child abuse and neglect, constituted by a multidisciplinary team including five pediatricians. About 500 children are referred each year in external consultations or from hospital units. In addition, the pediatricians participate in the "programme Santé-Enfance-Jeunesse", a prevention program in the Montreal area. They also act as expert witnesses in court. Thus Quebec's pediatricians fully participate in a child's protection with their activities in different levels of diagnosis, management and prevention of child abuse and neglect.


High nodal positivity rates even in good clinical responders after chemoradiation of rectal cancer: is organ preservation feasible?
Local excision (LE) is emerging as a treatment option for rectal cancer responding well to chemoradiation. However, it does not address the mesorectal nodal burden. We aimed to identify the factors influencing nodal positivity and subsequently defined a low-risk group by including only patients at low risk. A single-centre, retrospective database analysis was carried out of patients with radically resected rectal cancer after neoadjuvant chemoradiation. This study included 524 patients with predominantly low rectal tumours. Nodal positivity among ypT0, T1 and T2 groups was 14.7%, 28% and 30%, respectively. Multivariate analysis with stepwise logistic regression identified the following low-risk features: age ≥ 40 years, nonsignet ring cell carcinoma (SRCC) histology and pathological complete response (pCR). Sixty-nine patients fulfilling all three criteria were analysed and the nodal positivity was found to be 10.1%, which implies that, if these patients had been selected for LE, one in 10 would have had positive mesorectal nodes. Even in patients with low-risk criteria (pCR, non-SRCC histology and age ≥ 40 years), the residual positive nodal disease burden is 10%. Whether this high incidence of residual nodal disease translates into a similar risk of locoregional recurrence if an organ-preservation strategy is adopted is unclear.


Anticoagulant flavonoid oligomers from the rhizomes of Alpinia platychilus.
Two pairs of enantiomers of flavonoid oligomers (1a and 1b, 2a and 2b) along with one known chalcone (3) were isolated from the rhizomes of Alpinia platychilus. Their structures were elucidated on the basis of spectroscopic data (MS and 1D/2D NMR). The absolute configurations of the flavonoid oligomers were established by their ECD spectra. Separation of the enantiomeric mixtures (1a and 1b, 2a and 2b) was achieved on a chiral column using hexane:isopropyl alcohol:ethanol (7:2:1) as eluents. The anticoagulant assay showed that 2a, 2b and 3 exhibited potent activities to prolong the prothrombin times (PT) and the thrombin times (TT).


Solid-phase capture and release of arginine peptides by selective tagging and boronate affinity chromatography.
A method for the selection of arginine-containing peptides from a mixture by a solid phase capture and release technique is presented. The method is based on the covalent modification of the guanidine group of arginine with 2,3-butanedione and phenylboronic acid under alkaline conditions. Using polymeric materials with immobilised phenylboronic acid the arginine-peptides can be captured on a solid support while arginine-free peptides are not covalently bound and can be washed away. Finally, the arginine-peptides can be cleaved again from the boronic acid beads due to the reversibility of the reaction. The recovered peptides are then analysed by liquid chromatography-tandem mass spectrometry. The method was optimised with model peptides with regard to the non-specific binding of arginine-free peptides and quantitative cleavage of the label after the selection step. Using an adequate protocol, the applicability towards more complex samples was successfully tested with a tryptic digest of a mixture of three standard proteins.


[Computed tomography as an aid in the differential diagnosis of radiolucent stones and tumors of the upper urinary tract].
The difficult differential diagnosis of urothelial tumors and nonopaque calculi of the upper urinary tract has been considerably improved by the introduction of computed tomography (CT) in urological diagnosis. Nonopaque calculi although urographically not visible can be determined by CT. Usually urothelial tumors can be traced by CT without invasive methods. In case of doubt in addition to the primary scan a so called flow-study, after application of contrast medium, will furnish additional information. The diagnostic facilities provided by CT are illustrated in 18 cases.


Auto-immune features in patients with idiopathic chronic active hepatitis who are seronegative for conventional auto-antibodies.
In patients with chronic active hepatitis (CAH), the absence of the conventional serum auto-antibodies (antinuclear, smooth muscle and liver-kidney microsomal) is often taken as evidence against an auto-immune aetiology and as indicative that the disease is unlikely to respond to immunosuppressive therapy. We report 12 British patients (11 female) who presented with histologically florid CAH (11 with cirrhosis or fibrosis and seven with ascites) but without significant titres of these antibodies or any other demonstrable aetiological feature (cryptogenic CAH), who have been followed up for a median of 5.25 years (range: 0.75-16 years). Ten had hypergammaglobulinaemia and/or specific elevations of serum IgG concentrations at presentation and five of 10 patients tested were found to have the HLA allotypes B8 and DR3. Remission was initially induced with prednisolone with or without azathioprine in all patients. Six patients subsequently relapsed on one or more occasions, either spontaneously while on maintenance therapy or during attempts to withdraw corticosteroids, and required increases or reintroduction of immunosuppressive therapy to regain disease control. Retrospective analysis of pretreatment samples from 11 of the patients revealed that all had been seropositive at presentation for auto-antibodies against the liver membrane lipoprotein preparation known as liver-specific membrane lipoprotein (LSP) and/or against the hepatic asialoglycoprotein receptor (ASGP-R), titres of which subsequently fluctuated in direct relation to response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


The role of prosody in the interpretation of structural ambiguities: a study of anticipatory eye movements.
An eye-tracking experiment examined whether prosodic cues can affect the interpretation of grammatical functions in the absence of clear morphological information. German listeners were presented with scenes depicting three potential referents while hearing temporarily ambiguous SVO and OVS sentences. While case marking on the first noun phrase (NP) was ambiguous, clear case marking on the second NP disambiguated sentences towards SVO or OVS. Listeners interpreted case-ambiguous NP1s more often as Subject, and thus expected an Object as upcoming argument, only when sentence beginnings carried an SVO-type intonation. This was revealed by more anticipatory eye movements to suitable Patients (Objects) than Agents (Subjects) in the visual scenes. No such preference was found when sentence beginnings had an OVS-type intonation. Prosodic cues were integrated rapidly enough to affect listeners' interpretation of grammatical function before disambiguating case information was available. We conclude that in addition to manipulating attachment ambiguities, prosody can influence the interpretation of constituent order ambiguities.


Morphine action on cholecystokinin octapeptide release from rat periaqueductal grey slices: sensitisation by naloxone.
Cholecystokinin (CCK) has potent antinociceptive properties when given either peripherally or centrally. An interaction between opiate and CCK-induced antinociception is indicated as CCK-induced analgesia is potentiated by naloxone. Since CCK cells in Periaqueductal grey (PAG) are known to be sensitive to both noxious stimuli and i.v. morphine, the possibility that the PAG was the site of such an interaction was investigated by an in vitro study of the effects of morphine and naloxone on CCK release in PAG. The K+-evoked release of CCK from tissue slices of PAG was unaffected by a wide range of concentrations of morphine. However, after pretreatment with naloxone (10(-9) M), morphine (10(-7)-10(-6) M) caused a significant, dose dependent attenuation of CCK release (70% inhibition at 10(-6) M). These results suggest that the release of CCK in PAG is modulated by opioid systems.


Effects of chromium-loaded chitosan nanoparticles on growth, blood metabolites, immune traits and tissue chromium in finishing pigs.
Effects of chromium-loaded chitosan nanoparticles (Cr-CNP) on growth performance, blood metabolites, immune traits, and tissue chromium in finishing pigs were investigated. A total of 160 crossbred barrows (66.06 ± 1.01 kg initial weight) were randomly divided into four groups, each group with four pens, ten pigs per pen. Pigs were fed on the same basal diet supplemented with 0 (the control), 100, 200, and 400 μg/kg Cr from Cr-CNP. All pigs were given free access to feed and water. Eight pigs from each treatment were selected to collect blood and tissue samples after 35 days on trial for analysis of blood metabolites and immune traits and tissue chromium. The results of feeding trial showed that there were no significant difference in growth performance between control and Cr-CNP-treated groups. The supplementation of Cr-CNP decreased serum glucose (P < 0.001) in a linear and quadratic manner. Serum immunoglobulins A and M were linearly increased in Cr-CNP-treated groups (P < 0.001), and serum complement 4 in Cr-CNP-treated groups was also linearly increased (P < 0.05). Cr-CNP supplementation linearly increased the chromium content in the blood, longissimus muscle, heart, liver, kidney, and pancreas (P < 0.001). These results suggested that dietary supplementation of Cr as Cr-CNP affects serum glucose, influences immune status, and increases the tissue chromium content of blood, muscle, and selected organs in finishing pigs.


I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation.
A decrease in orexin-A (OX-A) levels has been reported to be associated with depression. It is also well known that stress and depression can disrupt neurogenesis in the dentate gyrus of the hippocampus; however, it is unclear how OX-A is involved in depression and/or neurogenesis. In the present study, we investigated the effect of i.c.v. administration of OX-A on the forced swimming test (FST), an accepted behavioral screen of antidepressant-like activity, and on the cell proliferation with bromodeoxyuridine (BrdU) in the dentate gyrus at 4 days after i.c.v. administration of OX-A. OX-A administration (140 pmol/mouse) led to a significant reduction in animal immobility in the FST, without affecting spontaneous locomotor activities or serum corticosterone levels. In addition, the number of BrdU-positive cells in the dentate gyrus was significantly increased in OX-A-treated mice in vivo; however, OX-A did not affect the percentage of doublecortin-positive cells in the dentate gyrus. The proliferation of neural progenitor cells derived from rat fetal brain was not affected by OX-A treatment in vitro, and the orexin receptor 1 (OXR1) protein was not expressed in these cells. Treatment with the OXR1 antagonist SB-334867 (30 mg/kg, i.p.) blocked both the OX-A-induced decrease in the immobility of FST and increase in BrdU-positive. Moreover, the OX-A-induced increase in neuropeptide Y (NPY)-positive cells in the hilus of the dentate gyrus was blocked by SB-334867. These results suggest that OX-A induces an antidepressive-like effect, at least in part, via the enhancement of cell proliferation in the dentate gyrus. These effects of OX-A also may be partly relevant to the regulation of the NPY system in the hilus of the dentate gyrus.


No evidence of carbapenemase-producing Enterobacteriaceae in stool samples of 1,544 asylum seekers arriving in Rhineland-Palatinate, Germany, April 2016 to March, 2017.
Since 2015, increased migration from Asia and Africa to Europe has raised public health concerns about potential importation of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), specifically those producing carbapenemases (C-PE), into European hospitals. To inform infection control practices about ESBL-PE prevalence in asylum seekers and to investigate whether C-PE prevalence exceeds that in the German population. Cross-sectional study from April 2016-March 2017. Routinely collected stool samples from asylum seekers were tested for antibiotic resistant Enterobacteriaceae. Country/region of origin and demographic characteristics were explored as risk factors for faecal colonisation. Of 1,544 individuals, 294 tested positive for ESBL-PE colonisation (19.0%; 95% confidence intervals (CI): 17.0-21.0). Asylum seekers originating from Afghanistan/Pakistan/Iran had a prevalence of 29.3% (95% CI: 25.6-33.2), from Syria 20.4% (95% CI: 16.1-25.2) and from Eritrea/Somalia 11.9% (95% CI: 8.7-15.7). CTX-M-15 (79%) and CTX-M-27 (10%) were the most common ESBL determinants. Highest ESBL-PE prevalences were observed in boys under 10 years and women aged 20-39 years (interaction: p = 0.03). No individuals tested positive for C-PE. Faecal C-PE colonisation prevalence in asylum seekers was not statistically significantly different from prevalence reported in German communities. In absence of other risk factors, being a newly arrived asylum seeker from a region with increased faecal ESBL-PE colonisation prevalence is not an indicator for C-PE colonisation and thus not a reason for pre-emptive screening and isolation upon hospital admission.


Plasma alpha-tocopherol, total lipids and total cholesterol in wild rockhopper, magellanic and gentoo penguins before and after moulting.
Post moult rockhopper penguins (Eudyptes crestatus) had significantly higher plasma alpha-tocopherol (vitamin E), total lipid and total cholesterol concentrations than their pre-moult counterparts. In the magellanic penguins (Spheniscus magellanicus) there were post moult increases in total lipid, cholesterol and alpha-tocopherol concentrations, but only the increase in alpha-tocopherol was significant. Plasma alpha-tocopherol, total lipid and total cholesterol concentrations in post moult gentoo (Pygoscelis papua) chicks were similar to those in non-moulting adult gentoos. Species differences in the levels of these nutrients in plasma may be due to differences in their dietary habits.


Repeated (isolation) stress increases tribulin-like activity in the rat.
1. The effect of repeated isolation stress on MAO inhibitory activity (tribulin) in rat tissues as well as on plasma catecholamine levels was investigated. 2. Animals were subjected to a daily period of isolation (9 min) and sacrificed on days 1, 2, 4, and 5. 3. In brain and cerebellum the levels of both inhibitory activities were found to be significantly higher in animals sacrificed on days 1-2 than in either controls or animals sacrificed on days 4-5. 4. In heart and kidney the highest levels of both activities were found in animals sacrificed on days 4-5. 5. Plasma levels of dopamine on day 4 were significantly higher than those in controls or in any of the experimental groups. Plasma levels of epinephrine showed step-by-step increments from day 1 up to day 5, reaching statistical significance only on day 5. Plasma levels of norepinephrine were significantly increased on days 2, 4, and 5. 6. Under the experimental conditions of this study, we have shown a rapid and short-lasting increment of tribulin in the central nervous system. Its disappearance on days 4-5 could be related to adaptation to the novel situation. Changes in the peripheral tissues appeared later, and a similar adaptation was absent during the period of observation. 7. Tribulin would be related to the stressful situation not only as an anxiety-promoting agent but also in contributing to the maintenance of high levels of circulating catecholamines.


Splenic ellipsoids: an early target for deposition of AA amyloid induced in mink.
The spleen is the primary target for spontaneous as well as experimental AA amyloidosis in animals such as mice and mink, and is therefore a valuable organ for study of the initial phases of amyloid fibrillogenesis and deposition. We have investigated splenic amyloid AA deposits induced in the mink, and we demonstrate a novel target for AA, namely the splenic ellipsoids. We show presence of amyloid P component (AP), glycosaminoglycans (GAGs) and apolipoprotein E (apoE), all well-known common elements of amyloid, co-localizing with AA. In addition, apolipoprotein AI (apoAI) was seen co-localized to the AA deposits in the ellipsoids. We hypothesize that the ellipsoids may be important splenic structures for initial AA formation. The apoAI in the ellipsoids could displace SAA from acute phase HDL at this site, thereby making SAA available for amyloid formation and deposition.


Tuning of nanoparticle biological functionality through controlled surface chemistry and characterisation at the bioconjugated nanoparticle surface.
We have used a silica - PEG based bionanoconjugate synthetic scheme to study the subtle connection between cell receptor specific recognition and architecture of surface functionalization chemistry. Extensive physicochemical characterization of the grafted architecture is capable of capturing significant levels of detail of both the linker and grafted organization, allowing for improved reproducibility and ultimately insight into biological functionality. Our data suggest that scaffold details, propagating PEG layer architecture effects, determine not only the rate of uptake of conjugated nanoparticles into cells but also, more significantly, the specificity of pathways via which uptake occurs.


Frequent ventricular ectopic activity without underlying cardiac disease: analysis of 45 subjects.
Forty-five subjects, aged 2 weeks to 62 years, who presented with frequent (greater than 100/day) ventricular ectopic beats (VEBs) and without evidence of underlying cardiac disease were studied. The spectrum of ventricular dysrhythmia was assessed by 24-hour ambulatory electrocardiography and exercise tolerance test. Sinus rhythm was the prevailing rhythm in all subjects. VEB frequency averaged 444 +/- 454 per hour (range 0 to 1,863) over the 24-hour monitoring period and was not significantly different during waking or sleeping periods. There was no simple correlation of VEB frequency with prevailing sinus rate (r = -0.0006; p = not significant [NS]). The prevalence of complex VEBs (multiform, R-on-T and repetitive) was relatively high (18 of 45 patients), and was equally distributed about the median VEB frequency of 314 VEBs/hour (7 of 18 versus 11 of 18; NS). Of the 43 subjects who had exercise tests, 37 had VEBs during the preexercise rest phase, compared with only 11 at peak exercise (p less than 0.0001). To assess the short-term natural history of the VEBs, 27 subjects had repeat clinical examinations and 24-hour electrocardiograms at a mean interval of 8 months. All remained well. Although there was considerable individual temporal variability of VEB frequency in this subgroup, there was no significant change in group mean values (415 +/- 409 VEBs/hour initially versus 401 +/- 383 VEBs/hour at follow-up study; NS). The relative temporal constancy of VEB frequency in the group as a whole was also reflected in a high linear correlation of VEB frequency at initial and follow-up studies (r = 0.816; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming.
Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers. Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer. WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis. The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.


Effects of autologous platelet concentrate and serum on retinal wound healing in an animal model.
The beneficial effects of adjuvant treatment with agents such as autologous platelet concentrate (APC) or autologous serum (AS) in the surgical management of macular holes remain uncertain. The purpose of this study was to determine the histological changes induced by these agents compared with control on retinal wound healing in an animal model. The right eyes of 51 pigmented rabbits were used. Under anaesthesia, full-thickness sensory retinal incisions 2 mm in length were made into avascular retina down to the level of the retinal pigment epithelium using a 23-gauge needle via a superotemporal sclerotomy. APC, AS or sterilised balanced salt solution was placed directly over the wound site. Animals were killed at 3, 7 or 14 days and the wounds examined immunohistologically. Proliferating cell nuclear antigen (PCNA) was used to detect proliferating cells. No difference was observed between serum-treated eyes and control eyes. A greater displacement or migration of cells toward the retinal surface was consistently found in the APC-treated wounds than in control wounds. These cells were of mixed origin but appeared to arise predominantly from the outer nuclear layer. A significantly greater number of PCNA-staining cells was found in the platelet-treated group than in controls at 3 days (P=0.038), 7 days (P=0.039) and 14 days (P=0.038). We have demonstrated a significantly greater proliferative cellular response in the healing of retinal wounds with the use of platelet concentrate than in control wounds. We consider that this model may be used in further studies on the effects of other agents on retinal wound healing.


Functional expression of human and mouse low density lipoprotein receptors in hybridomas.
Though a mouse.human-human heterohybridoma, N12-16.63, secreting an antitetanus toxoid human monoclonal antibody grew well in a serum-free medium, its high producing subclone N12-69 required SSGF-I, a low density lipoprotein (LDL) from swine serum, or human-LDL (h-LDL) for growth. The growth-promoting action of SSGF-I was caused by its lipid fraction, and SSGF-I could be replaced completely with cholesterol in the presence of bovine serum albumin (BSA). Thus, cell line N12-69 is a cholesterol auxotroph of the heterohybridoma. N12-69 cells express both mouse and human LDL receptors on the cell surface in a ratio of 1:4. SSGF-I bound to both receptors with the same binding affinity, and h-LDL was also take up by the same receptors, though the affinity constant of the receptors for SSGF-I was 1.5 times stronger than that for h-LDL. The growth of N12-69 cells was completely inhibited by the addition of dextran sulfate, which is known to inhibit the binding of LDL to LDL receptors, to an SSGF-I or h-LDL containing medium but was not inhibited at all when dextran sulfate was added to a serum-free medium supplemented with cholesterol and BSA. Furthermore, an anti-human LDL receptor monoclonal antibody partially inhibited the growth of N12-69 cells in an SSGF-I or h-LDL containing medium. These findings suggest that N12-69 cells express both biologically active mouse and human LDL receptors on their cell surfaces and that SSGF-I or h-LDL is taken up by the both receptors to be utilized as a cholesterol source for the growth.


Radiosensitizer-DNA interactions in relation to intracellular uptake.
We have studied the intracellular uptake of a number of neutral, acidic, and basic radiosensitizers. For neutral sensitizers, we observed a correlation between the measured intracellular concentration and sensitization, but for bases, a large change in average intracellular concentration results in only a small change in sensitization. In addition, by modifying the intralysosomal pH, we have altered the measured average intracellular concentration of the weak base pimonidazole by a factor of two, although this had no detectable effect upon sensitization. Using spin filtration of solutions of sensitizers with naked calf thymus DNA or chromatin we have assessed the affinity of DNA for sensitizers with different prototropic and lipophilic properties. We have also shown that this anomalous behavior of the basic sensitizers could be partly explained on the basis of intracellular localization adjacent to the DNA due to ionic interactions. Thus, intracellular localization needs to be considered when interpreting average intracellular uptake data.


A comparison of temperature measurements using three ear thermometers.
Following anecdotal and research-based reports of inaccuracies encountered with the use of ear thermometers in patient care settings, this two-phase study was designed to compare the accuracy of three ear thermometers when used in a multioperator environment. The within-subject variation (limits of agreement) in ear temperature measurements obtained with the three ear thermometers in a multioperator condition by using an oral temperature reference standard ranged from +/- 1.25 degrees F to 1.85 degrees F. In multioperator, multisubject patient care environments using a pulmonary artery catheter core temperature as the reference standard, the limits of agreement for ear temperature measurements obtained with the three different ear thermometers ranged from +/- 2.19 degrees F to 2.85 degrees F. These results suggest that there is substantial variation in ear measurements and raise questions about the use of ear thermometers when there are multiple personnel taking temperatures, as occurs in hospital-based clinical practice environments. Handedness of the operator, position of the patient, and the ear used for measurement did not produce clinically significant variability in ear temperature measurements.


Efficacy and safety of chemoradiation therapy using one-shot cisplatin via hepatic arterial infusion for advanced hepatocellular carcinoma with major macrovascular invasion: a single-arm retrospective cohort study.
Patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) who receive systemic chemotherapy have a poor prognosis. This study aimed to determine if one-shot cisplatin (CDDP) chemotherapy via hepatic arterial infusion (HAI) combined with radiation therapy (RT) prior to systemic chemotherapy could improve the outcomes of these patients. This study consisted of 32 HCC patients with the following eligibility criteria: (i) portal vein invasion 3/4 and/or hepatic vein invasion 2/3; (ii) received one-shot CDDP via HAI; (iii) received RT for MVI, (iv) a Child-Pugh score ≤ 7; and (v) an Eastern Clinical Oncology Group Performance Status score of 0 or 1. To determine the therapeutic effect, we collected information on patient characteristics and took contrast-enhanced computed tomography at the start of the therapy and every 2 to 4 months after the start of therapy. We evaluated the overall response of the tumor and tumor thrombosis according to modified Response Evaluation Criteria in Solid Tumors. We assessed patient data using the Mann-Whitney U and Fisher exact tests and evaluated overall survival and progression-free survival using the log-rank test. The overall response rate at the first evaluation performed a median of 1.4 weeks after HAI was 16% for the main intrahepatic tumor and 59% for the MVI. The best responses were the same as those of the first-time responses. The duration of median survival was 8.6 months, and progression-free survival of the main intrahepatic tumor was 3.2 months. Predictive factors for overall survival were the relative tumor volume in the liver and the first therapeutic response of MVI. There were no severe adverse events or radiation-induced hepatic complications. One-shot CDDP via HAI and RT were well tolerated and showed immediate and favorable control of MVI. Thus, this combination shows potential as a bridging therapy to systemic chemotherapy.


Application of RNA-Seq Technology in Cancer Chemoprevention.
RNA-sequencing is a revolutionary tool to follow differential expression after treatment with cancer chemopreventive agents. It allows a real genome-wide screening independent of prior assumptions and is well suited for analyzing coding but also long noncoding RNAs. It still consents the discovery of new genes and isoforms and increased our knowledge of antisense and other noncoding RNAs in a tremendous manner. Moreover, it permits to detect low-abundance and biologically critical isoforms and reveals genetic variants and gene fusions in one single assay. Here, we provide a detailed protocol for stranded RNA-sequencing.


[Cervical myelography after lumbar application of metrizamide (author's transl)].
Cervical myelography by means of lumbar application of metrizamide was performed on 110 patients. The exploration technique, the results, the quality of the myelograms, and the side effects observed are discussed. The most frequent complaint was headache. There were also cases of vertigo, vomitus, pain in the back and legs, and one case of tachycardia. Complications of a more serious nature, in particular epileptic seizures, did not occur.


Calculated CT volumes of lacrimal glands in normal Caucasian orbits.
The objective was to describe the range of normal volumes for the lacrimal gland calculated from CT. A retrospective review with institutional review board approval of 293 CT scans of 586 orbits was performed. Patients were included if they were Caucasian and aged 18 years or older. Orbits were excluded if there was a disease or trauma. OsiriX software was used to outline the lacrimal gland in consecutive axial slices and to calculate the volume. Inter-rater agreement was assessed in a subset of 30 randomly selected orbits by observers of different levels of training using the intraclass correlation coefficient (ICC). Two hundred sixty orbits of 187 patients were included. The mean volume of the lacrimal gland was 0.696 cm2 in right orbits (SD = 0.261) and 0.649 cm2 in left orbits (SD = 0.231), with no significant difference between right and left (p= 0.125). The mean volume was 0.680 cm2 in men (SD = 0.241) and 0.662 cm2 in women (SD = 0.260), with no significant difference between men and women (p = 0.564). There was an inverse relationship between gland volume and age (Pearson r= -0.428 right orbits and -0.469 left orbits). Of the 73 bilateral patients, right and left orbits correlated well (Pearson r = 0.712). Agreement was good among the observers (ICC = 0.727). This is the first study to report the range of normal volume for Caucasian lacrimal glands measured on CT scans. The volume of the lacrimal gland decreases with age, and there is no gender or laterality difference.


Adenocarcinoma at the site of ureterosigmoidostomies for exstrophy of the bladder.
Adenocarcinoma of the colon is a rare complications of ureterosigmoidostomy done for exstrophy of the bladder. Only 13 cases have been previously reported, occurring from 10 to 46 yr after the procedure. In a series of 150 patients who have had ureterosigmoidostomies carried out at the Children's Hospital Medical Center, Boston, over the past 40 yr, 4 patients have been treated at our institution for this complication. The tumor was noted 20 to 32 yr after the initial procedure. Two patients are alive and well 1 and 4 yr after resection. The increasing incidence of this complication with advancing age will require careful observation and will undoubtedly influence the indications for the procedure. An additional question of great importance is how to evaluate and follow the thousands of patients who have had this procedure done at one time in their lives. It is suggested that an annual intravenous pyelogram is indicated in those patients with functioning ureterostomies and that a colonoscopy to the level of the anastomoses be carried out at 6-mo intervals in all patients. In those patients in whom the ureterosigmoidostomies have been taken down, a sleeve resection of that area of the colon should be strongly considered.


Endocytic transport of integrins during cell migration and invasion.
Early studies describing the endocytic-exocytic cycling of integrins prompted proposals that this process regulates cell migration. However, it is only relatively recently that more detailed descriptions of the molecular machinery responsible for directing integrin trafficking have enabled us to properly address the role of these events during the various modes of cell migration. Here, we review recent advances in our understanding of the protein complexes and signallosomes controlling integrin trafficking, and we describe how these influence cell migration and signalling events downstream of integrin engagement. Furthermore, we consider recent evidence for integrin trafficking during the invasive migration of cancer cells through 3D microenvironments, and conclude with a discussion of the use of novel photoactivatable integrin probes to visualize these processes.


Hospital Outcomes Among Infants With Interrupted Aortic Arch With Simple and Complex Associated Heart Defects.
There is a lack of current, multi-institutional data regarding hospital outcomes of infants with interrupted aortic arch (IAA). We analyzed the Pediatric Health Information System database to identify infants with IAA who underwent repair during 2004 to 2019. We classified patients as simple or complex based on associated heart defects. We evaluated factors associated with hospital mortality and complications related to 22q11.2 deletion syndrome (22q11.2del) using mixed logistic regression, accounting for hospital clustering. In 1,283 infants included (904 simple, 379 complex), mortality was higher in the complex group (11.7% vs 4.4%, p <0.001). Factors associated with mortality in the simple group were low birth weight (adjusted risk ratio [aRR] 3.77, 95% confidence interval [95% CI] 1.83 to 7.77), non-22q11.2del genetic conditions (aRR 6.44, 95% CI 1.73 to 23.96), and gastrointestinal anomalies (aRR 8.47, 95% CI 3.12 to 22.95), whereas surgery between 2012 and 2015 (aRR 0.36, 95% CI 0.13 to 0.99) was protective. In the complex group, factors associated with mortality were male (aRR 2.32, 95% CI 1.10 to 4.24) and central nervous system anomalies (aRR 3.73, 95% CI 1.62 to 8.59). Compared with their nonsyndromic counterparts, infants with simple IAA and 22q11.2del were at higher risk of sepsis (aRR 1.63, 95% CI 1.02 to 2.39) and gastrostomy tube placement (aRR 3.18, 95% CI 2.13 to 4.74), and infants with complex IAA and 22q11.2del were at higher risk of gastrostomy tube placement (aRR 2.42, 95% CI 1.20 to 4.88). In conclusion, presence of complex cardiac lesions is associated with increased mortality after IAA repair. The co-occurrence of extracardiac congenital anomalies and non-22q11.2del genetic conditions elevates mortality risk. Presence of 22q11.2del is associated with hospital complications.


Drug shortages in the United States: a critical evaluation of root causes and the need for action.
Every day it is easy to find news articles detailing the impact of drug shortages on patients. Where this was once only a concern of patients with rare, orphan diseases, it is now the concern of patients receiving even the most common chemotherapeutic regimens, the most efficacious antimicrobial therapy, or even the most rapid-acting analgesics, largely as a result of manufacturing quality problems. Unfortunately for many of these patients, there are no efficacious alternatives.


Disentangling the Association Between Child Abuse and Eating Disorders: A Systematic Review and Meta-Analysis.
The aim of this systematic review and meta-analysis was to estimate the association between distinct types of child abuse--sexual (CSA), physical (CPA), and emotional (CEA)--and different eating disorders (EDs). Electronic databases were searched through January 2014. Studies reporting rates of CSA, CPA, and CEA in people with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED), as compared with individuals without EDs, were included. Pooled analyses were based on odds ratios (ORs), with relevant 95% confidence intervals (CIs), weighting each study with inverse variance models with random effects. Risk of publication bias was estimated. Thirty-two of 1714 studies assessed for eligibility met the inclusion criteria, involving more than 14,000 individuals. The association between EDs and any child abuse showed a random-effects pooled OR of 3.21 (95% CI = 2.29-4.51, p < .001) with moderate heterogeneity (I2 = 57.2%, p = .005), whereas for CSA, this was 1.92 (95% CI = 1.13-3.28, p = .017), 2.73 (95% CI = 1.96-3.79, p < .001), and 2.31 (95% CI = 1.66-3.20, p < .001), for AN, BN, and BED, respectively. However, adjusting for publication bias, the estimate for CSA and AN was not significant (OR = 1.06, 95% CI = 0.59-1.88, p = .85). Although CPA was associated with AN, BN, and BED, CEA was associated just with BN and BED. BN and BED are associated with childhood abuse, whereas AN shows mixed results. Individuals with similar trauma should be monitored for early recognition of EDs. The protocol was registered in PROSPERO (an international prospective register of systematic reviews) with the reference number CRD42014007360.


Deletion of Stk40 impairs definitive erythropoiesis in the mouse fetal liver.
The serine threonine kinase Stk40 has been shown to involve in mouse embryonic stem cell differentiation, pulmonary maturation and adipocyte differentiation. Here we report that targeted deletion of Stk40 leads to fetal liver hypoplasia and anemia in the mouse embryo. The reduction of erythrocytes in the fetal liver is accompanied by increased apoptosis and compromised erythroid maturation. Stk40-/- fetal liver cells have significantly reduced colony-forming units (CFUs) capable of erythroid differentiation, including burst forming unit-erythroid, CFU-erythroid (CFU-E), and CFU-granulocyte, erythrocyte, megakaryocyte and macrophage, but not CFU-granulocyte/macrophages. Purified Stk40-/- megakaryocyte-erythrocyte progenitors produce substantially fewer CFU-E colonies compared to control cells. Moreover, Stk40-/- fetal liver erythroblasts fail to form normal erythroblastic islands in association with wild type or Stk40-/- macrophages, indicating an intrinsic defect of Stk40-/- erythroblasts. Furthermore, the hematopoietic stem and progenitor cell pool is reduced in Stk40-/- fetal livers but still retains the multi-lineage reconstitution capacity. Finally, comparison of microarray data between wild type and Stk40-/- E14.5 fetal liver cells reveals a potential role of aberrantly activated TNF-α signaling in Stk40 depletion induced dyserythropoiesis with a concomitant increase in cleaved caspase-3 and decrease in Gata1 proteins. Altogether, the identification of Stk40 as a regulator for fetal erythroid maturation and survival provides new clues to the molecular regulation of erythropoiesis and related diseases.


Local cerebral glucose metabolism in rats with chronic portacaval shunts.
Local cerebral glucose utilization was measured with the autoradiographic [14C]deoxyglucose method in rats at 2 days and 1, 4, 8, and 12 weeks after the construction of a portacaval shunt, and in weight-matched controls. Local glucose utilization in brain was altered in shunted animals, but the magnitude and direction of the changes differed among 36 neuroanatomical structures, depending upon the length of time that the animals had been shunted. In rats shunted for 4 weeks or less, glucose utilization did not differ from control (30 of 36 structures) or was decreased (6 structures). The largest decreases of glucose utilization, noted at 1 week, occurred in the parietal (-25%) and frontal cortices (-28%) and subcortical white matter (-50%. In rats shunted for 8 weeks, however, glucose utilization was higher than control in many brain structures (13 of 36), and after 12 weeks it was higher than control in most structures (25 of 36). Only the parietal cortex did not follow this trend; it exhibited a decreased rate of glucose utilization in rats shunted for 8 weeks (-21%) that normalized in animals shunted for 12 weeks. Portal-systemic shunting of blood increased arterial blood ammonia concentrations to twice the control value of 85 +/- 3 microM in animals shunted for 1 week, and to approximately 2.5 times control in animals shunted for 4-12 weeks. Kety-Schmidt measurements of cerebral blood flow and arterial-venous (torcular) differences for ammonia across the brains of control rats and rats with portacaval shunts for 8 weeks revealed an increased cerebral uptake of ammonia in the shunted animals. The late-developing morphological changes known to occur in astrocytes and the delayed increases in local glucose consumption in rats with portacaval shunts may be related, and represent an adaptive response to sustained hyperammonemia.


Cathepsin B S-nitrosylation promotes ADAR1-mediated editing of its own mRNA transcript via an ADD1/MATR3 regulatory axis.
Genetic information is generally transferred from RNA to protein according to the classic "Central Dogma". Here, we made a striking discovery that post-translational modification of a protein specifically regulates the editing of its own mRNA. We show that S-nitrosylation of cathepsin B (CTSB) exclusively alters the adenosine-to-inosine (A-to-I) editing of its own mRNA. Mechanistically, CTSB S-nitrosylation promotes the dephosphorylation and nuclear translocation of ADD1, leading to the recruitment of MATR3 and ADAR1 to CTSB mRNA. ADAR1-mediated A-to-I RNA editing enables the binding of HuR to CTSB mRNA, resulting in increased CTSB mRNA stability and subsequently higher steady-state levels of CTSB protein. Together, we uncovered a unique feedforward mechanism of protein expression regulation mediated by the ADD1/MATR3/ADAR1 regulatory axis. Our study demonstrates a novel reverse flow of information from the post-translational modification of a protein back to the post-transcriptional regulation of its own mRNA precursor. We coined this process as "Protein-directed EDiting of its Own mRNA by ADAR1 (PEDORA)" and suggest that this constitutes an additional layer of protein expression control. "PEDORA" could represent a currently hidden mechanism in eukaryotic gene expression regulation.


Neuroblastic Tumors of the Adrenal Gland in Elderly Patients: A Case Report and Review of the Literature.
Neuroblastic neoplasms (NN) include ganglioneuromas (GN), ganglioneuroblastomas (GNB), and neuroblastomas (NB). They generally arise in childhood from primitive sympathetic ganglion cells. Their incidence in adults, especially among elderly, is extremely low. This is the case of a 74-year-old woman with history of abdominal pain, weakness and night sweating since several months. Blood pressure was normal. CT-scan showed a 10 cm left adrenal mass, without other pathologic findings. An open left-sided adrenalectomy was performed. Recovery was uneventful with hospital length of stay of 8 days. Based on morphological, immunohistochemical, and molecular features the diagnosis was a nodular GNB. A positron emission tomography (PET) performed 6 weeks after the resection did not show any residual tumor or distant metastases. The patient was followed-up with annual clinical and radiological exams. This case presentation, associated with a review of the literature, illustrates the importance to include NN in the preoperative differential diagnosis of adrenal tumors in adults and highlights the need for multidisciplinary patient work-up and management.


Psychophysiological correlates of interpersonal cooperation and aggression.
Mimicking real world situations, the Chicken Game allows scientists to examine human decision-making when the outcome is not entirely within one person's control. In this social dilemma task, two players independently choose either to safely cooperate with, or riskily aggress against, the other player, and the unique combination of their choices specifies the outcome for each. Coupling the Chicken Game with psychophysiological measures, we confirmed our two hypotheses: that an individual perceives an outcome as most negative when she chooses to cooperate and the other player violates that trust and aggresses, and that motivational salience of an outcome is greater when an individual chooses to aggress and when she gains money. Collectively, the data demonstrate the utility of pairing true social dilemma tasks like the Chicken Game with psychophysiological measures to better understand decision-making.


Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation.
Patients with hematologic malignancies undergoing allogeneic stem cell transplantation (HSCT) commonly have an elevated serum ferritin prior to HSCT, which has been associated with increased mortality after transplantation. This has led to the suggestion that iron overload is common and deleterious in this patient population. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. We report a prospective study of 48 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) undergoing myeloablative HSCT, using magnetic resonance imaging (MRI) to estimate liver iron content (LIC) and cardiac iron. The median (and range) pre-HSCT value of serum ferritin was 1549 ng/mL (20-6989); serum hepcidin, 59 ng/mL (10-468); labile plasma iron, 0 LPI units (0.0-0.9). Eighty-five percent of patients had hepatic iron overload (HIO), and 42% had significant HIO (LIC ≥5.0 mg/gdw). Only 1 patient had cardiac iron overload. There was a strong correlation between pre-HSCT serum ferritin and estimated LIC (r = .75), which was mostly dependent on prior transfusion history. Serum hepcidin was appropriately elevated in patients with HIO. Labile plasma iron elevation was rare. A regression calibration analysis supported the hypothesis that elevated pre-HSCT LIC is significantly associated with inferior post-HSCT survival. These results contribute to our understanding of the prevalence, mechanism, and consequences of iron overload in HSCT.


Effective inhibition of Japanese encephalitis virus replication by shRNAs targeting various viral genes in vitro and in vivo.
Japanese encephalitis virus (JEV) is a serious mosquito-borne flavivirus that causes acute encephalitis in humans and many animals, with a high fatality rate. RNA interference (RNAi) is an evolutionarily conserved mechanism for the specific suppression of gene expression, which can be used as a reasonable antiviral strategy. In this study, 10 shRNAs targeting different regions of the JEV genome were designed, and their inhibition of viral replication in vitro and in vivo was determined. Treatment with these shRNAs significantly inhibited JEV replication in BHK-21 and SK-N-SH cells. An immunohistochemical analysis of suckling mice showed that brain sections pretreated with pGP-JE-1, pGP-JE-2 or pGP-JE-3 lacked viral particles. The survival of BALB/c mice challenged with 20 LD50 of the JEV NJ2008 strain at 24h post-injection or simultaneously with pGP-JE-2 was 83.3% and 66.7%, respectively. The results demonstrated that the efficiency of gene silencing and virus inhibition varied between shRNAs to different target genes and sites. Meanwhile, the shRNA-mediated antiviral effect was dose- and time-dependent, including prophylactic and therapeutic effect on virus infection both in vitro and in vivo. The whole results indicate that these shRNAs can inhibit JEV infection sufficiently in vitro and in vivo and might be a potential new tool for controlling JEV infection.


Imaging evaluation of patients with soft tissue sarcoma.
Imaging provides the clinician with crucial information in the diagnosis, staging, treatment planning, treatment evaluation, and post-treatment assessment of patients with soft tissue sarcoma. MRI, including contrast-enhanced sequences, usually is preferred for evaluating the primary site in extremity sarcomas and lesions of the head and neck. CT generally is preferred for imaging of the chest, abdomen, and pelvis, either in the evaluation of the primary site in those regions or for identifying metastatic disease. The experienced radiologist often can suggest a specific diagnosis or narrow differential diagnosis from the imaging characteristics, particularly with MRI. It is imperative that imaging be performed in a manner specific for the evaluation of soft tissue masses, and before biopsy or surgery, to provide the most accurate preoperative assessment and treatment planning [56, 57].


Combined dynamics of EEG and evoked potentials. I. Studies of simultaneously recorded EEG-EPograms in the auditory pathway, reticular formation, and hippocampus of the cat brain during the waking stage.
This study is carried out on single (not averaged) recordings combining the spontaneous activity preceding the stimulus onset and the EP recorded upon acoustical stimulation. These recordings, which we call EEG-EPograms, are measured simultaneously from different subdural brain structures, such as the auditory cortex, medial geniculate nucleus, inferior colliculus, reticular formation and the hippocampus of awake cats. Using a combined analysis procedure (C.A.P.), the relevant frequency components of spontaneous EEG and EPs, recorded simultaneously from these brain nuclei, are analyzed according to the consistent selectivity bands depicted by the determined amplitude-frequency characteristics. These analyses provide us the following information: (1) there is an important congruency in the time courses of simultaneous response components in common frequency bands, especially in the alpha and beta frequency ranges; (2) there exist significant coupling and synchrony between the evoked amplitude enhancements in the simultaneously recorded single response components; (3) the inter-nuclei coherency in the brain's electrical activity is enormously increased upon stimulation; (4) the evoked response magnitude can be predicted, with reasonable accuracy, from the spontaneous activity preceding the stimulation. The strong dependence of the response magnitude on the stimulus-preceding EEG is explained by means of a model network consisting of a population of relaxation oscillators, which can be brought to different states of synchrony and asynchrony. Some suggestions and comments are also made for investigators working toward theories of signal transmission in the brain.


Differential expression of peroxisome proliferator-activated receptor γ, fatty acid synthase, and hormone-sensitive lipase in fat-tailed and thin-tailed sheep breeds.
Tail fat content affects meat quality, and it varies in different sheep breeds. Theoretically, lipid metabolism contributes to variation in tail fat content. Tail length, tail width, and tail girth were measured in live Tong sheep (with both short fat tail and long fat tail), Shaanbei fine wool sheep (long thin tail), Tan sheep (short fat tail), Kazakh sheep (hip fat tail), and Tibetan sheep (short thin tail). The expression levels of genes related to tail adipose tissue lipid metabolism were investigated, which included lipogenetic genes (PPARγ and FAS) and lipolytic gene (HSL). Differences were observed (P < 0.05) in PPARγ mRNA expression levels in the different breeds; FAS mRNA expression levels did not differ (P > 0.05) in Tong sheep with short fat tail, Tong sheep with long fat tail, Shaanbei fine wool sheep, and Tibetan sheep; HSL mRNA expression levels were not different (P > 0.05) in Tong sheep. PPARγ and HSL protein expression levels differed (P < 0.05) between the different breeds; FAS protein expression levels were different (P < 0.05) in Tong sheep with long fat tails, Tan sheep, Kazakh sheep, and Tibetan sheep, but did not differ (P > 0.05) in Tong sheep with short fat tails and Shaanbei fine wool sheep. These results provide useful information to further understand the function of PPARγ, FAS, and HSL in sheep tail lipid metabolism, which should be applicable to studies on the regulation of fat deposition and improvement of meat quality.